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WO2015065336A1 - Respiratory syncytial virus inhibitors - Google Patents

Respiratory syncytial virus inhibitors Download PDF

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Publication number
WO2015065336A1
WO2015065336A1 PCT/US2013/067264 US2013067264W WO2015065336A1 WO 2015065336 A1 WO2015065336 A1 WO 2015065336A1 US 2013067264 W US2013067264 W US 2013067264W WO 2015065336 A1 WO2015065336 A1 WO 2015065336A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
mmol
mixture
etoac
solution
Prior art date
Application number
PCT/US2013/067264
Other languages
French (fr)
Inventor
Christian Brochu
Anne Decor
Elise Ghiro
Marc Pesant
Cyrille Kuhn
Original Assignee
Medivir Ab
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Publication date
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Priority to PCT/US2013/067264 priority Critical patent/WO2015065336A1/en
Publication of WO2015065336A1 publication Critical patent/WO2015065336A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/14—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
    • 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
    • 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

Definitions

  • the present invention relates to quinazolinone analogs and their use as inhibitors of replication of the respiratory syncytial virus (RSV), pharmaceutical compositions containing such analogs, and methods of using these analogs in the treatment and prevention of RSV infection.
  • RSV respiratory syncytial virus
  • the annual death rate from RSV is estimated at more than 160,000 and the clinical burden of RSV infection is comparable to that of influenza (Bourgeois et al., 2009; Boyce et al., 2000; Hall et al., 2009; Stockman et al., 2012).
  • the epidemic season for RSV runs from late fall through early spring.
  • the primary populations at risk for poor outcome are children below 5 years of age, immunocompromised patients and older adults, particularly those who are institutionalized or have chronic underlying disease (Hall et al., 2009; Falsey et al., 2005).
  • Inhaled ribavirin is approved for the treatment of laboratory-diagnosed RSV infection but is administered only to some bone marrow transplant and immunocompromised patients, because of its limited effectiveness, complexity of administration and mutagenicity potential for patients and staff. Because of the absence of effective therapy for RSV infections and the significance of RSV morbidity and/or morality in at-risk populations, the introduction of an effective RSV agent will be considered a major breakthrough in the care of these patients.
  • the present invention provides a novel series of compounds that exhibit inhibitory activity on the replication of the RSV.
  • One aspect of the invention provides a compound, represented by Formula (I), or racemate, enantiomer, diastereoisomer or tautomer thereof:
  • R 1B is (Ci- 6 )alkyl, (C 3 - 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl;
  • R 2 is (Ci- 6 )alkyl, -(Ci- 6 )alkyl-(C 3 - 7 )cycloalkyl, -(Ci- 6 )alkyl-aryl, -(Ci- 6 )alkyl-heteroaryl or -(d- 6 )alkyl- heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl, either alone or in combination with another moiety, are optionally mono-, di- or tri-substituted with
  • R 2A is (Ci- 6 )alkyl, (C 3 - 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl;
  • R is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (Ci_ 6 )alkyl; n is 0, 1 , 2 or 3;
  • Another aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a medicament.
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
  • the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of an RSV infection in a human being having or at risk of having the infection.
  • Another aspect of the invention involves a method of treating or preventing RSV infection in a human being by administering to the human being an anti-RSV virally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
  • An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat RSV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by RSV; wherein the composition comprises a compound of Formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
  • Still another aspect of this invention relates to a method of inhibiting the replication of RSV comprising exposing the virus to an effective amount of the compound of Formula (I), or a salt thereof, under conditions where replication of RSV is inhibited.
  • Ci_ 6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the first named subgroup is the radical attachment point, for example, the substituent "-C ⁇ s-alkyl-aryl” means an aryl group which is bound to a C! -3-alkyl-group, with the C! -3-alkyl group bound to the core.
  • the substituent may be attached to either subgroup.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • enantiomers of the compounds of the present invention Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or
  • enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • These resolution methods generally rely on chiral recognition and include but not limited to chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by
  • halo generally denotes fluorine, chlorine, bromine and iodine.
  • Ci- n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • Ci- 3 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 - and H 3 C-CH(CH 3 )-.
  • Carbocyclyl or “carbocycle” as used herein, either alone or in combination with another radical, means a mono-, bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms.
  • the term “carbocyclyl” or “carbocycle” refers to fully saturated and aromatic ring systems and partially saturated ring systems.
  • the term “carbocyclyl” or “carbocycle” encompasses fused, bridged and spirocyclic systems.
  • C 3 . n -cycloalkyl wherein n is an integer 4 to n, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3 - 7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to at least one other 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
  • heterocyclyl or “heterocycle” is intended to include all the possible isomeric forms and all fused, bridged and spiro forms.
  • the “heterocyclyl” may be optionally substituted with substituents, such as, for example, with an oxo moiety.
  • substituents such as, for example, with an oxo moiety.
  • the term “heterocyclyl” or “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • a "heterocyclyl” substituted with an oxo moiety includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • heteroaryl is intended to include all the possible isomeric forms and all fused, bridged and spiro forms.
  • the “heteroaryl” may be optionally substituted with substituents, such as, for example, with an oxo moiety.
  • substituents such as, for example, with an oxo moiety.
  • heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • a "heteroaryl” substituted with an oxo moiety includes the following exemplary structures (each of which may in turn be optionally substituted) which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates,
  • phosphates/diphosphates polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines.
  • Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
  • treatment means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of RSV disease and/or to reduce viral load in a patient.
  • prevention means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus, to prevent the appearance of symptoms of the disease.
  • terapéuticaally effective amount means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • R 1B is (d- 6 )alkyl, (C 3 . 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl.
  • R 1 -B R 1 is a 9-14 membered heterocycle or heteroaryl optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R 1A , oxo, halo, -CN, (d_ 6 )haloalkyl, OH and -0(C 1-6 )alkyl;
  • R 1 -C R is , optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R 1A , halo, -CN, (d.
  • R 2A is (Ci- 6 )alkyl, (C 3 - 7 )cycloalkyl, aryl, heteroaryl or heterocyclyl.
  • R 3 -A:R 3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH,
  • R is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (d- 6 )alkyl.
  • R 3 -B:R 3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH, -(Ci- 6 )alkyl, -0-(Ci- 6 )alkyl, (C 3 - 7 )cycloalkyl, (Ci- 6 )haloalkyl, -NH 2 , -NH(Ci- 6 )alkyl and
  • R 3 -C:R 3 is each independently selected from the group consisting of H, halo, -CN, OH, (C 1-6 )alkyl, -0-(C 1 _ 6 )alkyl, (C 3 - 7 )cycloalkyl and (C 1 _ 6 )haloalkyl.
  • Examples of most preferred compounds according to this invention are each single compound of the invention, namely, compounds 1001 , 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009,
  • Suitable preparations for administering the compounds of the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders, etc.
  • the content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds of the invention with known excipients, for example inert diluents, carriers, binders, disintegrants, adjuvants, surfactants and/or lubricants.
  • excipients for example inert diluents, carriers, binders, disintegrants, adjuvants, surfactants and/or lubricants.
  • the tablets may also consist of several layers.
  • Suitable inhalatives may be obtained, for example, by administering one or more compounds of the invention in the form of a solution, dry powder or suspension.
  • the compounds of the invention may be administered via inhalation of a solution in nebulized or aerosolized doses.
  • the dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight.
  • Each dosage unit may conveniently contain from 5% to 95% active compound (w/w).
  • active compound w/w
  • preparations contain from 20% to 80% active compound.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. Therefore, according to one embodiment, the pharmaceutical composition of this invention additionally comprises one or more antiviral agents.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the production and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the production and/or replication of a virus in a human being.
  • Such agents can be selected from: RSV Fusion inhibitors, such as MDT-637 (MicroDose), BTA-9881 (Biota); RSV Polymerase inhibitors, such as ALS-81 12 (Alios), ALS-8176 (Alios) and Virazole (ribavirin); others, such as GS-5806 (Gilead Sciences) and RSV-604 (Novartis); antibodies, such as Synagis® (palimizumab), RespiGam® (RSV-IG), MEDI-557 (Medlmmune/AstraZeneca), ALX- 0171 (Ablynx), motavizumab (Medlmmune/AstraZeneca); other biological, such as ALN-RSV-01 (Alnylam) and Vaccines, such as MEDI-559 (Medlmmune/AstraZeneca), RSV F (Novavax), MEDI-534(Medlmmune/AstraZeneca).
  • Compounds and intermediates can be purified by a Teledyne ISCO Combiflash R, System at 254 nm using commercial normal phase silica 4-120 g Redisep R f or Silicycle columns at a flow rate of 18-85 ml. /min depending on column size.
  • Mass spectral analyses may be recorded using flow injection analysis mass spectrometry or Waters Acquity Ultraperformance LC System consisting of a sample organizer, PDA detector, column manager, sample manager, binary solvent manager and SQ detector.
  • Reactions performed in microwave conditions are conducted in a Biotage Initiator 2.0 microwave synthesizer equipped with a Robot Sixty for vial manipulations.
  • the temperature range is from 40-250 °C.
  • the pressure range is from 0-20 bar and the power range is from 0- 400 Watts at 2.45 GHz.
  • the vial size varies from 0.5 ml. to 20 ml_.
  • the solvent absorption level is high by default. Specific reaction times and temperatures are given in the experimental section when applicable.
  • Preparative HPLC is performed using a Waters instrument, using one of the conditions outlined below:
  • Eluent B ACN + 0.06% or 0.1 % TFA
  • ACN acetonitrile
  • AcOH acetic acid
  • AmFor Ammonium Formate aqueous solution
  • BEH ethylene bridged hybrid
  • Boc fertbutyloxycarbonyl
  • CDI 1 ,1 '-carbonyldiimidazole
  • DCM DCM
  • Step 1
  • Step 1 A solution of oxetan-3-amine (2.0 g, 27.4 mmol, Aldrich), 4-methoxy-3-nitropyridine (8.43 g, 54.7 mmol, Combi-Blocks) and diisopropylethylamine (7.14 ml_, 41 .0 mmol) in EtOH (50 ml.) is heated in a sealed tube for 16 hours. The mixture is cooled to RT and concentrated under reduced pressure to half of the volume, and then cooled to 0°C. The residue is filtered and triturated with Hex to afford 2a.
  • 3-Nitro-N-(oxetan-3-yl)pyridin-4-amine 2a (2.60 g, 13.3 mmol) is hydrogenated in anhydrous MeOH (50 ml.) in the presence of 5% palladium on carbon (0.80 g, Aldrich) at 40 psi for 2.5 hours at RT. The mixture is filtered through celite and the filter is washed with MeOH. The combined filtrate is concentrated under reduced pressure to afford 2b.
  • Solid 1 ,1 '-carbonyldiimidazole (1 .47 g, 9.07 mmol, Aldrich) is added to a solution of N-4-(oxetan- 3-yl)pyridine-3,4-diamine 2b (1 .0 g, 6.05 mmol) in anhydrous ACN (20 ml.) and anhydrous THF (10 ml.) at RT under N 2 .
  • the mixture is refluxed for 1 .5 hours.
  • the solvents are evaporated under reduced pressure.
  • the residue is dissolved in DCM (30 ml.) and washed with water (20 ml_).
  • the aqueous phase is extracted with DCM, and the combined organic extracts are dried over sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on a Biotage system (5:95 MeOH/EtOAc to 30:70 MeOH/EtOAc) to afford 2c.
  • Step 1
  • Step 1
  • Step 2 A solution of 9a (50.0 g, 254.9 mmol) and 10% Pd/C (5.0 g, 4.7 mmol) in EtOH (1 .3 L) is stirred for 16 hours under a hydrogen atmosphere (50 psi). The reaction mixture is filtered through celite, concentrated and purified by flash chromatography to afford 9b.
  • Step 1
  • Step 3 A high pressure vessel is filled with a solution of 11 b (0.50 g, 2.42 mmol), in AcOH (5 mL). To this solution is added chloroacetyl chloride (0.58ml_, 7.29 mmol). The reaction is then heated for 3 hours at 1 l O 'C. The mixture is cooled to RT and co-evaporated three times with benzene. The obtained residue is then diluted with an aqueous saturated solution of NaHC0 3 and extracted twice with EtOAc. The combined organic extracts are dried over MgS0 4 , concentrated and purified by Combiflash (20:80 Hex/EtOAc) to afford 11 c.
  • Step 1
  • Step 1
  • a high pressure vessel is filled with a solution of 13c (1 16 mg, 0.52 mmol), in AcOH (1 .5 mL). Chloroacetyl chloride (63 uj_, 0.79 mmol) is added to the mixture and the reaction is heated for 3 hours at 1 10°C. The mixture is cooled to RT and azeotroped three times with benzene. The obtained residue is then diluted with a saturated solution of NaHC0 3 and extracted twice with EtOAc. The combined organic extracts are dried over MgS0 4 , concentrated and purified by Combiflash (20:80 Hex/EtOAc) to afford 13d.
  • Step 1
  • Step 1
  • Step 3 To a solution of 16b (360 mg, 1 .44 mmol) in DMF (12.0 mL) are successively added HATU (660 mg, 1 .74 mmol), DIEA (0.75 mL, 4.31 mmol) and ammonium hydrogen carbonate (243 mg, 3.07 mmol). The resulting solution is stirred at RT for 3 hours. The reaction mixture is diluted with water and extracted twice with EtOAc. The combined organic extracts are washed with water (3x) and brine, dried over MgS0 4 , concentrated and purified by Combiflash (60:40 Hex/EtOAc) to afford 16c.
  • a high pressure vessel is filled with a solution of 16c (300 mg, 1 .21 mmol), in AcOH (3.0 mL). Chloroacetyl chloride (0.29 mL, 3.64 mmol) is added to the mixture and the reaction is heated for 3 hours at 1 10°C. The mixture is cooled to RT and co-evaporated with benzene. The residue obtained is then diluted with a saturated solution of NaHC0 3 and extracted twice with EtOAc. The combined organic extracts are dried over MgS0 4 , concentrated and purified by Combiflash (30:70 Hex/EtOAc) to afford 16d.
  • Step 1
  • Step 1
  • Step 1
  • Step 1
  • Step 2 To a solution of 34a (930 mg, 3.25 mmol) in DMF (12 ml.) at RT is added HATU (1 .54 g, 4.06 mmol), TEA (1 .81 ml_, 13.0 mmol), then ammonium bicarbonate (770.8 mg, 9.75 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC0 3 saturated and brine, dried over MgS0 4 , filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 34b.
  • Step 1
  • Step 2 To a solution of the 35a (40.5 mg, 0.139 mmol) in DMF (3 mL) at RT is added HATU (65.9 mg, 0.173 mmol), TEA (0.077 mL, 0.55 mmol), then ammonium bicarbonate (32.9 mg, 0.416 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC0 3 saturated and brine, dried over MgS0 4 , filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 90:10) to afford 35b.
  • Step 1
  • Step 2 To a solution of 36a (206.0 mg, 0.731 mmol) in DMF (6 ml.) at RT is added HATU (347.0 mg, 0.913 mmol), TEA (0.408 ml_, 2.93 mmol), then ammonium bicarbonate (173.5 mg, 2.194 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC0 3 saturated and brine, dried over MgS0 4 , filtered and concentrated. The residue is purified by Combiflash (Hex/EtO Ac 100:0 to 70:30) to afford 36b.
  • Step 1
  • Step 2 To a solution of 37a (100 mg, 0.414 mmol) in DMF (5 mL) at RT is added HATU (196.3 mg, 0.517 mmol), TEA (0.23 mL, 1 .66 mmol), then ammonium bicarbonate (98.1 mg, 1 .241 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC0 3 saturated and brine, dried over MgS0 4 , filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 0:100) to afford 37b.
  • Step 1
  • Step 2 A mixture of 38a (532.4 mg, 2.62 mmol), 2-5-dichlorobenzoic acid (250 mg, 1 .309 mmol, Aldrich), potassium carbonate (180.9 mg, 1 .309 mmol), copper powder (8.3 mg, 0.131 mmol) and copper(l) oxide (9.4 mg, 0.065 mmol) in DME (3 ml.) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x).
  • Step 1
  • Step 1
  • Step 1
  • Step 1
  • Step 1
  • Step 1
  • Table 1 lists the UPLC or HPLC retention time and M+ peak for compounds 1001 -1090.
  • Retention times (t R ) for each compound are measured using the standard analytical UPLC or HPLC conditions described in the Examples.
  • retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different UPLC or HPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual UPLC or HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual
  • CPE cytopathic effect
  • Assay plates are prepared by seeding 2,500 HEp-2 cells (ATCC) per well of a 384-well black clear-bottom plate (Greiner Bio-One) in 20 ⁇ _ of assay media (defined as DMEM supplemented with 2% heat-inactivated fetal bovine serum and 1 % Penicillin/Streptomycin). Assay plates are incubated overnight at 37 ⁇ C in an incubator containing 5% C0 2 . The following day, a 10-point serial dilution of test compound is prepared in DMSO. Compounds are subsequently diluted with assay media and 20 ⁇ _ of diluted compound (containing 1 .5% DMSO) is transferred to an assay plate for evaluation of antiviral activity.
  • assay media defined as DMEM supplemented with 2% heat-inactivated fetal bovine serum and 1 % Penicillin/Streptomycin.
  • Assay plates are incubated overnight at 37 ⁇ C in an incubator containing 5% C0 2 .
  • CPE assay For the CPE assay, cells are infected at a MOI of 0.015 using 20 ⁇ _ of RSV Long (ATCC) diluted in assay media. The DMSO concentration is constant throughout the assay plate, including the negative and positive controls. The assay plate is incubated for 3 days at 37 °C in an incubator containing 5% C0 2 . Cell viability is evaluated with the addition of 10 ⁇ of CellTiter- Glo (ProMega). Luminescence is measured using an EnVision plate reader (Perkin Elmer). EC 50 values are calculated using the raw data from the CPE assays.
  • Example A All compounds of the invention, namely compounds 1001 -1090 are tested in the assay described in Example A. Compounds tested in the assay of Example A showed EC 50 values in the range of 10 ⁇ or less. Representative data is shown in the table below: Example A

