Imidazotriazine derivatives as il-17 modulators

Abstract

3-cyclopropyl-N-[(S)-[3-[1-(2,2-difluoropropylcarbamoyl)-3-hydroxy-3-methyl-cyclobutyl]imidazo[1,2-b][1,2,4]triazin-6-yl]-[4- (trifluoromethyl)cyclohexyl]methyl]isoxazole-4-carboxamide or a pharmaceutically acceptable salt and / or solvate thereof, being a potent modulator of human IL-17 activity, is accordingly of benefit in the treatment and / or prevention of various human ailments, including inflammatory and autoimmune disorders.

Description

[0001] IMID AZOTRIAZINE DERIVATIVES AS IL-17 MODULATORS

[0002] The present invention relates to a heterocyclic compound, and to its use in therapy. More particularly, this invention is concerned with a pharmacologically active substituted imidazo[l,2-6][l,2,4]triazine derivative. This compound acts as a modulator of IL- 17 activity, and is accordingly of benefit as a pharmaceutical agent for the treatment and / or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.

[0003] BACKGROUND OF THE INVENTION

[0004] 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). Subsequently, 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, Thl7, that also express IL-21 and IL-22 signature cytokines (Kom 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-17RA, 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.

[0005] The compound in accordance with the present invention, being a potent modulator of human IL- 17 activity, is therefore beneficial in the treatment and / or prevention of various human ailments, including inflammatory and autoimmune disorders.

[0006] Furthermore, the compound in accordance with the present invention may be beneficial as a pharmacological standard for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compound of this invention may be useful as a radioligand in assays for detecting pharmacologically active compounds.

[0007] WO 2023 / 275301, WO 2020 / 261141 and also WO2024 / 126250, 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.

[0008] None of the prior art available to date, however, discloses or suggests the precise substituted imidazo| 1 ,2- / >|| 1 ,2.4|triazine derivative as provided by the present invention.

[0009] As well as being a potent modulator of human IL- 17 activity, the compound in accordance with the present invention possesses other notable advantages. In particular, the compound of the invention displays valuable metabolic stability, as determined in either microsomal or hepatocyte incubations using e.g. high performance liquid chromatography - high resolution mass spectrometry (HPLC-HRMS). The compound of the invention also displays valuable permeability as determined by standard assays, e.g. the Caco-2 permeability assay. It also displays advantageous “on kinetics” as and when determined by e.g. a Surface Plasmon Resonance (SPR) Assay.

[0010] SUMMARY OF THE INVENTION

[0011] In a first aspect, the present invention provides a compound of formula (I), or a salt and / or solvate thereof.

[0012] The compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of formula (I) is provided in the form of a salt. In one embodiment, the compound of formula (I) is provided in the form of a solvate. In one embodiment, the compound of formula (I) is provided in the form of the free base.

[0013] The compound in accordance with the present invention is encompassed within the generic scope of WO 2023 / 275301. There is, however, no specific disclosure therein of a compound of formula (I) as defined above, or a salt and / or solvate thereof, specifically a pharmaceutically acceptable salt and / or solvate thereof.

[0014] In a second aspect, the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for use in therapy.

[0015] In a third aspect, the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment and / or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.

[0016] In a fourth aspect, the present invention also provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate 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.

[0017] In a fifth aspect, 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 and / or solvate thereof.

[0018] In a sixth aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0019] In a seventh aspect, the present invention provides a novel intermediate of use in the preparation of compounds of formula (I).

