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WO2024126250A1 - Dérivés d'imidazotriazine en tant que modulateurs d'il-17 - Google Patents

Dérivés d'imidazotriazine en tant que modulateurs d'il-17 Download PDF

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Publication number
WO2024126250A1
WO2024126250A1 PCT/EP2023/084705 EP2023084705W WO2024126250A1 WO 2024126250 A1 WO2024126250 A1 WO 2024126250A1 EP 2023084705 W EP2023084705 W EP 2023084705W WO 2024126250 A1 WO2024126250 A1 WO 2024126250A1
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formula
compound
pharmaceutically acceptable
treatment
acceptable salt
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Jeffrey BRUFFAERTS
Gregory William HASLETT
James Thomas Reuberson
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UCB Biopharma SRL
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UCB Biopharma SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted imidazo[1,2-b][1,2,4]triazine derivatives. These compounds act as modulators of IL-17 activity, and are accordingly of benefit as pharmaceutical agents for the treatment and/or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.
  • IL-17A (originally named CTLA-8 and also known as IL-17) is a pro- inflammatory cytokine and the founder member of the IL-17 family (Rouvier et al., J. Immunol., 1993, 150, 5445-5456).
  • IL-17B to IL-17F five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174).
  • IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Th17, that also express IL-21 and IL-22 signature cytokines (Korn et al., Ann. Rev. Immunol., 2009, 27, 485-517).
  • IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al., J. Immunol., 2008, 181, 2799- 2805).
  • IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.
  • the compounds in accordance with the present invention being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • Copending international patent application PCT/EP2022/068165 published on 5 January 2023 as WO 2023/275301
  • WO 2020/261141 describe fused bicyclic imidazole derivatives that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.
  • the compounds in accordance with the present invention possess other notable advantages.
  • the compounds of the invention display valuable metabolic stability, as determined in either microsomal or hepatocyte incubations.
  • the compounds of the invention also display valuable permeability as determined by standard assays, e.g. the Caco-2 permeability assay.
  • the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof.
  • the compounds in accordance with the present invention are encompassed within the generic scope of co-pending international patent application PCT/EP2022/068165 (published on 5 January 2023 as WO 2023/275301). There is, however, no specific disclosure therein of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula (I) or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds according to the present invention are useful in the treatment and/or prophylaxis of a pathological disorder that is mediated by a pro-inflammatory IL-17 cytokine or is associated with an increased level of a pro-inflammatory IL-17 cytokine.
  • the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer’s Disease, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman’s disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie’s Disease, coeliac disease, gall bladder disease, Pilonidal disease, periton
  • WO 2009/089036 reveals that modulators of IL-17 activity may be administered to inhibit or reduce the severity of ocular inflammatory disorders, in particular ocular surface inflammatory disorders including Dry Eye Syndrome (DES). Consequently, the compounds in accordance with the present invention are useful in the treatment and/or prevention of an IL-17-mediated ocular inflammatory disorder, in particular an IL-17- mediated ocular surface inflammatory disorder including Dry Eye Syndrome.
  • a IL-17-mediated ocular inflammatory disorder in particular an IL-17- mediated ocular surface inflammatory disorder including Dry Eye Syndrome.
  • Ocular surface inflammatory disorders include Dry Eye Syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, Pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis.
  • Dry Eye Syndrome includes keratoconjunctivitis sicca (KCS), Sjögren syndrome, Sjögren syndrome-associated keratoconjunctivitis sicca, non-Sjögren syndrome- associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.
  • KCS keratoconjunctivitis sicca
  • Sjögren syndrome Sjögren syndrome-associated keratoconjunctivitis sicca
  • non-Sjögren syndrome- associated keratoconjunctivitis sicca keratitis sicca
  • sicca syndrome xerophthalmia
  • tear film disorder decreased tear production
  • ATD aqueous tear deficiency
  • meibomian gland dysfunction meibomian gland dysfunction
  • the compounds of the present invention may be useful in the treatment and/or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn’s disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).
  • a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, ps
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo- arthritis or ankylosing spondylitis.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.
  • Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds according to the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • the compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • the compounds according to the present invention may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound according to the present invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • a compound in accordance with the present invention may be co- administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.
  • the compound of formula (I) above may be prepared by a process which comprises reacting a compound of formula (II) with the compound of formula (III): in the presence of a transition metal catalyst.
  • Suitable transition metal catalysts of use in the reaction include [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis- ⁇ 3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl-N]phenyl-C ⁇ iridium(III) hexafluorophosphate; and tris[2-phenylpyridinato- C 2 ,N]iridium(III).
  • the reaction will generally be performed by exposing the reactants to a bright light source.
  • a suitable bright light source will typically comprise the ‘integrated photoreactor’ described in ACS Cent.
  • the reaction will conveniently be carried out at ambient temperature, optionally in the presence of trifluoroacetic acid, and in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or an organic sulfoxide such as dimethyl sulfoxide.
  • a suitable solvent e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, or an organic sulfoxide such as dimethyl sulfoxide.
  • the intermediate of formula (III) above may be prepared by a process which comprises reacting 4-methyl-1,2,5-oxadiazole-3-carboxylic acid with the compound of formula (IV): The reaction is conveniently accomplished in the presence of a coupling agent and a base.
  • Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; and 2-chloro-1-methylpyridinium iodide.
  • Suitable bases include organic amines, e.g. a trialkylamine such as N,N- diisopropylethylamine; or pyridine. The reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g.
  • the intermediate of formula (IV) above may be prepared by removal of the N- protecting group R p from a compound of formula (V): wherein R p represents a N-protecting group.
  • the N-protecting group R p will suitably be benzyloxycarbonyl, in which case the removal thereof may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, or palladium hydroxide on charcoal.
  • a hydrogenation catalyst e.g. palladium on charcoal, or palladium hydroxide on charcoal.
  • the N-protecting group R p is benzyloxycarbonyl
  • the removal thereof may be effected by treatment with hydrogen bromide and acetic acid.
  • the intermediates of formula (V) above may be prepared by reacting 1,2,4-triazin- 3-amine with a compound of formula (VI): wherein R p is as defined above, and L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is typically accomplished in the presence of a base.
  • the base may be an inorganic base, e.g. a bicarbonate salt such as sodium bicarbonate; or an organic base such as pyridine.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a C1-4 alkanol such as ethanol or isopropanol, or a cyclic ether such as 1,4-dioxane.
  • the intermediates of formula (II) above may be prepared by a two-step process which comprises: (i) saponifying a compound of formula (VII): wherein Alk 1 represents C 1-4 alkyl, e.g. methyl; and (ii) reaction of the carboxylic acid derivative thereby obtained with N-hydroxy- phthalimide.
  • Alk 1 represents methyl
  • the saponification reaction in step (i) will generally be effected by treatment with a base.
  • Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. The reaction is conveniently performed at ambient or elevated temperature in water and a suitable organic solvent, e.g.
  • Step (ii) may conveniently be accomplished in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-N ⁇ -ethylcarbodiimide hydrochloride.
  • a coupling agent such as N-(3-dimethylaminopropyl)-N ⁇ -ethylcarbodiimide hydrochloride.
  • the reaction is suitably performed at ambient temperature, optionally in the presence of 4-(dimethyl- amino)pyridine, and in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N- dimethylformamide.
  • the intermediates of formula (VII) above may be prepared by reacting a carboxylic acid derivative of formula (VIII): wherein Alk 1 is as defined above; with 3,3,3-trifluoropropylamine or a salt thereof, e.g. the hydrochloride salt; under conditions analogous to those described above for the reaction between compound (IV) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid.
  • the starting materials of formula (VI) and (VIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • protecting groups such as those described in Greene’s Protective Groups in Organic Synthesis, ed. P.G.M. Wuts, John Wiley & Sons, 5 th edition, 2014.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit IL-17 induced IL-6 release from human dermal fibroblasts.
  • the compounds of the present invention when tested in the HDF cell line assay described below, generally exhibit a pIC50 value in excess of 8.0 (pIC 50 equals -log 10 [IC 50 ], in which IC 50 is expressed as a molar concentration, so the skilled person will appreciate that a higher pIC50 figure denotes a more active compound).