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Abstract

Compounds of Formula (I): wherein R1, R2 and R3 are defined herein, are useful as inhibitors of RSV.

Description

RESPIRATORY SYNCYTIAL VIRUS INHIBITORS
FIELD OF THE INVENTION
The present invention relates to quinazolinone analogs and their use as inhibitors of replication of the respiratory syncytial virus (RSV), pharmaceutical compositions containing such analogs, and methods of using these analogs in the treatment and prevention of RSV infection.
BACKGROUND OF THE INVENTION
Globally, the annual death rate from RSV is estimated at more than 160,000 and the clinical burden of RSV infection is comparable to that of influenza (Bourgeois et al., 2009; Boyce et al., 2000; Hall et al., 2009; Stockman et al., 2012). The epidemic season for RSV runs from late fall through early spring. The primary populations at risk for poor outcome are children below 5 years of age, immunocompromised patients and older adults, particularly those who are institutionalized or have chronic underlying disease (Hall et al., 2009; Falsey et al., 2005). There is generally no available therapy for RSV infection, except for supportive care. Inhaled ribavirin is approved for the treatment of laboratory-diagnosed RSV infection but is administered only to some bone marrow transplant and immunocompromised patients, because of its limited effectiveness, complexity of administration and mutagenicity potential for patients and staff. Because of the absence of effective therapy for RSV infections and the significance of RSV morbidity and/or morality in at-risk populations, the introduction of an effective RSV agent will be considered a major breakthrough in the care of these patients.
SUMMARY OF THE INVENTION
The present invention provides a novel series of compounds that exhibit inhibitory activity on the replication of the RSV.
Further objects of this invention arise for the one skilled in the art from the following description and the examples.
One aspect of the invention provides a compound, represented by Formula (I), or racemate, enantiomer, diastereoisomer or tautomer thereof:
l
Figure imgf000003_0001
wherein
R1 is an 8-14 membered heterocycle or heteroaryl optionally substituted 1 to 4 times with substituents each independently selected from the group consisting of R1A, oxo, halo, -CN, (d. 6)haloalkyl, OH, -0(d-6)alkyl, -C(=0)OH and -C(=0)-0-(d-6)alkyl;
R1A is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl are optionally mono-, di- or tri-substituted with substituents each independently selected from the group consisting of (C^ejalkyl, (d-6)haloalkyl, halo, -0(d-6)alkyl, -CN, NH2, -N(H)R1B, -N((C1-6)alkyl)2, -C(=0)OH, -C(=0)-R1B, -C(=0)-(d- 6)alkyl-N((C1_6)alkyl)2, -C(=0)-0-R1B, -C(=0)-NH2, -C(=0)-N(H)R1B, -C(=0)-N((C1_6)alkyl)2, - S02(C1_6)haloalkyl or -S02R1B;
R1B is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl;
R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-aryl, -(Ci-6)alkyl-heteroaryl or -(d-6)alkyl- heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl, either alone or in combination with another moiety, are optionally mono-, di- or tri-substituted with
substituents each independently selected from the group consisting of halo, -CN, OH, -COOH, - (d-6)alkyl, -0-(d-6)alkyl, (C3-7)cycloalkyl, (d-6)haloalkyl, -0-C(=0)-R2A, -C(=0)-0-R2A, -S02NH2, -S02-N(H)R2A, -S02-N((d-6)alkyl)2, -SOR2A, -S02R2A, -C(=0)-NH2, -C(=0)-N(H)R2A,
-C(=0)-N((d-6)alkyl)2, -C(=0)-NH-S02R2A, -S02-NH-C(=0)R2A, -NH2, -N(H)R2A, -N((d-6)alkyl)2, -NH-C(=0)R2A, -NH-C(=0)0-R2A and -C(=0)-R2A (optionally substituted with (d-6)alkyl);
R2A is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl;
R3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH, - (Ci-6)alkyl, -0-(d-6)alkyl, (C3-7)cycloalkyl, (d-6)haloalkyl, -C(=0)-0-(d-6)alkyl, -S02NH2, -S02- NH(d-6)alkyl, -S02-N((d-6)alkyl)2, -SO(d-6)alkyl, -S02(d-6)alkyl, -C(=0)-NH2,
-C(=0)-NH(d_6)alkyl, -C(=0)-N((d_6)alkyl)2, -C(=0)-NH-S02(d_6)alkyl, -S02-NH-C(=0)- (d^alkyl, -NH2, -NH(C1-6)alkyl, -N((C1-6)alkyl)2, -NH(C3-7)cycloalkyl,
-N((C1_6)alkyl)(C3-7)cycloalkyl, -NH-C(=0)(C1_6)alkyl, -NH-C(=0)0(C1_6)alkyl and R
R is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (Ci_6)alkyl; n is 0, 1 , 2 or 3;
or a salt thereof.
Another aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a medicament.
Also within the scope of this invention is the use of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of RSV infection in a human being.
Included within the scope of this invention is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
According to a further aspect of this embodiment the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of an RSV infection in a human being having or at risk of having the infection.
Another aspect of the invention involves a method of treating or preventing RSV infection in a human being by administering to the human being an anti-RSV virally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat RSV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by RSV; wherein the composition comprises a compound of Formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
Still another aspect of this invention relates to a method of inhibiting the replication of RSV comprising exposing the virus to an effective amount of the compound of Formula (I), or a salt thereof, under conditions where replication of RSV is inhibited.
Further included in the scope of the invention is the use of a compound of Formula (I), or a salt thereof, to inhibit the replication of RSV.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
DEFINITIONS
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci_6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the first named subgroup is the radical attachment point, for example, the substituent "-C^s-alkyl-aryl" means an aryl group which is bound to a C! -3-alkyl-group, with the C! -3-alkyl group bound to the core. Unless specifically stated otherwise, for groups comprising two or more subgroups, the substituent may be attached to either subgroup.
In case a compound of the present invention is depicted in the form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk or the
designation, , may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
One skilled in the art would know how to separate, enrich, or selectively prepare the
enantiomers of the compounds of the present invention. Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or
enantiomeric purity, are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include but not limited to chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by
Chromatography, Am. Chem. Soc, 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, including but not limited to GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, including but not limited to CD, ORD, X-ray crystallography, or NMR.
The term "halo" generally denotes fluorine, chlorine, bromine and iodine.
The term "Ci-n-alkyl", wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term Ci-3-alkyl embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2- and H3C-CH(CH3)-.
The term "carbocyclyl" or "carbocycle" as used herein, either alone or in combination with another radical, means a mono-, bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms. The term "carbocyclyl" or "carbocycle" refers to fully saturated and aromatic ring systems and partially saturated ring systems. The term "carbocyclyl" or "carbocycle" encompasses fused, bridged and spirocyclic systems.
The term "C3.n-cycloalkyl", wherein n is an integer 4 to n, either alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "aryl" as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to at least one other 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
The term "heterocyclyl" or "heterocycle" means a saturated or unsaturated mono- or polycyclic- ring system including aromatic ring systems containing one or more heteroatoms selected from N, O or S(0)r ,wherein r=0, 1 or 2, consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term "heterocyclyl" or "heterocycle" is intended to include all the possible isomeric forms and all fused, bridged and spiro forms. The "heterocyclyl" may be optionally substituted with substituents, such as, for example, with an oxo moiety. Thus, the term "heterocyclyl" or "heterocyclyl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000007_0001
Thus, a "heterocyclyl" substituted with an oxo moiety includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000008_0001
The term "heteroaryl" means a mono- or polycyclic-ring system containing one or more heteroatoms selected from N, O or S(0)r, wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of an aromatic ring. The term "heteroaryl" is intended to include all the possible isomeric forms and all fused, bridged and spiro forms. The "heteroaryl" may be optionally substituted with substituents, such as, for example, with an oxo moiety. Thus, the term "heteroaryl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000008_0002
Thus, a "heteroaryl" substituted with an oxo moiety includes the following exemplary structures (each of which may in turn be optionally substituted) which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
Figure imgf000008_0003
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and
commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca-edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates,
hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napsylates, nitrates, oxalates, pamoates, pantothenates, phenylacetates,
phosphates/diphosphates, polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
As used herein, the term "treatment" means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of RSV disease and/or to reduce viral load in a patient.
As used herein, the term "prevention" means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus, to prevent the appearance of symptoms of the disease.
The term "therapeutically effective amount" means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
Further embodiments
In the following embodiments, groups and substituents of the compounds of Formula (I) according to this invention are described in detail.
Figure imgf000010_0001
(I) Any and each of the definitions below may be combined with each other.
R1-A: R1 is an 8-14 membered heterocycle or heteroaryl optionally substituted 1 to 4 times with substituents each independently selected from the group consisting of R1A, oxo, halo, -CN, (d. 6)haloalkyl, OH, -0(d-6)alkyl, -C(=0)OH and -C(=0)-0-(d-6)alkyl;
R1A is (d-6)alkyl, (C3.7)cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are optionally mono-, di- or tri-substituted with substituents each independently selected from the group consisting of (Ci-6)alkyl, (Ci-6)haloalkyl, halo, -0(d_6)alkyl, -CN, NH2, -N(H)R1B, -N((C1_6)alkyl)2, -C(=0)OH, -C(=0)-R1B, -C(=0)-(d_ 6)alkyl-N((C1_6)alkyl)2, -C(=0)-0-R1B, -C(=0)-NH2, -C(=0)-N(H)R1B, -C(=0)-N((C1_6)alkyl)2, - S02(C1_6)haloalkyl or -S02R1B;
R1B is (d-6)alkyl, (C3.7)cycloalkyl, aryl, heteroaryl or heterocyclyl.
R1-B: R1 is a 9-14 membered heterocycle or heteroaryl optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R1A, oxo, halo, -CN, (d_6)haloalkyl, OH and -0(C1-6)alkyl;
R1A is (Ci-6)alkyl, (C3-7)cycloalkyl or heterocycle, wherein each said alkyl, cycloalkyl, and heterocycle are optionally mono- or di-substituted with substituents each independently selected from the group consisting of (C1-4)alkyl, (C1-4)haloalkyl, halo, -0(C1-4)alkyl, -CN, NH2, NH(d_ 6)alkyl, N((C1_4)alkyl)2, -C(=0)-(C1_4)alkyl, -C(=0)-(C1_4)alkyl-N((C1_4)alkyl)2, -C(=0)-0-(C1_4)alkyl, - C(=0)-NH2, -C(=0)-NH(C1_4)alkyl, -C(=0)-N((C1_4)alkyl)2, -S02(C1_4)haloalkyl and -S02(C1_4)alkyl.
R1-C: R is
Figure imgf000011_0001
, optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R1A, halo, -CN, (d.
6)haloalkyl, OH and -0(d-6)alkyl;
R1A is (d-6)alkyl, (C3.7)cycloalkyl or heterocycle, wherein each said alkyl, cycloalkyl, and heterocycle are optionally mono- or di-substituted with substituents each independently selected from the group consisting of (Ci-4)alkyl, (Ci_4)haloalkyl, halo, -0(Ci-4)alkyl, -CN, NH2, NH(Ci- 6)alkyl, N((Ci-4)alkyl)2,
Figure imgf000012_0001
- C(=0)-NH2,
Figure imgf000012_0002
-S02(C1-4)haloalkyl and -S02(C1-4)alkyl.
R2:
R2-A: R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-aryl, -(Ci-6)alkyl-heteroaryl or -(d- 6)alkyl-heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl, either alone or in combination with another moiety, are optionally mono-, di- or tri-substituted with substituents each independently selected from the group consisting of halo, -CN, OH, -COOH, - (d-6)alkyl, -0-(Ci-6)alkyl, (C3-7)cycloalkyl, (Ci-6)haloalkyl, -0-C(=0)-R2A, -C(=0)-0-R2A, -S02NH2, -S02-N(H)R2A, -S02-N((C1_6)alkyl)2, -SOR2A, -S02R2A, -C(=0)-NH2, -C(=0)-N(H)R2A,
-C(=0)-N((C1_6)alkyl)2, -C(=0)-NH-S02R2A, -S02-NH-C(=0)R2A, -NH2, -N(H)R2A, -N((C1_6)alkyl)2, -NH-C(=0)R2A, -NH-C(=0)0-R2A and -C(=0)-R2A (optionally substituted with (C1-6)alkyl);
R2A is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl.
R2-B:R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-aryl, -(Ci-6)alkyl-heteroaryl or -(d- 6)alkyl-heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl are optionally mono- or di-substituted with substituents each independently selected from the group consisting of halo, -CN, OH, -COOH, -(C1-6)alkyl, -0-(C1-6)alkyl, (C3_7)cycloalkyl, (C1-6)haloalkyl, - 0-C(=0)-(C1-6)alkyl, -S02(C1_6)alkyl, -C(=0)-NH2, and -C(=0)-heterocycle (optionally substituted with (d_6)alkyl).
R2-C:R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-phenyl or -(Ci-6)alkyl-5- or 6- membered heterocyclyl wherein each said alkyl, phenyl and heterocyclyl are optionally mono- or di-substituted with substituents each independently selected from the group consisting of halo, - CN, OH, -COOH, -(C1-4)alkyl, -0-(C1-4)alkyl, (C3_7)cycloalkyl, (C1-4)haloalkyl, -0-C(=0)-(C1_4)alkyl, -S02(C1_4)alkyl and -C(=0)-NH2.
R3:
R3-A:R3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH,
-(Ci-6)alkyl, -0-(Ci-6)alkyl, (C3-7)cycloalkyl, (Ci-6)haloalkyl,
Figure imgf000012_0003
-S02NH2, -S02-
NH(C1-6)alkyl, -S02-N((C1-6)alkyl)2, -SO(d-6)alkyl, -S02(d-6)alkyl, -C(=0)-NH2,
-C(=0)-NH(d-6)alkyl, -C(=0)-N((d-6)alkyl)2, -C(=0)-NH-S02(d-6)alkyl, -S02-NH-C(=0)-
(d-6)alkyl, -NH2, -NH(d-6)alkyl, -N((d-6)alkyl)2, -NH(C3-7)cycloalkyl,
-N((d-6)alkyl)(C3-7)cycloalkyl, -NH-C(=0)(d-6)alkyl, -NH-C(=0)0(d-6)alkyl and R3a; R is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (d-6)alkyl.
R3-B:R3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH, -(Ci-6)alkyl, -0-(Ci-6)alkyl, (C3-7)cycloalkyl, (Ci-6)haloalkyl, -NH2, -NH(Ci-6)alkyl and
-N((C1-6)alkyl)2.
R3-C:R3 is each independently selected from the group consisting of H, halo, -CN, OH, (C1-6)alkyl, -0-(C1_6)alkyl, (C3-7)cycloalkyl and (C1_6)haloalkyl. n: n-A: n is 0, 1 , 2 or 3. n-B: n is 0 or 1 . n-C: n is 0.
Examples of preferred subgeneric embodiments of the present invention are set forth in the following table, wherein each substituent group of each embodiment is defined according to the definitions set forth above:
Figure imgf000013_0001
Figure imgf000014_0001
Examples of most preferred compounds according to this invention are each single compound of the invention, namely, compounds 1001 , 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009,
1010, 101 1 , 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021 , 1022, 1023, 1024,
1025, 1026, 1027, 1028, 1029, 1030, 1031 , 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039,
1040, 1041 , 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051 , 1052, 1053, 1054,
1055, 1056, 1057, 1058, 1059, 1060, 1061 , 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069,
1070, 1071 , 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081 , 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089 and 1090.
PHARMACEUTICAL COMPOSITION
Suitable preparations for administering the compounds of the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders, etc. The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.
Suitable tablets may be obtained, for example, by mixing one or more compounds of the invention with known excipients, for example inert diluents, carriers, binders, disintegrants, adjuvants, surfactants and/or lubricants. The tablets may also consist of several layers.
Suitable inhalatives may be obtained, for example, by administering one or more compounds of the invention in the form of a solution, dry powder or suspension. The compounds of the invention may be administered via inhalation of a solution in nebulized or aerosolized doses.
The dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight. Each dosage unit may conveniently contain from 5% to 95% active compound (w/w). Preferably such