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] In a first aspect, the present invention provides a compound of formula (I)

[0022]

[0023] In a second aspect, the present invention provides compounds of formula (IA), namely 3-cyclopropyl-A-[(S)-[3-[l-(2,2-difluoropropylcarbamoyl)-3-hydroxy-3-methyl- cyclobutyl]imidazo[l,2-b][l,2,4]triazin-6-yl]-[4- (trifluoromethyl)cyclohexyl]methyl]isoxazole-4-carboxamide (syn and anti stereoisomers), represented respectively by Formula (IA’) and (IA”):

[0024] In a particular embodiment according to this aspect, the present invention provides compounds of formula (IA’), the syn stereoisomer of 3-cyclopropyl-A-[(S)-[3-[l-(2,2- difluoropropylcarbamoyl)-3-hydroxy-3-methyl-cyclobutyl]imidazo[l,2-b][l,2,4]triazin-6- yl]-[4-(trifluoromethyl)cyclohexyl]methyl]isoxazole-4-carboxamide.

[0025] It will be appreciated that compounds of formula (IA) (specifically (IA’) and (IA”) are sub-formulae of compounds of formula (I). Any reference to compounds of formula (I) contained herein, will therefore include compounds of formula (IA).

[0026] The compound of formula (I) may be referred to herein as “the compound of the invention” or “the compound according to the invention”.

[0027] The invention further provides a salt of a compound of formula (I). The invention further provides a pharmaceutically acceptable salt of a compound of formula (I). The invention further provides a solvate of a compound of formula (I). The invention further provides a pharmaceutically acceptable solvate of a compound of formula (I). The invention further provides a pharmaceutically acceptable salt and / or solvate of a compound of formula (I). The invention further provides a compound of formula (I) as the free base.

[0028] The compound of formula (I), and salts and / or solvates thereof, may be referred to herein as “compound(s) of the invention”.

[0029] Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.

[0030] Stereoisomers of the compound of formula (I) include cis and trans isomers, optical isomers, diastereomers, geometric isomers, rotational isomers, atropisomers, and conformational isomers of the compound of formula (I), including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

[0031] Specific stereoisomers of the compound of formula (I) are compounds of the formulae (IA’) and (IA”). Specific stereoisomers of the compound of formula (II) are compounds of the formulae (IIA’) and (IIA”).

[0032] The carbon-carbon bonds of the compound of formula (I) are depicted herein using a solid line ( - 1 ), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that the compound of formula (I) may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.

[0033] In particular, the compounds of formulae (I) and (II) may exist as stereoisomers in syn (or cis) and anti (or trans) configurations. In the syn (or cis) configuration, the amide and alcohol reside on the same face of the cyclobutane ring. Alternatively, in the anti (or trans) configuration, the amide and alcohol reside on opposite faces of the cyclobutane ring. In a preferred embodiment, the compounds of formulae (I) and (II) exist in the syn configuration.

[0034] In addition, the compound of formula (I) may exist as a tautomer, for example an amide (NHC=O)^hydroxy imine (N=COH) tautomer. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.

[0035] It is also 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. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a1H,2H (deuterium, D) or3H (tritium, T) atom, preferably1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C or14C atom, preferably12C. Similarly, by way of example, each individual fluorine atom may be present as18F or19F. Thus, the present invention, also includes within its scope, isotopically-labelled compounds of Formula (I).

[0036] The present invention provides a compound of formula (I) as defined above or a pharmaceutically acceptable salt and / or solvate thereof, for use in therapy.

[0037] In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of diseases and / or disorders in which IL-17 plays a role.

[0038] 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.

[0039] 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. Generally, 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, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, Type I Diabetes, lyme arthritis, meningoencephalitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrosing disorders including pulmonary fibrosis, liver fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myelogenous leukaemia, chronic myelogenous leukemia, chronic lymphatic leukemia, gastric cancer and colon cancer), heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia and pain (particularly pain associated with inflammation).

[0040] 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. Ocular surface inflammatory disorders include Dry Eye Syndrome, penetrating keratoplasty, comeal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, comeal neovascularization, keratoprosthesis surgery, comeal 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. Particular categories of Dry Eye Syndrome include keratoconjunctivitis sicca (KCS), Sjogren syndrome, Sjogren syndrome-associated keratoconjunctivitis sicca, non-Sjogren 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.

[0041] Illustratively, 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).