  • Inhibition of IL-17A induced IL-6 release from Dermal Fibroblast Cell Line The purpose of this assay is to test the neutralising ability to IL-17 proteins, in a human primary cell system.
  • HDF normal human dermal fibroblasts
  • IL-17A 50 pM
  • TNF- ⁇ 25 pM
  • the resultant IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio. The kit utilises two monoclonal antibodies, one labelled with Eu- Cryptate (Donor) and the second with d2 or XL665 (Acceptor).
  • the intensity of the signal is proportional to the concentration of IL-6 present in the sample (Ratio is calculated by 665/620 x 104).
  • the ability of a compound to inhibit IL-17 induced IL-6 release from human dermal fibroblasts is measured in this assay.
  • HDF cells (Sigma #106-05n) were cultured in complete media (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in a tissue culture flask using standard techniques. Cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen #12605036). The TrypLE was neutralised using complete medium (45 mL) and the cells were centrifuged at 300 x g for 3 minutes.
  • the cells were re-suspended in complete media (5 mL) counted and adjusted to a concentration of 3.125 x 10 4 cells/mL before being added to the 384 well assay plate (Corning #3701) at 40 ⁇ L per well. The cells were left for a minimum of three hours, at 37°C/5% CO 2 , to adhere to the plate. Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 ⁇ L from the titration plate was transferred to 45 ⁇ L of complete media and mixed to give a solution containing 10% DMSO.
  • TNF ⁇ and IL-17 cytokine were prepared in complete media to final concentrations of TNF ⁇ 25 pM/IL-17A 50 pM, then 30 ⁇ L of the solution was added to a 384 well reagent plate (Greiner #781281). 10 ⁇ L from the aqueous dilution plate was transferred to the reagent plate containing 30 ⁇ L of the diluted cytokines, to give a 2.5% DMSO solution. The compounds were incubated with the cytokine mixtures for 5 h at 37°C. After the incubation, 10 ⁇ L was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO 2 .
  • Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1:1, as per kit insert.
  • a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 ⁇ L), then supernatant (10 ⁇ L) was transferred from the assay plate to Greiner reagent plate. The mixture was incubated at room temperature for 3 h with gentle shaking ( ⁇ 400 rpm) before being read on a Synergy Neo 2 plate reader (Excitation: 330 nm; Emission: 615/645 nm).
  • Example pIC 50 1 (Peak 1) 8.5 2 (Peak 2) 8.7
  • the following Examples illustrate the preparation of compounds according to the invention.
  • Method 5 Chiral analysis was performed using a Chiralpak IC, 150 x 4.6 mm, 3 ⁇ m column, flow rate 3 mL/minute, column temperature 35°C, eluting with a 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • the mass spectrometer was calibrated using a solution of sodium iodide and caesium iodide in a 1:1 mixture of IPA and water, and used leucine-enkephalin as an internal calibrant.
  • the inlet method was a 5-95% gradient of acetonitrile (+ 5% H2O + 0.08% formic acid + 0.02% TFA) in H 2 O (+ 0.08% formic acid + 0.02% TFA) over 2 minutes using a Waters BioResolve RP mAb Polyphenyl column (2.7 ⁇ m, 2.1 mm x 150 mm) held at 80°C. The flow rate was 1 mL/minute.
  • Peak 1 (methyl assigned as being syn to the amide): ⁇ H (400 MHz, DMSO-d 6 ) 9.50 (d, J 8.9 Hz, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.02 (t, J 5.7 Hz, 1H), 5.21 (t, J 8.5 Hz, 1H), 4.99 (s, 1H), 3.28 (q, J 5.4 Hz, 2H), 2.83-2.76 (m, 2H), 2.76-2.68 (m, 2H), 2.48 (s, 3H), 2.42- 2.26 (m, 3H), 2.22 (d, J 10.3 Hz, 1H), 2.12-1.56 (m, 6H), 1.48-1.27 (m, 4H), 1.26 (s, 3H).
  • Peak 2 (OH assigned as being syn to the amide): ⁇ H (400 MHz, DMSO-d 6 ) 9.51 (d, J 9.0 Hz, 1H), 8.58 (s, 1H), 8.30 (s, 1H), 7.91 (t, J 5.7 Hz, 1H), 5.22 (t, J 8.6 Hz, 1H), 3.27 (q, J 6.5 Hz, 2H), 2.78 (q, J 12.3 Hz, 4H), 2.48 (s, 3H), 2.44-2.29 (m, 2H), 2.27-1.07 (m, 10H), 1.05 (s, 3H).

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Abstract

Le N-[(S)-(4,4-difluorocyclohexyl){3-[3-hydroxy-3-méthyl-1-(3,3,3-trifluoropropyl- carbamoyl)cyclobutyl]imidazo[1,2-b] [1,2,4]triazin-6-yl }méthyl]-4-méthyl-1,2,5- oxadiazole-3-carboxamide, et un sel pharmaceutiquement acceptable de celui-ci, étant de puissants modulateurs de l'activité de l'IL-17 humaine, sont utiles dans le traitement et/ou la prévention de diverses affections humaines, y compris des troubles inflammatoires et auto-immuns.
PCT/EP2023/084705 2022-12-14 2023-12-07 Dérivés d'imidazotriazine en tant que modulateurs d'il-17 Ceased WO2024126250A1 (fr)

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GB2218860.1 2022-12-14
GBGB2218860.1A GB202218860D0 (en) 2022-12-14 2022-12-14 Therapeutic agents

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WO2024126250A1 true WO2024126250A1 (fr) 2024-06-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089036A2 (fr) 2008-01-09 2009-07-16 Schepens Eye Research Institute Compositions thérapeutiques utilisées pour le traitement des affections inflammatoires oculaires
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17

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