preparations contain from 20% to 80% active compound. The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
COMBINATION THERAPY
When the composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. Therefore, according to one embodiment, the pharmaceutical composition of this invention additionally comprises one or more antiviral agents.
Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the production and/or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the production and/or replication of a virus in a human being. Such agents can be selected from: RSV Fusion inhibitors, such as MDT-637 (MicroDose), BTA-9881 (Biota); RSV Polymerase inhibitors, such as ALS-81 12 (Alios), ALS-8176 (Alios) and Virazole (ribavirin); others, such as GS-5806 (Gilead Sciences) and RSV-604 (Novartis); antibodies, such as Synagis® (palimizumab), RespiGam® (RSV-IG), MEDI-557 (Medlmmune/AstraZeneca), ALX- 0171 (Ablynx), motavizumab (Medlmmune/AstraZeneca); other biological, such as ALN-RSV-01 (Alnylam) and Vaccines, such as MEDI-559 (Medlmmune/AstraZeneca), RSV F (Novavax), MEDI-534(Medlmmune/AstraZeneca).
EXAMPLES
Other features of the present invention will become apparent from the following non-limiting examples which illustrate the principles of the invention. As is well known to a person skilled in the art, reactions are performed in an inert atmosphere (including but not limited to nitrogen or argon) where necessary to protect reaction components from air or moisture. Temperatures are given in degrees Celsius ( °C). Solution percentages and ratios express a volume to volume relationship, unless stated otherwise. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.
All of the compounds of the invention are synthesized analogously to the Examples. It will be apparent to a skilled person that the analogous synthetic routes may be used, with appropriate modifications, to prepare the compounds of the invention as described herein.
Compounds and intermediates can be purified by a Teledyne ISCO Combiflash R, System at 254 nm using commercial normal phase silica 4-120 g Redisep Rf or Silicycle columns at a flow rate of 18-85 ml. /min depending on column size. Mass spectral analyses may be recorded using flow injection analysis mass spectrometry or Waters Acquity Ultraperformance LC System consisting of a sample organizer, PDA detector, column manager, sample manager, binary solvent manager and SQ detector.
Reactions performed in microwave conditions are conducted in a Biotage Initiator 2.0 microwave synthesizer equipped with a Robot Sixty for vial manipulations. The temperature range is from 40-250 °C. The pressure range is from 0-20 bar and the power range is from 0- 400 Watts at 2.45 GHz. The vial size varies from 0.5 ml. to 20 ml_. The solvent absorption level is high by default. Specific reaction times and temperatures are given in the experimental section when applicable.
Preparative HPLC is performed using a Waters instrument, using one of the conditions outlined below:
Sunfire Prep C18 column, OBD, 5 μιτι, 30 x 75 mm, 120 A, elution with a gradient of ACN/H20 containing 0.06% TFA, 60 mL/min.
Sunfire Prep C18 column, OBD, 5 μιτι, 19 x 50 mm, 120 A, elution with a gradient of ACN/H20 containing 0.06% TFA, 30 mL/min.
Sunfire Prep C18 column, OBD, 5 μιτι, 19 x 50 mm, 120 A at RT or 455C, elution with a gradient of MeOH or ACN/Ammonium formate 10 mM in H20, pH 3.8, 30 mL/min.
X-Bridge Prep C18 column, OBD, 5 μιτι, 19 x 50 mm, 120 A at RT or 455C, elution with a gradient of MeOH or ACN/Ammonium bicarbonate 10 mM in H20, pH 10, 30 mL/min. Analytical HPLC and UPLC-MS are carried out under standard conditions using one of the columns (Sunfire C18, CombiScreen ODS-AQ, HSS C18 or BEH C18) with the specific conditions shown below:
Column: Sunfire C18, 3.5 μηι, 4.6 x 30 mm
Eluent A: H20 + 0.06% or 0.1 % TFA
Eluent B: ACN + 0.06% or 0.1 % TFA
Gradient: Linear 2% B for 0.6 min, 2% to 50% B in 4.9 min, 50% to 100% B in 1 .8 min, isocratic at 100% B for 0.6 min
Column: CombiScreen ODS-AQ, S-5 μηι, 12 nm, 4.6 x 50 mm
Eluent A: H2O + 0.1 % TFA
Eluent B: ACN + 0.1 % TFA
Gradient: Linear 5% B for 0.5 min, 5% to 50% B in 5.5 min, 50% to 100% B in 4.5 min, isocratic at 100% B for 1 .0 min
Column: HSS C18, 1 .8 μηι, 2.1 x 30 mm
Eluent A: Ammonium formate 10 mM in H20, pH 3.8
Eluent B: MeOH
Gradient: 5% to 100% B in 2.3 min, isocratic at 100% B for 0.7 min
Column: HSS C18, 1 .8 μηι, 2.1 x 30 mm
Eluent A: H20 + 0.06% TFA
Eluent B: ACN
Gradient: 5% to 100% B in 2.2 min, isocratic at 100% B for 0.8 min
Column: BEH C18, Ι .Ί μπ, ΣΑ x 30 mm at 255C or 455C
Eluent A: Ammonium bicarbonate 10 mM in H20, pH 10.0
Eluent B: MeOH or ACN
Gradient: 5% to 100% B in 2.2 min, isocratic at 100% B for 0.8 min
Column: BEH C18, Ι .Ί μπ, ΣΑ x 30 mm at 255C or 455C
Eluent A: Ammonium bicarbonate 10 mM in H20, pH 10.0
Eluent B: MeOH or ACN Gradient: 5% to 100% B in 2.2 min, isocratic at 100% B for 0.8 min
Column: HSS C18, 1 .8 μηι, 2.1 x 30 mm at 455C
Eluent A: Ammonium formate 10 mM in H20, pH 3.8
Eluent B: ACN
Gradient: 5% to 100% B in 2.3 min, isocratic at 100% B for 0.7 min
All of the compounds of the invention are synthesized according to the Examples described herein. It will be apparent to a skilled person that analogous synthetic routes may be used, with appropriate modifications, to prepare the compounds of the invention as described herein.
Abbreviations used in the examples include:
ACN: acetonitrile; AcOH: acetic acid; AmFor: Ammonium Formate aqueous solution; BEH: ethylene bridged hybrid; Boc: fertbutyloxycarbonyl; CDI: 1 ,1 '-carbonyldiimidazole; DCM:
dichloromethane; DIEA or DIPEA: diisopropylethylamine; DMA: dimethylacetamide; DMAP: 4- dimethylaminopyridine; DME: 1 ,2-dimethoxyethane; DMEM: Dulbecco's modified Eagle's medium; DMF: A/JV-dimethylformamide; DMSO: dimethylsulfoxide; EC50: 50% effective concentration; Et: ethyl; EtOAc: ethyl acetate; EtOH: ethanol; HATU: [0-(7-azabenzotriazol-1 - yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate]; Hex: hexanes; HPLC: high performance liquid chromatography; HSS: high strength silica; [M+H]+: protonated molecular ion; Me: methyl; MeOH: methanol; MOI: Multiplicity of Infection; MS: mass spectrometry; OBD: optimum bed density; PCC: Pyridinium chlorochromate; Ph: phenyl; RP-HPLC: reverse phase-high pressure liquid chromatography; RT: room temperature (18 to 22 5C); TBAF: tetrabutylammonium fluoride; TEA: triethylamine;TFA: trifluoroacetic acid; THF: tetrahydrofuran; tR: retention time; UPLC-MS: ultra performance liquid chromatography mass spectrometry
Example 1 : Preparation of intermediate 1 c
Figure imgf000019_0001
1a 1 b 1c
Step 1 :
To a stirred solution of 1 -fluoro-2-nitrobenzene (40.0 g, 283.5 mmol, Avra) in THF (400 mL) is added cyclopropylamine (49.0 mL, 708.7 mmol). The resulting solution is refluxed overnight. The reaction is cooled to 0°C, diluted with water and DCM. The layers are separated and the organic extracts are washed with water, dried over Na2S04, filtered and concentrated. The crude product 1a is used as is in the next step.
Step 2:
A solution of 1a (10.0 g, 56.1 mmol) and 10% Pd/C (2.4 g, 2.3 mmol) in EtOH (980 mL) is stirred for 2 hours under a hydrogen atmosphere (50 psi). The reaction mixture is filtered through celite and concentrated to afford 1 b.
Step 3:
To a stirred solution of 1 b (20.0 g, 135.0 mmol) in THF (400 mL) at 0°C is added CDI (43.8 g, 270.0 mmol) and the resulting mixture is warmed to RT and stirred overnight. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude material is purified by flash
chromatography to afford 1 c.
Example 2: Preparation of intermediate 2c
Figure imgf000019_0002
Step 1 : A solution of oxetan-3-amine (2.0 g, 27.4 mmol, Aldrich), 4-methoxy-3-nitropyridine (8.43 g, 54.7 mmol, Combi-Blocks) and diisopropylethylamine (7.14 ml_, 41 .0 mmol) in EtOH (50 ml.) is heated in a sealed tube for 16 hours. The mixture is cooled to RT and concentrated under reduced pressure to half of the volume, and then cooled to 0°C. The residue is filtered and triturated with Hex to afford 2a.
Step 2:
3-Nitro-N-(oxetan-3-yl)pyridin-4-amine 2a (2.60 g, 13.3 mmol) is hydrogenated in anhydrous MeOH (50 ml.) in the presence of 5% palladium on carbon (0.80 g, Aldrich) at 40 psi for 2.5 hours at RT. The mixture is filtered through celite and the filter is washed with MeOH. The combined filtrate is concentrated under reduced pressure to afford 2b.
Step 3:
Solid 1 ,1 '-carbonyldiimidazole (1 .47 g, 9.07 mmol, Aldrich) is added to a solution of N-4-(oxetan- 3-yl)pyridine-3,4-diamine 2b (1 .0 g, 6.05 mmol) in anhydrous ACN (20 ml.) and anhydrous THF (10 ml.) at RT under N2. The mixture is refluxed for 1 .5 hours. The solvents are evaporated under reduced pressure. The residue is dissolved in DCM (30 ml.) and washed with water (20 ml_). The aqueous phase is extracted with DCM, and the combined organic extracts are dried over sodium sulfate. After filtration and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on a Biotage system (5:95 MeOH/EtOAc to 30:70 MeOH/EtOAc) to afford 2c.
Example 3: Preparation of intermediate 3c
Figure imgf000020_0001
3a 3b 3c
Intermediate 3c is made analogously to the procedure described in Example 2 using (S)- tetrahydrofuran-3-amine from Small-Mol as the starting material.
Example 4: Preparation of intermediate 4c
Figure imgf000021_0001
4a 4b 4c
Intermediate 4c is made analogously to the procedure described in Example 2 using (R)- tetrahydrofuran-3-amine from Broadpharm as the starting material.
Exam le 5: Preparation of intermediate 5c
Figure imgf000021_0002
5a 5b 5c
Intermediate 5c is made analogously to the procedure described in Example 2 using 4- aminotetrahydropyran from Combi-Blocks as the starting material.
Example 6: Preparation of intermediate 6c
Figure imgf000021_0003
6a 6b 6c
Intermediate 6c is made analogously to the procedure described in Example 2 using 1 ,1 - dioxidotetrahydrothien-3-ylamine from Intermed as the starting material.
Example 7: Preparation of intermediate 7a
Figure imgf000022_0001
7a
To a stirred solution of 4-(2-keto-1 -benzimidazolinyl)piperidine (250.0 mg, 1 .15 mmol, Acros) in DCM (15 mL) are added Boc20 (333.0 mg, 1 .53 mmol) and DMAP (28.0 mg, 0.23 mmol). The resulting solution is stirred for 6 hours. The reaction is diluted with DCM and washed with citric acid (2x) and a saturated solution of NaHC03 (2x). The organic layer is washed with brine, dried over Na2S04, filtered, concentrated and purified by Combiflash (50:50 Hex/EtOAc) to afford 7a.
Exam le 8: Preparation of intermediate 8d
Figure imgf000022_0002
8a 8b
Figure imgf000022_0003
8c 8d
Step 1 :
To a stirred solution of 3-hydroxy-2-nitropyridine (55.0 g, 393 mmol, Aldrich) in DCM (825.0 mL,) is added TEA (81 .3 mL, 583.3 mmol) and triflic anhydride (80.3 mL, 477.3 mmol) at 0 <C.The mixture is stirred for 2 hours at RT. The suspension is diluted with water and extracted with DCM. The organic layer is dried over Na2S04, filtered, concentrated and purified by flash chromatography to afford 8a. Step 2:
To a stirred solution of 8a (5.0g, 19.0 mmol) in toluene (50.0 mL) is added cyclopropylamine (2.3 mL, 33.2 mmol, Avra). The mixture is stirred for 1 hour at 90°C. The suspension is diluted with water and extracted with DCM. The organic layer is dried over Na2S04, filtered, concentrated and purified by flash chromatography to afford 8b.
Step 3:
A solution of 8b (30.0 g, 167.0 mmol) and 10% Pd/C (6.5 g, 6.1 mmol) in EtOH (567 mL) is stirred for 1 hour under a hydrogen atmosphere (50 psi). The reaction mixture is filtered through celite, concentrated and purified by flash chromatography to afford 8c.
Step 4:
To a stirred solution of 8c (20.0 g, 135.0 mmol) in THF (625 mL) at 0°C is added CDI (45.7 g, 281 .5 mmol). The resulting mixture is warmed to RT and stirred overnight. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude material is washed with EtOAc and cooled ACN to give 8d.
Ex mple 9: Preparation of intermediate 9c
Figure imgf000023_0001
9a 9b 9c
Step 1 :
To a stirred solution of 2,5-difluoronitrobenzene (50.0 g, 314.3 mmol) in DMF (1 .7 L) is added cyclopropylamine (21 .7 mL, 314.3 mmol) and TEA (73.0 g, 722.9 mmol). The resulting solution is stirred overnight at RT. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulphate, filtered, concentrated under reduced pressure and purified by flash chromatography (5:95 EtOAc/Petroleum ether) to afford 9a.
Step 2: A solution of 9a (50.0 g, 254.9 mmol) and 10% Pd/C (5.0 g, 4.7 mmol) in EtOH (1 .3 L) is stirred for 16 hours under a hydrogen atmosphere (50 psi). The reaction mixture is filtered through celite, concentrated and purified by flash chromatography to afford 9b.
Step 3:
To a stirred solution of 9b (17.0 g, 102.3 mmol) in THF (204 mL) at 0°C is added CDI (23.8 g, 204.6 mmol). The resulting mixture is warmed to RT and stirred overnight. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material is washed with diethyl ether to give 9c.
Exam le 10: Preparation of intermediate 10c
Figure imgf000024_0001
10a 10b 10c
Step 1 :
To a stirred solution of isatoic anhydride (10.0 g, 61 .3 mmol, Lancaster) in EtOH (100.0 mL) is added TEA (8.48 mL, 61 .3 mmol). Cyclopropylamine (6.51 mL, 61 .3 mmol, Avra) is added at a rate such that the reaction temperature does not rise above 30 °C. After the addition is complete, the mixture is heated to 70 ^ for 16 hours. The reaction mixture is cooled to RT. The resulting solid is collected by filtration and washed with diethyl ether. The solid is then stirred in diethyl ether for 1 hour, filtered and washed with diethyl ether to give 10a.
Step 2:
To a stirred solution of lithium aluminium hydride (2.9 g, 76.7 mmol, Aldrich) in THF (77 mL) at 0°C is added 10a (5.0 g, 28.4 mmol) in THF (60 mL) at a rate such that the reaction temperature does not rise above 10°C. After the addition is complete, the reaction is heated at 60°C for 16 hours. The reaction is quenched with a 1 N aqueous solution of NaOH. The mixture is filtered through celite and the filtrate is washed with EtOAc and water. The aqueous layer is separated and extracted with EtOAc. The combined organic extracts are dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by flash chromatography (50:50 EtOAc/Petroleum ether) to afford 10b.
Step 3:
To a stirred solution of 10b (2.0 g, 12.3 mmol) in THF (22.0 mL) is added CDI (3.0 g, 18.5 mmol) and the resulting mixture is stirred at RT overnight. The reaction mixture is concentrated under reduced pressure. The crude product is diluted with DCM and washed with water. The organic layer is washed with a 1 N aqueous solution of HCI, dried over sodium sulphate, filtered and concentrated. The crude material is purified by flash chromatography to obtain 10c.
Example 11 : Preparation of intermediate 11 c
Figure imgf000025_0001
To a solution of anthranilic acid (1 .00 g, 7.29 mmol, Aldrich), in MeOH (50 mL), are successively added isovaleraldehyde (1 .20 mL, 1 1 .19 mmol, Aldrich), AcOH (0.58 mL, 10.13 mmol) and sodium cyanoborohydride (0.69 g, 10.98 mmol). The resulting solution is stirred at RT for 1 hour. The MeOH is evaporated in vacuo. The residue, diluted with water, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04, concentrated and purified by Combiflash (90:10 Hex/EtOAc) to afford 11 a.
Step 2:
To a solution of 11 a (1 .33 g, 6.42 mmol), in DMF (25 mL), are successively added HATU (2.95 g, 7.76 mmol), DIEA (3.35 mL, 19.23 mmol) and ammonium hydrogen carbonate (1 .00 g, 12.65 mmol). The resulting solution is stirred at RT for 3 hours. The reaction mixture, diluted with water, is extracted twice with EtOAc. The combined organic extracts are washed with water (3x) and brine, dried over MgS04, concentrated and purified by Combiflash (80:20 Hex/EtOAc) to afford 11 b.
Step 3: A high pressure vessel is filled with a solution of 11 b (0.50 g, 2.42 mmol), in AcOH (5 mL). To this solution is added chloroacetyl chloride (0.58ml_, 7.29 mmol). The reaction is then heated for 3 hours at 1 l O 'C. The mixture is cooled to RT and co-evaporated three times with benzene. The obtained residue is then diluted with an aqueous saturated solution of NaHC03 and extracted twice with EtOAc. The combined organic extracts are dried over MgS04, concentrated and purified by Combiflash (20:80 Hex/EtOAc) to afford 11 c.
Exam le 12: Preparation of compound 1001
Figure imgf000026_0001
11c 1001
Step 1 :
To a solution of 11 c (30 mg, 0.1 13 mmol) and 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridine- 2-one (20 mg, 0.1 14 mmol, BetaPharma), in DMF (1 mL), is added Cs2C03 (1 1 1 mg, 0.341 mmol). The resulting suspension is stirred at RT for 3 hours. The reaction mixture, diluted with MeOH and water, is purified by preparative RP- HPLC to provide compound 1001.
The following compounds are made analogously to the procedure described in Example 12.
Figure imgf000026_0002
Figure imgf000027_0001