[0042] Suitably, the compounds of the present invention are useful in the treatment and / or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis or ankylosing spondylitis.

[0043] Therefore, in a first aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for use 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.

[0044] In a first embodiment of this aspect, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof for use 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). In particular, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment and / or prophylaxis of a pathological disorder selected from the group consisting of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo-arthritis or ankylosing spondylitis.

[0045] In a second aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament useful for 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.

[0046] In a first embodiment of this aspect, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament useful for 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).

[0047] In particular, the present invention provides for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and / or solvate thereof for the manufacture of a medicament useful for the treatment and / or prophylaxis of a pathological disorder selected from the group consisting of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo-arthritis or ankylosing spondylitis.

[0048] In a third aspect, the present invention provides a method for the treatment of 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, 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 and / or solvate thereof.

[0049] In a first embodiment according to this aspect, the present invention provides a method for 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), 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 and / or solvate thereof.

[0050] In particular, the present invention provides a method for the treatment and / or prophylaxis of a pathological disorder selected from the group consisting of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo-arthritis or ankylosing spondylitis, 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 and / or solvate thereof.

[0051] As used herein, the term “patient” refers to a mammal that is afflicted with one or more disorders associated with mediated by a pro-inflammatory IL- 17 cytokine or is associated with an increased level of a pro-inflammatory IL -17 cytokine. It will be understood that the most preferred patient is a human.

[0052] It is also recognized that one skilled in the art may affect the disorders by treating a patient presently afflicted with the disorders, or by prophylactically treating a patient afflicted with the disorders with an effective amount of the compound of Formula (I). Thus, the terms “treatment” and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, and is intended to include prophylactic treatment of such disorders, but does not necessarily indicate a total elimination of all disorder symptoms.

[0053] Activity in any of the above-mentioned therapeutic indications or disorders can of course be determined by carrying out suitable clinical trials in a manner known to a person skilled in the relevant art for the particular indication and / or in the design of clinical trials in general.

[0054] For use in medicine, the salts of the compound of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compound of formula (I) or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley -VCH, 2002. 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.

[0055] Typically, the phrase "pharmaceutically acceptable" is used to refer to those compounds, materials, compositions, dosage forms and the like which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, for example human beings, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0056] The present invention includes within its scope solvates of the compound of formula (I) above. Such solvates may be formed with common organic solvents or water.

[0057] The present invention also includes within its scope co-crystals of the compound of formula (I) above. The technical term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).

[0058] The invention also includes within its scope pro-drug forms of the compound of formula (I) and its various sub-scopes and sub-groups.

[0059] PHARMACEUTICAL COMPOSITIONS

[0060] For treating diseases, the compound of formula (I) or its pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.

[0061] Therefore, 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 diluent(s) or carrier(s). To prepare a pharmaceutical composition according to the invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.

[0062] 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.

[0063] For oral administration, the pharmaceutical compositions may be solids or liquids and 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). The tablets may be coated by methods well known in the art. 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.

[0064] Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0065] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0066] 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. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. In addition to the formulations described above, 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.

[0067] For nasal administration or administration by inhalation, 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.

[0068] 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.

[0069] For topical 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. Alternatively, 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.

[0070] For ophthalmic administration 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. Alternatively, for ophthalmic administration the compounds according to the present invention may be formulated in an ointment such as petrolatum.

[0071] For rectal administration the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with 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. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

[0072] These pharmaceutical forms are prepared using methods which are routinely used by pharmacists. 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. around 0.01 mg / kg to 40 mg / kg body weight, for oral or buccal administration, from around 10 ng / kg to 50 mg / kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation. However, it should be understood that the specific doses can be adapted to particular cases depending on the individual requirements, at the physician’s discretion.

[0073] If desired, a compound in accordance with the present invention may be coadministered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.