Figure imgf000028_0001

Figure imgf000029_0001
Figure imgf000030_0001
Step 1 :
To a suspension of PCC (4.75 g, 22.0 mmol, Aldrich) in DCM (70 mL) is added a solution of 3- methoxy-1 -butanol (1 .5 g, 14.4 mmol) in 30 mL of DCM. The reaction is stirred at RT for 3 hours. The mixture is diluted in DCM and the residue is removed by filtration. The filtrate is concentrated and purified by Combiflash (90:10 Hex/EtOAc) to afford 13a.
Step 2:
To a solution of anthranilic acid (180 mg, 1 .31 mmol) in MeOH (7.5 mL), are successively added aldehyde 13a (160 mg, 1 .57 mmol), AcOH (0.1 1 mL, 1 .92 mmol) and sodium cyanoborohydride (125 mg, 1 .99 mmol). The resulting solution is stirred at RT for 1 hour. MeOH is evaporated in vacuo and the residue is diluted with water. The mixture is extracted twice with EtOAc, dried over MgS04, concentrated and purified by Combiflash (80:20 Hex/EtOAc) to afford 13b.
Step 3:
To a solution of 13b (180 mg, 0.81 mmol) in DMF (2.5 mL) are successively added HATU (368 mg, 0.97 mmol), DIEA (0.42 mL, 2.41 mmol) and ammonium hydrogen carbonate (128 mg, 1 .62 mmol). The resulting solution is stirred at RT for 3 hours. The reaction mixture is diluted with water and extracted twice with EtOAc. The combined organic extracts are washed with water (3x) and brine, dried over MgS04, concentrated and purified by Combiflash (60:40 Hex/EtOAc) to afford 13c. Step 4:
A high pressure vessel is filled with a solution of 13c (1 16 mg, 0.52 mmol), in AcOH (1 .5 mL). Chloroacetyl chloride (63 uj_, 0.79 mmol) is added to the mixture and the reaction is heated for 3 hours at 1 10°C. The mixture is cooled to RT and azeotroped three times with benzene. The obtained residue is then diluted with a saturated solution of NaHC03 and extracted twice with EtOAc. The combined organic extracts are dried over MgS04, concentrated and purified by Combiflash (20:80 Hex/EtOAc) to afford 13d.
Step 5:
To a solution of 13d (25 mg, 0.09 mmol) and 1 c (17 mg, 0.10 mmol) in DMF (1 .25 mL), is added Cs2C03 (87 mg, 0.27 mmol). The resulting suspension is stirred at RT for 3 hours, quenched with water and purified by preparative RP-HPLC to provide compound 1068.
Exam le 14: Preparation of intermediate 14b
Figure imgf000031_0001
Step 1 :
To a solution of the 4-(dimethyl-tert-butylsilyloxy)butan-1 -ol (2.0 g, 9.79 mmol, Aldrich) in EtOAc (10.0 mL) are added pyridine (0.87 mL, 10.8 mmol) and acetic anhydride (1 .2 mL, 12.7 mmol). The resulting mixture is stirred at RT overnight. The mixture is diluted with EtOAc, washed with a 1 N aqueous solution of HCI then washed with a saturated solution of NaHC03. The organic layer is washed with brine, dried over MgS04, filtered and concentrated. The crude product 14a is directly used for the next step.
Step 2:
To a solution of 14a (2.4 g, 9.74 mmol) in THF (10.0 mL) is added a 1 M solution of TBAF in THF
(25.0 mL, 25.0 mmol). The reaction mixture is stirred at RT for 48 hours. The volatiles are removed in vacuo and the crude product is purified by Combiflash (50:50 Hex/EtOAc) to afford
Example 15: Preparation of intermediate 15a
Figure imgf000032_0001
A solution of mono-methyl succinate (2.0 g, 15.1 mmol, Aldrich) in THF (30.0 ml.) is cooled to 0°C and TEA (2.2 ml_, 15.7 mmol) followed by isobutyl chloroformate (2.05 g, 15.0 mmol) are added. The resulting mixture is stirred at 0°C for 30 minutes. The resulting residue is filtered on Millex and directly added to a solution of NaBH4 (1 .15 g, 30.4 mmol) in 20 ml. of water. The reaction is stirred for 2 hours at RT. The mixture is diluted with water, acidified with a 1 N solution of HCI and extracted twice with EtOAc. The organic layers are combined, washed with brine, dried over MgS04, filtered and concentrated. The crude product is purified by Combiflash (50:50 Hex/EtOAc) to afford 15a.
The following compounds are made analogously to the procedure described in Example 13.
Figure imgf000032_0002
Figure imgf000033_0001
32
Figure imgf000034_0001
33
Figure imgf000035_0001
Example 16: Preparation of compound 1008
Figure imgf000036_0001
Step 1 :
To a solution of 2-(tetrahydro-2H-pyran-3-yl)ethanamine (600 mg, 4.64 mmol, ChemBridge) and methyl-2-fluorobenzoate (1 .2 mL, 9.42 mmol) in 35 mL of DMSO are added K2C03 (1 .28 g, 9.26 mmol) and Bu4NI (172 mg, 0.47 mmol, Aldrich). The reaction is stirred at 140°C for 5 hours. The mixture is diluted in water and extracted twice with EtOAc. The organic layers are combined, washed with water, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (90:10 Hex/EtOAc) to afford 16a.
Step 2:
To a solution of the ester 16a (0.41 g, 1 .56 mmol) in 21 mL of a 2.5:1 mixture of THF:water is added a 1 N aqueous solution of NaOH (3.1 mL, 3.1 mmol). MeOH is added to obtain a clear solution. The reaction mixture is stirred at RT for 16 hours and then for 3 hours at 60°C. The mixture is quenched with a 1 N aqueous solution of HCI, extracted with EtOAc, washed with brine, dried over MgS04, filtered and concentrated. The crude product 16b is directly used for the next step.
Step 3: To a solution of 16b (360 mg, 1 .44 mmol) in DMF (12.0 mL) are successively added HATU (660 mg, 1 .74 mmol), DIEA (0.75 mL, 4.31 mmol) and ammonium hydrogen carbonate (243 mg, 3.07 mmol). The resulting solution is stirred at RT for 3 hours. The reaction mixture is diluted with water and extracted twice with EtOAc. The combined organic extracts are washed with water (3x) and brine, dried over MgS04, concentrated and purified by Combiflash (60:40 Hex/EtOAc) to afford 16c.
Step 4:
A high pressure vessel is filled with a solution of 16c (300 mg, 1 .21 mmol), in AcOH (3.0 mL). Chloroacetyl chloride (0.29 mL, 3.64 mmol) is added to the mixture and the reaction is heated for 3 hours at 1 10°C. The mixture is cooled to RT and co-evaporated with benzene. The residue obtained is then diluted with a saturated solution of NaHC03 and extracted twice with EtOAc. The combined organic extracts are dried over MgS04, concentrated and purified by Combiflash (30:70 Hex/EtOAc) to afford 16d.
Step 5:
To a solution of 16d (33 mg, 0.1 1 mmol) and 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridine-2- one (19 mg, 0.1 1 mmol) in DMF (1 .0 mL) is added Cs2C03 (105 mg, 0.32 mmol). The resulting suspension is stirred at RT for 14 hours, diluted with water and purified by preparative RP-HPLC to provide compound 1008.
The following compounds are made analogously to the procedure described in Example 16.
Figure imgf000037_0001
Figure imgf000038_0001

Figure imgf000039_0001

Figure imgf000040_0001

Figure imgf000041_0001
Figure imgf000042_0001
To a solution of compound 1077 (166 mg, 0.38 mmol) in 7 mL of a 2.5:1 mixture of THF:water is added a 1 N aqueous solution of NaOH (0.96 mL, 0.96 mmol). MeOH is added to obtain a clear solution and then the mixture is stirred at RT for 16 hours. The mixture is quenched with a 1 N aqueous solution of HCI, extracted with EtOAc, washed with brine, dried over MgS04, filtered and concentrated. Purification of the residue by preparative RP-HPLC affords compound 1078.
Exam le 18: Preparation of compound 1069
Figure imgf000042_0002
To a solution of compound 1078 (25 mg, 0.06 mmol) in DMF (1 .25 mL) are successively added HATU (26.0 mg, 0.07 mmol), DIEA (35 μΐ, 0.20 mmol) and ammonium hydrogen carbonate (1 1 .0 mg, 0.14 mmol). The resulting solution is stirred at RT for 16 hours, diluted with water and purified by preparative RP-HPLC to provide compound 1069.
Example 19: Preparation of compound 1070
Figure imgf000043_0001
To a solution of compound 1078 (25 mg, 0.06 mmol) in DMF (1 .25 mL) are successively added HATU (26.0 mg, 0.07 mmol), DIEA (35 μΐ, 0.20 mmol) and methylamine hydrochloride (8.0 mg, 0.12 mmol). The resulting solution is stirred at RT for 16 hours, diluted with water and purified by preparative RP-HPLC to provide compound 1070.
Exam le 20: Preparation of compound 1072
Figure imgf000043_0002
To a solution of compound 1078 (25 mg, 0.06 mmol) in DMF (1 .25 mL) are successively added HATU (26.0 mg, 0.07 mmol), DIEA (35 μί, 0.20 mmol) and 1 -methylpiperazine (10.0 μί, 0.1 1 mmol). The resulting solution is stirred at RT for 16 hours, diluted with AcOH (0.1 mL) and purified by preparative RP-HPLC to provide compound 1072.
Example 21 : Preparation of compound 1018
Figure imgf000044_0001
To a solution of compound 1019 (55 mg, 0.123 mmol), in 3.5 mL of a THF:H20 (2.5/1 ) mixture, is added a 1 M solution of NaOH (0.31 mL, 0.310 mmol). MeOH (0.5 mL) is added and the resulting solution is stirred at RT for 2 hours. The solvents are evaporated in vacuo. The residue, diluted with MeOH, is purified by preparative RP- HPLC to provide compound 1018.
Exam le 22: Preparation of compound 1026
Figure imgf000044_0002
To a solution of compound 1024 (20 mg, 0.045 mmol), in 3.5 mL of a THF:H20 (2.5/1 ) mixture, is added a 1 M solution of NaOH (0.12 mL, 0.120 mmol). MeOH (0.5 mL) is added and the resulting solution is stirred at RT for 2 hours. The solvents are evaporated in vacuo. The residue, diluted with MeOH, is purified by preparative RP- HPLC to provide compound 1026.
Example 23: Preparation of compound 1021
Figure imgf000045_0001
Step 1 :
To a solution of 23a (30 mg, 0.097 mmol) and 1 -propyl-1 ,3-dihydro-2H-benzimidazol-2-one (17 mg, 0.096 mmol, Enamine), in DMF (1 mL), is added Cs2C03 (95 mg, 0292 mmol). The resulting suspension is stirred for 2 hours at RT. The reaction mixture, diluted with water, is extracted twice with EtOAc. The combined organic extracts are washed three times with water, dried over MgS04 and concentrated to afford 23b.
Step 2:
To a solution of 23b (42 mg, 0.094 mmol), in 3.5 mL of a THF:H20 (2.5/1 ) mixture, is added a 1 M solution of NaOH (0.235 mL, 0.235 mmol). MeOH (0.5 mL) is added and the resulting solution is stirred for 2 hours at RT. The solvents are evaporated in vacuo. The residue, diluted with MeOH and water, is purified by preparative RP- HPLC to provide compound 1021.
Exam le 24: Preparation of compound 1031
Figure imgf000045_0002
Step 1 :
To a solution of 23a (33 mg, 0.107 mmol) and 9c (21 mg, 0.109 mmol), in DMF (1 mL), is added Cs2C03 (105 mg, 0322 mmol). The resulting suspension is stirred for 3 hours at RT. The reaction mixture, diluted with water, is extracted twice with EtOAc. The combined organic extracts are washed three times with water, dried over MgS04 and concentrated to afford 24a.
Step 2:
To a solution of 24a (45 mg, 0.097 mmol), in 3.5 mL of a THF:H20 (2.5/1 ) mixture, is added a 1 M solution of NaOH (0.245 mL, 0.245 mmol). MeOH (0.5 mL) is added and the resulting solution is stirred for 2 hours at RT. The solvents are evaporated in vacuo. The residue, diluted with MeOH, is purified by preparative RP-HPLC to provide compound 1031.
Exam le 25: Preparation of compound 1074
Figure imgf000046_0001
Step 1 :
To a solution of 23a (40 mg, 0.130 mmol) and 8d (23 mg, 0.131 mmol), in DMF (1 mL), is added Cs2C03 (127 mg, 0390 mmol). The resulting suspension is stirred for 3 hours at RT. The reaction mixture, diluted with water, is extracted twice with EtOAc. The combined organic extracts are washed three times with water, dried over MgS04, concentrated and purified by Combiflash (95:5 DCM/MeOH) to afford 25a.
Step 2:
To a solution of 25a (33 mg, 0.074 mmol), in 3.5 mL of a THF:H20 (2.5/1 ) mixture, is added a 1 M solution of NaOH (0.185 mL, 0.185 mmol). MeOH (0.5 mL) is added and the resulting solution is stirred for 2 hours at RT. The solvents are evaporated in vacuo. The residue, diluted with MeOH, is purified by preparative RP-HPLC to provide compound 1074.
Example 26: Preparation of compound 1063
Figure imgf000047_0001
2.5 mL of a 4M solution of HCI in dioxane is added to compound 1062 (128 mg, 0.235 mmol). MeOH (1 mL) is added and the reaction is stirred for 1 hour at RT. The solvents are evaporated in vacuo. The residue, diluted with a saturated solution of NaHC03, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04 and concentrated. This residue is dissolved in a mixture of DMF/MeOH and purified by preparative RP- HPLC to provide compound 1063.
Example 27: Preparation of compound 1061
Figure imgf000047_0002
To a solution of compound 1063 (37 mg, 0.083 mmol), in 1 .5 mL of DMF, are successively added AcOH (0.010 mL, 0.175 mmol), HATU (63 mg, 0.166 mmol) and DIEA (0.075 mL, 0.431 mmol). The resulting solution is stirred at RT overnight. The reaction mixture, diluted with MeOH, is purified by preparative RP- HPLC to provide compound 1061. Example 28: Preparation of compound 1076
Figure imgf000048_0001
To 28a (25 mg, 0.052 mmol), in 1 .5 mL of THF, is added DIEA (0.045 mL, 0.258 mmol) followed by methanesulfonyl chloride (0.015 mL, 0.191 mmol). The resulting solution is stirred for 1 hour at RT. The solvent is evaporated in vacuo. The residue, diluted with a mixture of DMF/MeOH, is purified by preparative RP- HPLC to afford compound 1076.
Example 29: Preparation of compound 1079
Figure imgf000048_0002
To a suspension of 28a (25 mg, 0.052 mmol), in 1 .5 mL of THF, is added DIEA (0.050 mL, 0.287 mmol) followed by 3,3,3 trifluoropropane-1 -sulfonyl chloride (31 mg, 0.158 mmol). The resulting solution is stirred overnight at RT. Additional sulfonyl chloride is added (16mg, 0.081 mmol). The reaction mixture is stirred for 2 hours, and then the solvent is evaporated in vacuo. The residue, diluted with H20 and 1 mL of DMF, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04 and concentrated. The obtained residue, diluted with MeOH, is purified by preparative RP- HPLC to afford compound 1079.
Exam le 30: Preparation of compound 1080
Figure imgf000049_0001
To a suspension of 28a (25 mg, 0.052 mmol), in 1 .5 mL of THF, is added DIEA (0.050 mL, 0.287 mmol) followed by methyl chloroformate (0.012 mL, 0.155 mmol). The resulting solution is stirred for 2 hours at RT. The solvent is evaporated in vacuo. The residue, diluted with a mixture of DMF/MeOH, is purified by preparative RP- HPLC to afford compound 1080.
Exam le 31 : Preparation of compound 1081
Figure imgf000049_0002
To a suspension of 28a (25 mg, 0.052 mmol), in 1 .5 mL of THF, is added DIEA (0.050 mL, 0.287 mmol) followed by the HCI salt of dimethylaminoacetyl chloride (25 mg, 0.158 mmol). The resulting solution is stirred overnight at RT. The solvent is evaporated in vacuo. The residue, diluted with H20 and 1 mL of DMF, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04 and concentrated. The obtained residue, diluted with MeOH, is purified by preparative RP- HPLC to afford compound 1081.
Exam le 32: Preparation of compound 1082
Figure imgf000050_0001
To a suspension of 28a (25 mg, 0.052 mmol), in 1 .5 ml. of THF, is added DIEA (0.050 ml_, 0.287 mmol) followed by methyl isocyanate (0.010 ml_, 0.162 mmol). The resulting solution is stirred for 3 hours at RT. The solvent is evaporated in vacuo. The residue, diluted with H20 and 1 ml. of DMF, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04 and concentrated. The obtained residue, diluted with MeOH, is purified by preparative RP- HPLC to afford compound 1082.
Exam le 33: Preparation of compound 1083
Figure imgf000050_0002
To a suspension of 28a (25 mg, 0.052 mmol), in 1 .5 mL of THF, is added DIEA (0.050 mL, 0.287 mmol) followed by dimethylcarbamyl chloride (0.010 mL, 0.162 mmol). The resulting solution is stirred at RT overnight. The solvent is evaporated in vacuo. The residue, diluted with H20 and 1 mL of DMF, is extracted twice with EtOAc. The combined organic extracts are dried over MgS04 and concentrated. The obtained residue, diluted with MeOH, is purified by preparative RP- HPLC to afford compound 1083.
Example 34: Preparation of intermediate 34c
Figure imgf000051_0001
34c
Step 1 :
A mixture of isoamylamine (0.99 mL, 8.49 mmol, Aldrich), 5-bromo-2-chlorobenzoic acid (1 .0 g, 4.25 mmol, Aldrich), potassium carbonate (587.0 mg, 4.25 mmol), copper powder (27.0 mg, 0.425 mmol) and copper(l) oxide (30.4 mg, 0.212 mmol) in DME (10 mL) is heated to 100°C for 1 .5 hours. The reaction mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and the mixture is extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 34a.
Step 2: To a solution of 34a (930 mg, 3.25 mmol) in DMF (12 ml.) at RT is added HATU (1 .54 g, 4.06 mmol), TEA (1 .81 ml_, 13.0 mmol), then ammonium bicarbonate (770.8 mg, 9.75 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 34b.
Step 3:
To a solution of the 34b (700 mg, 2.46 mmol) in AcOH (10 ml.) is added chloro-acetyl chloride (0.59 ml_, 7.36 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 34c, which is used as such in subsequent steps.
Example 35: Preparation of intermediate 35c
Figure imgf000052_0001
35a 35b 35c
Step 1 :
A mixture of 3-methanesulfonyl-propylamine hydrochloride (181 .8 mg, 1 .05 mmol, Enamine), 2- 5-dichlorobenzoic acid (100 mg, 0.524 mmol, Aldrich), potassium carbonate (144.7 mg, 1 .05 mmol), copper powder (3.3 mg, 0.052 mmol) and copper(l) oxide (3.7 mg, 0.026 mmol) in DME (3 ml.) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and the mixture is extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 90:10) to afford 35a.
Step 2: To a solution of the 35a (40.5 mg, 0.139 mmol) in DMF (3 mL) at RT is added HATU (65.9 mg, 0.173 mmol), TEA (0.077 mL, 0.55 mmol), then ammonium bicarbonate (32.9 mg, 0.416 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 90:10) to afford 35b.
Step 3:
To a solution of 35b (37.0 mg, 0.127 mmol) in AcOH (5 mL) is added chloro-acetyl chloride (0.030 mL, 0.382 mmol). The mixture is heated to 100°C for 1 hour. The reaction is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 35c, which is used as such in subsequent steps.
Example 36: Preparation of intermediate 36c
Figure imgf000053_0001
36a 36b 36c
Step 1 :
A mixture of 4,4,4-trifluorobutylamine (332.7 mg, 2.618 mmol, Enamine), 2-5-dichlorobenzoic acid (250 mg, 1 .309 mmol, Aldrich), potassium carbonate (180.9 mg, 1 .309 mmol), copper powder (8.3 mg, 0.131 mmol) and copper(l) oxide (9.4 mg, 0.065 mmol) in DME (3 mL) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 90:10) to afford 36a.
Step 2: To a solution of 36a (206.0 mg, 0.731 mmol) in DMF (6 ml.) at RT is added HATU (347.0 mg, 0.913 mmol), TEA (0.408 ml_, 2.93 mmol), then ammonium bicarbonate (173.5 mg, 2.194 mmol). The reaction is stirred at RT for 2 hours. EtOAc and water are added to the mixture. The layers are separated and the organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtO Ac 100:0 to 70:30) to afford 36b.
Step 3:
To a solution of 36b (164.0 mg, 0.584 mmol) in AcOH (5 ml.) is added chloro-acetyl chloride (0.14 ml_, 1 .75 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 36c, which is used as such in subsequent steps.
Example 37: Preparation of intermediate 37c
Figure imgf000054_0001
37a 37b 37c
Step 1 :
A mixture of 3-methylbutylamine (0.243 ml_, 2.09 mmol, Aldrich), 2-5-dichlorobenzoic acid (200 mg, 1 .047 mmol, Aldrich), potassium carbonate (144.7 mg, 1 .047 mmol), copper powder (6.7 mg, 0.105 mmol) and copper(l) oxide (7.5 mg, 0.052 mmol) in DME (2 ml.) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 0:100) to afford 37a.