[0074] SYNTHETIC SCHEMES

[0075] It will be apparent to the person skilled in the art that there are various synthetic pathways that can lead to the compounds according to the invention. The following processes are aimed at illustrating some of these synthetic pathways but should not be construed in any way as a limitation on how the compounds according to the invention should be made.

[0076] The following description of synthetic schemes provides for means of preparing the compound of formula (I). However, analogous methods as understood by the person skilled in the art of synthetic organic chemistry, may be used in the preparation of the compound of formula (I).

[0077] The compound of formula (I) above may be prepared by a process which comprises reacting 3-cyclopropylisoxazole-4-carboxylic acid with the compound of formula (II), namely l-[6-[(<S)-amino-[4-(trifluoromethyl)cyclohexyl]methyl]imidazo[l,2- b][l,2,4]triazin-3-yl]-N-(2,2-difluoropropyl)-3-hydroxy-3-methyl- cyclobutanecarboxamide (syn stereoisomer):

[0078] The reaction may conveniently be accomplished in the presence of a coupling agent such as l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU) or N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDCI.HCL). The reaction is suitably performed at an appropriate temperature, e.g. a temperature in the region of 0°C to room temperature, in a suitable solvent, e.g. an organic nitrile solvent such as acetonitrile.

[0079] The intermediate of formula (II) above may be prepared by removal of the N- protecting group (Rp) from a compound of formula (III): wherein Rp, represents a N-protecting group, such as benzyloxy carbonyl, the removal of which 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 carbon (Pd / C). The reaction is generally performed at ambient temperature in a suitable solvent, e.g a secondary alcohol such as 2-propanol.

[0080] The intermediate of formula (III) above may be prepared by reacting a compound of formula (IV) with a compound of formula (V):

[0081] The reaction may conveniently be accomplished in a suitable solvent, e.g. a secondary alcohol such as 1 -butanol, in the presence of a base, such as 2-6-lutidine. The reaction generally proceeds using a molecular sieve at an elevated temperature, such as 65°C.

[0082] The intermediate of formula (V) above may be prepared by the procedure described in WO 2023 / 275301, for example the procedure of Intermediate 43, or by methods analogous thereto.

[0083] The intermediate of formula (IV) above may be prepared by reacting a compound of formula (VI) with 2,2-difluoropropylamine hydrochloride:

[0084] The reaction generally proceeds in the presence of a non-nucleophilic base, such as lithium bis(trimethylsilyl)amide in a suitable solvent e.g. a cyclic ether such as tetrahydrofuran. The reaction generally starts at reduced temperatures, such as 0°C, followed by elevating the temperature, to e.g. ambient temperature.

[0085] The intermediate of formula (VI) above may be prepared by treating a compound of formula (VII): in a suitable chlorinated solvent such as di chloromethane with an acid, e.g. a mineral acid such as hydrochloric acid, in a solvent such as 1,4-di oxane. The reaction suitably proceeds at a suitable temperature, such as room temperature.

[0086] The intermediate of formula (VII) above may be prepared by reacting a compound of formula (VIII), in a two step process:

[0087] Firstly, reaction with an oxidising agent such as 3-chloroperoxybenzoic acid, in a suitable chlorinated solvent such as dichloromethane. The reaction generally starts at reduced temperatures, such as 0°C, followed by elevating the temperature, to e.g. ambient temperature. Secondly, the resulting sulfone is then cooled to a suitable temperature, such as 0°C and reacted with a suitable nucleophilic substance such as ammonia, in a suitable solvent such as 1,4-dioxane, is added and the reaction is allowed to warm e.g. to ambient temperature.

[0088] The intermediate of formula (VIII) above may be prepared by reacting a compound of formula (IX): typically in the presence of a base, e.g. non-nucleophilic base such as di-iso- propylethylamine, with trimethylsilyltrifluoromethane sulphonate. The reaction is conveniently effected in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. The reaction generally starts at reduced temperatures, such as 0°C, followed by elevating the temperature, to e.g. ambient temperature. The intermediate of formula (IX) above may be prepared by reacting a compound of formula (X): with a dehydrogenating agent, such as 2, 3-di chi oro-5, 6-di cyano- 1 ,4-benzoquinone, in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, at a suitable temperature such as 0 °C.