Step 2: To a solution of 37a (100 mg, 0.414 mmol) in DMF (5 mL) at RT is added HATU (196.3 mg, 0.517 mmol), TEA (0.23 mL, 1 .66 mmol), then ammonium bicarbonate (98.1 mg, 1 .241 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 0:100) to afford 37b.
Step 3:
To a solution of 37b (85.0 mg, 0.353 mmol) in AcOH (4 mL) is added chloro-acetyl chloride (0.084 mL, 1 .059 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 37c, which is used as such in subsequent steps.
Example 38: Preparation of intermediate 38d
Figure imgf000055_0001
38b 38c 38d
Step 1 :
To a solution of 4-aminobutanol (2.08 mL, 22.44 mmol, Aldrich) in DCM (20 mL) is added TEA (3.44 mL, 24.68 mmol) at 0°C. Tert-butyldimethylchlorosilane (3.72 g, 24.68 mmol, Aldrich) is added at the same temperature and stirred at RT for 18 hours. The reaction mixture is diluted with water. The organic layer is washed with water and brine, dried over MgS04, filtered and concentrated to give crude 38a, which is used as such for the next step.
Step 2: A mixture of 38a (532.4 mg, 2.62 mmol), 2-5-dichlorobenzoic acid (250 mg, 1 .309 mmol, Aldrich), potassium carbonate (180.9 mg, 1 .309 mmol), copper powder (8.3 mg, 0.131 mmol) and copper(l) oxide (9.4 mg, 0.065 mmol) in DME (3 ml.) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 38b.
Step 3:
To a solution of 38b (220 mg, 0.615 mmol) in DMF (6 ml.) at RT is added HATU (291 .6 mg, 0.767 mmol), TEA (0.34 ml_, 2.46 mmol), then ammonium bicarbonate (145.8 mg, 1 .84 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 38c.
Step 4:
To a solution of 38c (182.0 mg, 0.510 mmol) in AcOH (5 ml.) is added chloro-acetyl chloride (0.12 ml_, 1 .53 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 38d, which is used as such in subsequent steps.
Example 39: Preparation of intermediate 39c
Figure imgf000056_0001
39a 39b
Step 1 :
A mixture of 3-methylbutylamine (1 .22 ml_, 10.47 mmol, Aldrich), 2-4-dichlorobenzoic acid (1 .0 g, 5.23 mmol, Aldrich), potassium carbonate (723.6 mg, 5.24 mmol), copper powder (33.3 mg,
37.5 mmol) and copper(l) oxide (37.5 mg, 0.262 mmol) in DME (15 ml.) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then is extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 50:50) to afford 39a.
Step 2:
To a solution of 39a (852.0 mg, 3.53 mmol) in DMF (15 mL) at RT is added HATU (1 .67 g, 4.40 mmol), TEA (1 .97 mL, 14.10 mmol), then ammonium bicarbonate (836.0 mg, 10.57 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 60.40) to afford 39b.
Step 3:
To a solution of 39b (523.9 mg, 2.176 mmol) in AcOH (6 mL) is added chloro-acetyl chloride (0.433 mL, 5.44 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated on the rotovap. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 39c, which is used as such in subsequent steps.
Example 40: Preparation of intermediate 40c
Figure imgf000057_0001
40a 40b
Step 1 :
A mixture of 3-methylbutylamine (1 .97 mL, 16.99 mmol, Aldrich), 4-bromo-2-chlorobenzoic acid (2.0 g, 8.49 mmol, Aldrich), potassium carbonate (1 .17 mg, 8.49 mmol), copper powder (54.0 mg, 0.849 mmol) and copper(l) oxide (60.8 mg, 0.425 mmol) in DME (40 mL) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 50:50) to afford 40a.
Step 2:
To a solution of 40a (1 .60 g, 5.60 mmol) in DMF (20 mL) at RT is added HATU (2.66 g, 6.992 mmol), TEA (3.12 mL, 22.4 mmol), and then ammonium bicarbonate (1 .33 g, 16.8 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is triturated in DCM/Hex to afford 40b.
Step 3:
To a solution of 40b (1 .35 g, 4.73 mmol) in AcOH (12 mL) is added chloro-acetyl chloride (0.94 mL, 1 1 .84 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 40c, which is used as such in subsequent steps.
Example 41 : Preparation of intermediate 41 c
Figure imgf000058_0001
41a 41 b 41c
Step 1 :
A mixture of 3-methylbutylamine (1 .36 mL, 1 1 .72 mmol, Aldrich), 2-chloro-6-methylbenzoic acid (1 .0 g, 5.86 mmol, Aldrich), potassium carbonate (810.2 mg, 5.86 mmol), copper powder (37.3 mg, 0.586 mmol) and copper(l) oxide (41 .9 mg, 0.293 mmol) in DME (10 mL) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 41a.
Step 2:
To a solution of 41 a (581 .0 mg, 2.63 mmol) in DMF (20 mL) at RT is added HATU (1 .25 g, 3.28 mmol), TEA (1 .46 mL, 10.50 mmol), and then ammonium bicarbonate (0.63 g, 7.88 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 50:50) to afford 41 b.
Step 3:
To a solution of 41 b (255.0 mg, 1 .157 mmol) in AcOH (10 mL) is added chloro-acetyl chloride (0.28 mL, 3.47 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 41 c, which is used as such in subsequent steps.
Example 42: Preparation of intermediate 42c
Figure imgf000059_0001
42a 42b 42c
Step 1 :
A mixture of 3-methylbutylamine (1 .33 mL, 1 1 .46 mmol, Aldrich), 2-chloro-6-methylbenzoic acid (1 .0 g, 5.73 mmol, Aldrich), potassium carbonate (791 .8 mg, 5.73 mmol), copper powder (36.4 mg, 0.573 mmol) and copper(l) oxide (41 .0 mg, 0.286 mmol) in DME (20 mL) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 70:30) to afford 42a.
Step 2:
To a solution of 42a (710.0 mg, 3.15 mmol) in DMF (20 mL) at RT is added HATU (1 .50 g, 3.94 mmol), TEA (1 .76 mL, 12.61 mmol), and then ammonium bicarbonate (0.75 g, 9.46 mmol). The mixture is stirred at RT for 2 hours. EtOAc and water are added to the mixture and the layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (Hex/EtOAc 100:0 to 80:20) to afford 42b.
Step 3:
To a solution of 42b (463 mg, 2.064 mmol) in AcOH (10 mL) is added chloro-acetyl chloride (0.49 mL, 6.19 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 42c, which is used as such in subsequent steps.
Example 43: Preparation of intermediate 43c
Figure imgf000060_0001
Step 1 :
A mixture of 4-aminobutan-1 -ol (0.97 mL, 10.47 mmol, Aldrich), 2-4-dichlorobenzoic acid (1 .0 g, 5.23 mmol, Aldrich), potassium carbonate (723.6 mg, 5.24 mmol), copper powder (33.3 mg, 0.524 mmol) and copper(l) oxide (37.5 mg, 0.262 mmol) in DME (20 mL) is heated to 100°C for 1 .5 hours. The mixture is cooled to RT, and water is added. The mixture is neutralized with HCI 1 N until slightly acidic (pH 5-6) and then extracted with EtOAc (3x). The organic layers are combined, washed with water (2x), NH4CI saturated (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (DCM/MeOH 100:0 to 90:10) to afford 43a.
Step 2:
To a solution of 43a (830 mg, 3.41 mmol) in DMF (15 mL) at RT is added HATU (1 .62 g, 4.25 mmol), TEA (1 .90 mL, 13.62 mmol), then ammonium bicarbonate (807.8 mg, 10.2 mmol). The mixture is stirred at RT for 2 hours and then EtOAc and water are added to the mixture. The layers are separated. The organic layer is washed with water (2x), NaHC03 saturated and brine, dried over MgS04, filtered and concentrated to afford 43b, which is re-crystallized from EtOAc.
Step 3:
To a solution of 43b (50.0 mg, 0.206 mmol) in AcOH (5 mL) is added chloro-acetyl chloride (0.049 mL, 0.618 mmol). The mixture is heated to 100°C for 1 hour. The mixture is cooled to RT and concentrated to dryness. The residue is diluted with EtOAc, washed with NaHC03 saturated (2x) and brine (2x), dried over MgS04, filtered and concentrated to provide 43c, which is used as such in subsequent steps.
Ex mple 44: Preparation of compound 1060
Figure imgf000061_0001
To a solution of 4-methyl-2-oxo-1 ,2-dihydroquinoline-3-carbonitrile (21 .4 mg, 0.1 16 mmol, Matrix) in DMF (1 mL, containing 15% of water) is added potassium carbonate (48.3 mg, 0.349 mmol). The mixture is stirred at RT for 10 minutes, then 34c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1060.
Example 45: Preparation of compound 1040
Figure imgf000062_0001
34c 1 c 1040
To a solution of 1 c (25.3 mg, 0.145 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.045 mL, 0.582 mmol). The mixture is stirred at RT, then 34c (25.3 mg, 0.145 mmol) is added to as a DMA solution (1 mL). This mixture is stirred at RT for 3 hours, then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1040.
Exam le 46: Preparation of compound 1058
Figure imgf000062_0002
1040 1058
Nitrogen gas is bubbled through a solution of compound 1040 (44.0 mg, 0.091 mmol) in DMF (3 mL) for 5 minutes. To this mixture is added zinc cyanide (10.7 mg, 0.091 mmol, Aldrich) and Pd(PPh3)4 (10.6 mg, 0.009 mmol). The reaction mixture is heated in a microwave at 130°C for 10 minutes. The mixture is diluted with EtOAc, washed with water (2x) and brine (2x), dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1058. Exam le 47: Preparation of compound 1041
Figure imgf000063_0001
34c 9c 1041
To a solution of 9c (28.0 mg, 0.145 mmol) in DMF (2 mL, containing 15% of water) is added cesium carbonate (142.2 mg, 0.436 mmol). The mixture is stirred at RT for 10 minutes, then 34c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1041.
Example 48: Preparation of compound 1042
Figure imgf000063_0002
34c 5c 1042
To a solution of 5c (31 .9 mg, 0.145 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (142.2 mg, 0.436 mmol). The reaction is stirred at RT for 10 minutes, then 34c is added, as a solution in DMF (1 mL), to the mixture. The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1042.
Example 49: Preparation of compound 1043
Figure imgf000064_0001
34c 6c 1043
To a solution of 6c (36.9 mg, 0.145 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (142.2 mg, 0.436 mmol). The mixture is stirred at RT for 10 minutes, then 34c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1043.
Exam le 50: Preparation of compound 1044
Figure imgf000064_0002
34c 1044
To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (25.5 mg, 0.145 mmol, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added cesium carbonate (142.2 mg, 0.436 mmol). The mixture is stirred at RT for 10 minutes, then 34c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1044.
Exam le 51 : Preparation of compound 1045
Figure imgf000065_0001
35c 1c 1045
To a solution of 1 c (1 1 .0 mg, 0.063 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (61 .6 mg, 0.189 mmol). The mixture is stirred at RT for 10 minutes, then 35c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1045.
Exam le 52: Preparation of compound 1046
Figure imgf000065_0002
35c 1046 To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (1 1 .0 mg, 0.063 mmol, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added cesium carbonate (61 .6 mg, 0.189 mmol). The mixture is stirred at RT for 10 minutes, then 35c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1046.
Exam le 53: Preparation of compound 1047
Figure imgf000066_0001
36c 1 c 1047
To a solution of 1 c (25.7 mg, 0.147 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (144.1 mg, 0.442 mmol). The mixture is stirred at RT for 10 minutes, then 36c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1047.
Exam le 54: Preparation of compound 1048
Figure imgf000067_0001
36c 1048
To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (25.8 mg, 0.147 mmol, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added cesium carbonate (144.1 mg, 0.442 mmol). The mixture is stirred at RT for 10 minutes, then 36c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1048.
Example 55: Preparation of compound 1049
Figure imgf000067_0002
36c 5c 1049
To a solution of 5c (32.3 mg, 0.147 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.046 mL, 0.590 mmol). The mixture is stirred at RT, then 36c (50.0 mg, 0.147 mmol) is added as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1049.
Example 56: Preparation of compound 1050
Figure imgf000068_0001
36c 6c 1050
To a solution of 6c (37.3 mg, 0.147 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.046 mL, 0.590 mmol). The reaction is stirred at RT, then 36c (50.0 mg, 0.147 mmol) is added as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours. The reaction is diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1050.
Exam le 57: Preparation of compound 1020
Figure imgf000068_0002
37c 1020
To a solution of 1 -Cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (29.3 mg, 0.167 mmol, Beta Pharma Scientific) in DMA (1 .0 mL) is added KOH 12.7N in water (0.053 mL, 0.668 mmol). The reaction is stirred at RT, then 37c (50.0 mg, 0.167 mmol) is added to the mixture as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours. The reaction is diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1020.
Exam le 58: Preparation of compound 1036
Figure imgf000069_0001
37c 1 c 1036