[0089] The intermediate of formula (X) above may be prepared by reacting a compound of formula (XI) as follows:

[0090] Firstly, the compound of formula (XI) is mixed with 3-methylthio-l,2,4-triazine in the presence of a base, such as N,N,N’.N’-tetra-methylethylene diamine, in a suitable solvent such as toluene at a suitable temperature, such as 0°C. Secondly, a non-nucleophilic base, such as lithium bis(trimethylsilyl)amide is added in a suitable solvent such as toluene, at a suitable temperature, such as 0°C or ambient temperature.

[0091] The intermediate of formula (XI) above may be prepared by reacting methyl 3- oxocyclobutanecarboxylate with a nucleophilic substance, such as methylmagnesium chloride, in a suitable solvent e.g. a cyclic ether such as tetrahydrofuran, at a suitable temperature, such as -72°C initially, then raising to ambient temperature.

[0092] Where they are not commercially available, the starting materials may be prepared by methods known to the person skilled in the art.

[0093] Where a mixture of products is obtained from any of the processes described above for the preparation of a compound according to the invention, 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.

[0094] Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. Alternatively the non desired enantiomer may be racemized into the desired enantiomer, in the presence of an acid or a base, according to methods known to the person skilled in the art, or according to methods described in the accompanying Examples.

[0095] During any of the above synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Greene ’s Protective Groups in Organic Synthesis, ed. P.G.M. Wuts, John Wiley & Sons, 5thedition, 2014. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

[0096] In another aspect, the present invention provides a synthetic intermediate of formula (II)

[0097] In a another aspect, the present invention provides compounds of formula (IIA), namely l-[6-[(<S)-amino-[4-(trifluoromethyl)cyclohexyl]methyl]imidazo[l,2- b][l,2,4]triazin-3-yl]-N-(2,2-difluoropropyl)-3-hydroxy-3-methyl- cyclobutanecarboxamide (syn and anti stereoisomers), represented respectively by Formula (IIA’) and (IIA”):

[0098] In a particular embodiment according to this aspect, the present invention provides compounds of formula (IIA’), the syn stereoisomer of l-[6-[(S)-amino-[4- (trifluoromethyl)cyclohexyl]methyl]imidazo[l,2-b][l,2,4]triazin-3-yl]-N-(2,2- difluoropropyl)-3-hydroxy-3-methyl-cyclobutanecarboxamide. It will be appreciated that compounds of formulae (IIA) (specifically (IIA’) and (IIA”)) are sub-formulae of the compound of formula (II). Any reference to compound of formula (II) contained herein, will therefore include compounds of formulae (IIA).

[0099] In yet another aspect, the present invention relates to the use of intermediates of formula (II) for the synthesis of compounds of formula (I). Included as an aspect of the invention are salts such as pharmaceutically acceptable salts and / or solvates of compounds of formula (II).

[0100] BIOLOGICAL ACTIVITY

[0101] The compound of formula (I) potently inhibits IL- 17 induced IL-6 release from human dermal fibroblasts. Therefore, the effect of the compound of formula (I) on IL- 17 induced IL-6 from human dermal fibroblasts release was assessed in two independent cell assays.

[0102] Thus, when tested in either Primary Human Dermal Fibroblast cell assay or the Primary Thl7-Human Dermal Fibroblast Co-culture cell assay as described below, the compound of formula (I) generally exhibits a pICso value in excess of 6.0 (pICso equals - logio[ICso], in which ICso is expressed as a molar concentration, so the skilled person will appreciate that a higher pICso figure denotes a more active compound).

[0103] Additionally, the compound of formula (I) has advantageous “on-rates” when tested in a relevant assay, such as Surface Plasmon Resonance (SPR). SPR is a technique for analysis of the interactions of two biomolecules with respect to binding kinetics and affinity as well as binding specificity and the "on-rate" is a measure of how quickly a compound can bind its target protein / receptor.

[0104] EXPERIMENTAL SECTION

[0105] The following Examples illustrate the preparation of compounds according to the invention.

[0106] I. ABBREVIATIONS

[0107] Abbreviations used herein are defined below. Any abbreviations not defined are intended to convey their generally accepted meaning.

[0108] DCM: dichloromethane MeOH: methanol

[0109] THF: tetrahydrofuran

[0110] EtOAc: ethyl acetate

[0111] DMSO: dimethyl sulfoxide

[0112] DIPEA: N,N-diisopropylethylamine

[0113] HC1: hydrochloric acid

[0114] EDCI.HC1: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0115] HATU: l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid Hexafluorophosphate

[0116] TMEDA: N,N,N’,N’-tetra-methylethylene diamine

[0117] LiHMDS: lithium 6 / .s(trimeth lsil l)amide

[0118] DDQ: 2,3-dichloro-5,6-dicyano-l,4-benzoquinone h: hour r.t.: ambient temperature

[0119] M: mass; molar

[0120] RT: retention time

[0121] HPLC: High Performance Liquid Chromatography

[0122] LCMS: Liquid Chromatography Mass Spectrometry

[0123] NMR: Nuclear Magnetic Resonance

[0124] Naming convention:

[0125] IUPAC names of chemical reagents, Intermediates and Examples have been generated using (Biovia Draw 2024) version 24.1 (24.1.0.1865). Depending on the Kekule structures of chemical reagents, Intermediates and Examples, Bovia Draw may generate different chemical names.

[0126] II. ANALYTICAL AND SYNTHETIC METHODS

[0127] All reactions involving air or moisture-sensitive reagents are performed under a nitrogen atmosphere (inert atmosphere) using dried solvents and glassware. Experiments requiring microwave irradiation are performed on a Biotage Initiator Sixty microwave oven upgraded with version 2.0 of the operating software. Experiments are run to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercial solvents and reagents are generally used without further purification, including anhydrous solvents when appropriate (generally Sure-Seal™ products from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). In general, reactions are followed by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) or mass spectrometry (MS) analyses.

[0128] NMR spectra were recorded on a Bruker Advance III HD 300 MHz or 400 MHz spectrometer. The chemical shifts (6) reported are given in parts per million (ppm), and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, and m = multiplet.

[0129] Mass spectrometric measurements in LC-MS mode are performed as follows:

[0130] Method 1

[0131] Stationary phase: Phenomenex Gemini NX-C18 2 x 20 mm, 3 pM

[0132] Mobile Phase A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0133] Mobile Phase B: Acetonitrile + 5% water + 0.1% Ammonia Solution

[0134] Flow rate: 1 mL / min

[0135] Gradient program: Time A% B%

[0136] 0.00 95.00 5.00

[0137] 1.50 5.00 95.00

[0138] 2.25 5.00 95.00

[0139] 2.50 95.00 5.00

[0140] Method 2

[0141] Stationary phase: Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 pM column

[0142] Mobile Phase A: 10 mM Ammonium formate in water + 0.1% Ammonia solution

[0143] Mobile Phase B: Acetonitrile + 5% water + 0.1% Ammonia Solution

[0144] Fl ow rate : 1.5 mL / min

[0145] Gradient program: Time A% B%

[0146] 0.00 95.00 5.00

[0147] 0.10 95.00 5.00

[0148] 3.50 5.00 95.00

[0149] 4.00 5.00 95.00

[0150] 4.05 95.00 5.00 When analytical methods are not specified in the below protocols, the methods used were similar to the ones described above. It will be apparent to the person skilled in the art that there are analytical and preparative chromatographic methods analogues to the ones described above can be use for the below procedures.