To a solution of 1 c (29.1 mg, 0.167 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.053 mL, 0.668 mmol). The reaction is stirred at RT, then 37c (50.0 mg, 0.167 mmol) is added to the mixture as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours. The reaction is diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is then diluted in AcOH (1 mL) and heated to reflux for 1 hour. The solvent is removed under vacuum and the residue is purified by preparative RP- HPLC to provide compound 1036.
Exam le 59: Preparation of compound 1037
Figure imgf000069_0002
37c 9c 1037
To a solution of 9c (32.1 mg, 0.167 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.053 mL, 0.668 mmol). The reaction is stirred at RT, then 37c (50.0 mg, 0.167 mmol) is added to the mixture as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is diluted in AcOH (1 mL) and heated to reflux for 1 hour. The solvent is removed under vacuum and the residue is purified by preparative RP- HPLC to provide compound 1037.
Example 60: Preparation of compound 1038
Figure imgf000070_0001
37c 5c 1038
To a solution of 5c (36.6 mg, 0.167 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.053 mL, 0.668 mmol). The mixture is stirred at RT, then 37c (50.0 mg, 0.167 mmol) is added as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is diluted in AcOH (1 mL) and heated to reflux for 1 hour. The solvent is removed under vacuum and the residue is purified by preparative RP- HPLC to provide compound 1038.
Example 61 : Preparation of compound 1039
Figure imgf000071_0001
37c 6c 1039
To a solution of 6c (42.3 mg, 0.167 mmol) in DMA (1 .0 mL) is added KOH 12.7N in water (0.053 mL, 0.668 mmol). The mixture is stirred at RT, then 37c (50.0 mg, 0.167 mmol) is added as a DMA solution (1 mL). The mixture is stirred at RT for 3 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is diluted in AcOH (1 mL) and heated to reflux for 1 hour. The solvent is removed under vacuum and the residue is purified by preparative RP- HPLC to provide compound 1039.
Example 62: Preparation of compounds 1055 and 1056
Figure imgf000071_0002
38d 5c 1055 1056
To a solution of 5c (26.3 mg, 0.120 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (1 17.3 mg, 0.360 mmol). The mixture is stirred at RT for 10 minutes, then 38d is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compounds 1055 and 1056. Ex mple 63: Preparation of compounds 1051 and 1052
Figure imgf000072_0001
38d 1c 1051 1052
To a solution of 1 c (20.9 mg, 0.120 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (1 17.3 mg, 0.360 mmol). The mixture is stirred at RT for 10 minutes, then 38d is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compounds 1051 and 1052.
Ex mple 64: Preparation of compounds 1053 and 1054
Figure imgf000072_0002
38d 1053 1054
To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (21 .0 mg, 0.120 mmol, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added cesium carbonate (1 17.3 mg, 0.360 mmol). The reaction is stirred at RT for 10 minutes, then 38d is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compounds 1053 and 1054.
Exam le 65: Preparation of compound 1057
Figure imgf000073_0001
To a solution of 1 c (17.8 mg, 0.102 mmol) in DMF (1 mL, containing 15% of water) is added cesium carbonate (99.7 mg, 0.360 mmol). The mixture is stirred at RT for 10 minutes, then 43c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1057.
Exam le 65: Preparation of compound 1059
Figure imgf000073_0002
39c 1059
To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (24.6 mg, 0.140 mmol, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added potassium carbonate (77.6 mg, 0.562 mmol). The mixture is stirred at RT for 10 minutes, then 39c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1059.
Example 67: Preparation of compound 1075
Figure imgf000074_0001
40c 67a 1075
Step 1 :
To a solution of 1 -Cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (362.0 mg, 2.07 mmol, Beta Pharma Scientific) in DMF (15 mL, containing 15% of water) is added potassium carbonate (1 .142 g, 8.26 mmol). The reaction is stirred at RT for 10 minutes, then 40c is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by Combiflash (DCM/MeOH 100:0 to 90:10) to afford 67a.
Step 2:
To a solution of 67a (40.0 mg, 0.083 mmol) and 3-pyridineboronic acid (12.2 mg, 0.100 mmol, Aldrich) in a mixture of dioxane (2 mL) and water (0.25 mL), is added potassium carbonate (34.4 mg, 0.249 mmol). The mixture is purged with argon for 5 minutes, then Pd(PPh3)4 (9.6 mg, 0.008 mmol) is added. The mixture is heated at 120°C for 1 .5 hours, then is cooled to RT. Water is added with DCM and this mixture is stirred for 5 minutes. The mixture is passed through a phase separator and the aqueous layer is washed twice with DCM. The organic layer is concentrated to dryness. The residue is diluted with DMF/MeOH and purified by preparative RP- HPLC to provide compound 1075.
Example 68: Preparation of compound 1006
Figure imgf000075_0001
41 c 1006
To a solution of 41 c (25 mg, 0.090 mmol) and 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2- one (17 mg, 0.097 mmol, Beta Pharma Scientific), in DMF (1 mL), is added Cs2C03 (88 mg, 0.27 mmol). The resulting suspension is stirred at RT for 1 hour. The mixture, diluted with H20, is purified by preparative RP- HPLC to provide compound 1006.
Exam le 69: Preparation of compound 1007
Figure imgf000075_0002
41c 1c 1007
To a solution of 41 c (25 mg, 0.090 mmol) and 1 c (17 mg, 0.098 mmol), in DMF (1 mL), is added Cs2C03 (88 mg, 0.27 mmol). The resulting suspension is stirred at RT for 1 hour. The mixture, diluted with H20, is purified by preparative RP- HPLC to provide compound 1007.
Example 70: Preparation of compound 1088
Figure imgf000076_0001
41 C 8d 1088
To a solution of 8d (31 .4 mg, 0.179) in DMF (1 mL, containing 15% of water) is added potassium carbonate (99.2 mg, 0.717 mmol). The mixture is stirred at RT for 10 minutes, then 41 c (50.0 mg, 0.179 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1088.
Example 71 : Preparation of compound 1089
Figure imgf000076_0002
41 c 5c 1089
To a solution of 5c (39.3 mg, 0.179) in DMF (1 mL, containing 15% of water) is added potassium carbonate (99.2 mg, 0.717 mmol). The mixture is stirred at RT for 10 minutes, then 41 c (50.0 mg, 0.179 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1089. Example 72: Preparation of compound 1090
Figure imgf000077_0001
41 c 2c 1090
To a solution of 2c (34.3 mg, 0.179) in DMF (1 mL, containing 15% of water) is added potassium carbonate (99.2 mg, 0.717 mmol). The mixture is stirred at RT for 10 minutes, then 41 c (50.0 mg, 0.179 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1090.
Exam le 73: Preparation of compound 1084
Figure imgf000077_0002
42c 1 c 1084
To a solution of 1 c (30.8 mg, 0.177) in DMF (1 mL, containing 15% of water) is added potassium carbonate (97.8 mg, 0.707 mmol). The mixture is stirred at RT for 10 minutes, then 42c (50.0 mg, 0.177 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1084.
Exam le 74: Preparation of compound 1085
Figure imgf000078_0001
42c 1085
To a solution of 1 -cyclopropyl-1 ,3-dihydro-imidazo[4,5-c]pyridin-2-one (31 .0 mg, 0.177, Beta Pharma Scientific) in DMF (1 mL, containing 15% of water) is added potassium carbonate (97.8 mg, 0.707 mmol). The mixture is stirred at RT for 10 minutes, then 42c (50.0 mg, 0.177 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1085.
Exam le 75: Preparation of compound 1086
Figure imgf000078_0002
42c 8d 1086
To a solution of 8d (31 .0 mg, 0.177) in DMF (1 mL, containing 15% of water) is added potassium carbonate (97.8 mg, 0.707 mmol). The mixture is stirred at RT for 10 minutes, then 42c (50.0 mg, 0.177 mmol) is added, as a solution in DMF (1 mL). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1086.
Example 76: Preparation of compound 1087
Figure imgf000079_0001
42c 5c 1087
To a solution of 5c (38.8 mg, 0.177) in DMF (1 ml_, containing 15% of water) is added potassium carbonate (97.8 mg, 0.707 mmol). The mixture is stirred at RT for 10 minutes, then 42c (50.0 mg, 0.177 mmol) is added, as a solution in DMF (1 ml_). The mixture is stirred at RT for 2 hours, and then diluted with EtOAc and water. The layers are separated and the aqueous layer is extracted twice with EtOAc. The organic layers are combined, washed with water (2x) and brine, dried over MgS04, filtered and concentrated. The residue is purified by preparative RP- HPLC to provide compound 1087.
Table 1 lists the UPLC or HPLC retention time and M+ peak for compounds 1001 -1090.
Retention times (tR) for each compound are measured using the standard analytical UPLC or HPLC conditions described in the Examples. As is well known to one skilled in the art, retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different UPLC or HPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual UPLC or HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual
measurements taken on different occasions. TABLE 1
Cmpd # [M+H]+ tR (min) Cmpd # [M+H]+ tp (min)
1001 404.6 1.31 1046 488.3 1.09
1002 377.6 1.64 1047 477.3 1.93
1003 417.1 1.84 1048 478.3 1.53
1004 403 1.77 1049 522.3 1.55
1005 406.3 1.81 1050 556.3 1.44
1006 418.6 1.54 1051 439.3 1.6
1007 417.3 1.9 1052 481.2 1.29
1008 446.4 1.21 1053 440.3 1.13
1009 445.4 1.67 1054 482.3 1.37
1010 447.4 1.73 1055 484.3 1.17
1011 425.3 1.31 1056 526.4 1.39
1012 423 1.81 1057 481.3 1.75
1013 458.3 1.52 1058 428.4 1.79
1014 457.3 1.94 1059 438.3 1.64
491.3
1015 403.3 1.24 1060 2.08
493.3
1016 444.3 1.27 1061 488.5 1.68
1017 443.3 1.78 1062 546.5 2.04
1018 405.3 1.42 1063 446.4 1.44
1019 447.4 1.6 1064 420.3 1.3
1020 438.6 1.08 1065 434.4 1.37
1021 407.3 1.49 1066 434.4 1.37
1022 448.4 1.42 1067 420.4 1.15
1023 482.3 1.3 1068 419.4 1.68
1024 448.3 1.13 1069 418.3 1.36
1025 454.3 0.82 1070 432.3 1.44
1026 406.3 0.87 1071 404 1.69
1027 453.3 1.39 1072 501.5 1.21
1028 421.4 1.86 1073 446.4 1.49
1029 438.4 1.33 1074 406.4 1.18
1030 437.3 1.82 1075 481.4 1.47
1031 423.3 1.45 1076 524.4 1.7
1032 432.3 1.04 1077 433.4 1.59
1033 431.4 1.55 1078 419.3 1.44
1034 446.4 1.15 1079 606.4 1.9
1035 445.4 1.63 1080 504.5 1.83
1036 437.3 1.97 1081 531.5 1.5
1037 455.3 1.98 1082 503.5 1.68
1038 482.4 1.63 1083 517.5 1.78
1039 398.3 1.45 1084 421.3 1.8
481.3
1040 2.00 1085 422.3 1.31
483.3
499.3
1041 2.00 1086 422.5 1.64
501.3
1042 526.3 1.67 1087 466.4 1.36 528.3
560.3
1043 1 .57 1088 418.6 1 .84
562.3
482.3
1044 1 .65 1089 462.4 1 .62
484.3
1045 487.2 1 .1 1 1090 434.4 1 .53
Example A: RSV cytopathic effect
Compounds of the invention are initially tested in a cytopathic effect (CPE)-based viral replication assay using immortalized cells and a laboratory strain of RSV (Long). This assay evaluates the ability of a compound to inhibit viral replication.
Procedure:
Assay plates are prepared by seeding 2,500 HEp-2 cells (ATCC) per well of a 384-well black clear-bottom plate (Greiner Bio-One) in 20 μΙ_ of assay media (defined as DMEM supplemented with 2% heat-inactivated fetal bovine serum and 1 % Penicillin/Streptomycin). Assay plates are incubated overnight at 37 <C in an incubator containing 5% C02. The following day, a 10-point serial dilution of test compound is prepared in DMSO. Compounds are subsequently diluted with assay media and 20 μΙ_ of diluted compound (containing 1 .5% DMSO) is transferred to an assay plate for evaluation of antiviral activity.
For the CPE assay, cells are infected at a MOI of 0.015 using 20 μΙ_ of RSV Long (ATCC) diluted in assay media. The DMSO concentration is constant throughout the assay plate, including the negative and positive controls. The assay plate is incubated for 3 days at 37 °C in an incubator containing 5% C02. Cell viability is evaluated with the addition of 10 μΐ of CellTiter- Glo (ProMega). Luminescence is measured using an EnVision plate reader (Perkin Elmer). EC50 values are calculated using the raw data from the CPE assays.
All compounds of the invention, namely compounds 1001 -1090 are tested in the assay described in Example A. Compounds tested in the assay of Example A showed EC50 values in the range of 10 μΜ or less. Representative data is shown in the table below:
Figure imgf000081_0001
Example A
1001 180
1003 1600
1010 170
1013 2100
1017 130
1018 190
1023 3200
1040 210
1047 400
1060 1200
1070 2600
1075 1200
1076 5.8
1081 75
1089 790
Each reference, including all patents, patent applications, and publications cited in the present application is incorporated herein by reference in its entirety, as if each of them is individually incorporated. Further, it would be appreciated that, in the above teaching of invention, the skilled in the art could make certain changes or modifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended claims of the application.

Claims

1 . A compound having Formula (I), or racemate, enantiomer, diastereoisomer or tautomer thereof:
Figure imgf000083_0001
wherein
R1 is an 8-14 membered heterocycle or heteroaryl optionally substituted 1 to 4 times with substituents each independently selected from the group consisting of R1A, oxo, halo, -CN, (d. 6)haloalkyl, OH, -0(Ci-6)alkyl, -C(=0)OH and
Figure imgf000083_0002
R1 A is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl are optionally mono-, di- or tri-substituted with substituents each independently selected from the group consisting of (Ci_6)alkyl, (Ci-6)haloalkyl, halo, -CKC^alkyl, -CN, NH2, -N(H)R1 B, -N((C1_6)alkyl)2, -C(=0)OH, -C(=0)-R1 B, -C(=0)-(C^ 6)alkyl-N((C1_6)alkyl)2, -C(=0)-0-R1 B, -C(=0)-NH2, -C(=0)-N(H)R1 B, -C(=0)-N((C1_6)alkyl)2, - SO^d^haloalkyl or -S02R1 B;
R1 B is (Ci-6)alkyl, (C3-7)cycloalkyl, aryl, heteroaryl or heterocyclyl;
R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-aryl, -(Ci-6)alkyl-heteroaryl or -(Ci-6)alkyl- heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl, either alone or in combination with another moiety, are optionally mono-, di- or tri-substituted with
substituents each independently selected from the group consisting of halo, -CN, OH, -COOH, - (Ci-6)alkyl, -0-(Ci-6)alkyl, (C3-7)cycloalkyl, (Ci-6)haloalkyl, -0-C(=0)-R2A, -C(=0)-0-R2A, -S02NH2, -S02-N(H)R2A, -S02-N((Ci-6)alkyl)2, -SOR2A, -S02R2A, -C(=0)-NH2, -C(=0)-N(H)R2A,
-C(=0)-N((C1_6)alkyl)2, -C(=0)-NH-S02R2A, -S02-NH-C(=0)R2A, -NH2, -N(H)R2A, -N((C1_6)alkyl)2, -NH-C(=0)R2A, -NH-C(=0)0-R2A and -C(=0)-R2A (optionally substituted with (C^alkyl); R is (C1-6)alkyl, (C3.7)cycloalkyl, aryl, heteroaryl or heterocyclyl;
R3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH, - (Ci-6)alkyl, -0-(Ci-6)alkyl, (C3-7)cycloalkyl, (Ci-6)haloalkyl,
Figure imgf000084_0001
-S02NH2, -S02- NH(Ci-6)alkyl, -S02-N((Ci-6)alkyl)2, -SO(Ci-6)alkyl, -S02(Ci-6)alkyl, -C(=0)-NH2,
Figure imgf000084_0002
(Ci-6)alkyl, -NH2, -NH(Ci-6)alkyl, -N((Ci-6)alkyl)2, -NH(C3-7)cycloalkyl,
-N((C1_6)alkyl)(C3-7)cycloalkyl, -NH-C(=0)(C1_6)alkyl, -NH-C(=0)0(C1_6)alkyl and R3a;
R3a is heterocyclyl or heteroaryl, wherein each said heterocyclyl and heteroaryl is optionally mono-, di- or tri-substituted with (d-6)alkyl; n is 0, 1 , 2 or 3;
or a salt thereof.
2. The compound according to claim 1 , wherein R1 is a 9-14 membered heterocycle or heteroaryl optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R1A, oxo, halo, -CN, (d^haloalkyl, OH and -©(Chalky!;
R1A is (Ci-6)alkyl, (C3-7)cycloalkyl or heterocycle, wherein each said alkyl, cycloalkyl, and heterocycle are optionally mono- or di-substituted with substituents each independently selected from the group consisting of (Ci_4)alkyl, (Ci-4)haloalkyl, halo, -0(Ci-4)alkyl, -CN, NH2, NH(Ci- 6)alkyl, N((Ci-4)alkyl)2,
Figure imgf000084_0003
- C(=0)-NH2,
Figure imgf000084_0004
-S02(Ci-4)haloalkyl and -S02(Ci-4)alkyl; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein
R is
Figure imgf000084_0005
, optionally mono, di- or tri-substituted with substituents each independently selected from the group consisting of R1A, halo, -CN, (Ci- 6)haloalkyl, OH and -Oid^alkyl; R1A is (C1-6)alkyl, (C3.7)cycloalkyl or heterocycle, wherein each said alkyl, cycloalkyi, and heterocycle are optionally mono- or di-substituted with substituents each independently selected from the group consisting of (d-4)alkyl, (Ci-4)haloalkyl, halo, -0(Ci-4)alkyl, -CN, NH2, NH(Ci- 6)alkyl, N((Ci-4)alkyl)2,
Figure imgf000085_0001
- C(=0)-NH2,
Figure imgf000085_0002
-S02(Ci-4)haloalkyl and -S02(Ci-4)alkyl; or a pharmaceutically acceptable salt thereof.
4. The compound according to any one of claims 1 to 3, wherein
R2 is (Ci-6)alkyl, -(Ci-6)alkyl-(C3-7)cycloalkyl, -(Ci-6)alkyl-aryl, -(Ci-6)alkyl-heteroaryl or -(d-6)alkyl- heterocyclyl, wherein each said alkyl, cycloalkyi, aryl, heteroaryl and heterocyclyl are optionally mono- or di-substituted with substituents each independently selected from the group consisting of halo, -CN, OH, -COOH, -(d_6)alkyl, -0-(d_6)alkyl, (C3-7)cycloalkyl, (d_6)haloalkyl, -O- C(=0)-(C1_6)alkyl, -S02(d_6)alkyl, -C(=0)-NH2, and -C(=0)-heterocycle (optionally substituted with (Ci-6)alkyl); or a pharmaceutically acceptable salt thereof.
5. The compound according claim 4, wherein
R2 is (C1-6)alkyl, -(C1.6)alkyl-(C3.7)cycloalkyl, -(d-6)alkyl-phenyl or -(d.6)alkyl-5- or 6-membered heterocyclyl, wherein each said alkyl, phenyl and heterocyclyl are optionally mono- or di- substituted with substituents each independently selected from the group consisting of halo, - CN, OH, -COOH, -(Ci-4)alkyl, -0-(Ci-4)alkyl, (C3-7)cycloalkyl, (Ci-4)haloalkyl,
Figure imgf000085_0003
-S02(Ci-4)alkyl and -C(=0)-NH2; or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1 to 5, wherein
R3 is each independently selected from the group consisting of H, halo, -CN, OH, -COOH, - (d_6)alkyl, -0-(d_6)alkyl, (C3_7)cycloalkyl, (d_6)haloalkyl, -NH2, -NH(d_6)alkyl and
-N((d_6)alkyl)2; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6, wherein R3 is each independently selected from the group consisting of H, halo, -CN, OH, (C1-6)alkyl, -O- (Ci-6)alkyl, (C3-7)cycloalkyl and (d-6)haloalkyl; or a pharmaceutically acceptable salt thereof.
8. The compound according to any one of claims 1 to 7, or wherein n is 0 or 1 ; a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8, wherein n is 0; or a pharmaceutically acceptable salt thereof.
10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, as a medicament.
1 1 . Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of RSV infection in a human being.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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