[0151] III. INTERMEDIATES

[0152] INTERMEDIATE 1: Methyl 3-hydroxy-3-methyl-cvclobutanecarboxylate

[0153] To a solution of methyl 3-oxocyclobutanecarboxylate (50g, 380 mmol) in anhydrous THF (1.1 L) under nitrogen cooled to -72°C was added dropwise methylmagnesium chloride (3.0M in THF, 150mL, 450 mmol) such that the internal temperature was maintained below -65°C. Following addition, the reaction mixture was stirred at -70°C for 2 hours before being allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was cooled to -60°C and quenched with saturated ammonium chloride solution (150 mL). The resulting mixture was diluted with water (500 mL) and / .so-hexane (150 mL) and stirred at room temperature for 30 minutes. The aqueous layer was separated, extracted with tert-butyl methyl ether (250 mL x 2), the combined organic extracts dried over sodium sulfate, filtered and concentrated in vacuo to a pale residue which was purified by chromatography on silica with a gradient of 0% to 70% ethyl acetate in / .so-hexane to afford the title compound as a colourless oil and a mixture of diastereoisomers. 'H NMR (300 MHz, CDC13) 6 3.69 (s, 3H), 2.77 - 2.60 (m, 1H), 2.36 - 2.28 (m, 4H), 2.27 (s, 1H), 1.37 (s, 3H).

[0154] INTERMEDIATE 2: Methyl 3-hydroxy-3-methyl-l-(3-methylsulfanyl-4,5-dihydro- l,2.4-triazin-5-yl)cyclobutanecarboxylate A mixture of 3-methylthio-l,2,4-triazine (24.5g 189 mmol), methyl 3-hydroxy-3-methyl- cyclobutanecarboxylate (prepared according to the procedure of Intermediate 1) (41g, 280 mmol) and TMEDA (145mL, 951 mmol) in anhydrous toluene (200 mL) under nitrogen was cooled to 0°C. To the mixture was added a solution of LiHMDS (1.0M in toluene, 1.1 L, 1100 mmol) via a dropping funnel at a rate such that the internal temperature was maintained below 10°C. Following addition, the mixture was stirred at 0°C for 5 minutes before being warmed to 33°C and stirred for 24 hours. The reaction mixture was cooled to 0°C and quenched with saturated ammonium chloride solution (700 mL) and water (700 mL). The separated aqueous layer was extracted with ethyl acetate (700 mL x 2), the combined organic extracts washed with brine (700 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give a dark brown residue.JH NMR (300 MHz, DMSO) indicated product as an approximate 1:1 mixture of diastereoisomers. LC-MS Method 1 indicated product as a mixture of diastereoisomers at RT: 0.53 minutes (minor desired syn diastereomer) and 0.64 min (major undesired anti diastereomer), 272.0 (M+H), in an approximate 55:45 ratio. The crude product was purified by chromatography on silica eluting with a gradient of 0% to 70% ethyl acetate in / .so-hexane to provide the title compound (syn diastereomer with alcohol and ester on the same face of the cyclobutane) (11.5 g, 23%) as a yellow solid. 'H NMR (300 MHz, DMSO) 6 10.61 (s, 1H), 6.62 (d, J = 1.9 Hz, 1H), 4.81 (s, 1H), 3.70 - 3.52 (m, 4H), 2.46 - 2.36 (m, 2H), 2.34 - 2.24 (m, 4H), 2.21 - 2.10 (m, 1H), 1.22 (s, 3H). LC-MS (ESI+): Method 1 RT 0.53 minutes m / z = 272.2 (M+H).

[0155] INTERMEDIATE 3: Methyl 3-hydroxy-3-methyl-l-(3-methylsulfanyl-1.2,4-triazin-5- vDcvclobutanecarboxylate

[0156] To a solution of methyl 3-hydroxy-3-methyl-l-(3-methylsulfanyl-4,5-dihydro-l,2,4- triazin-5-yl)cyclobutanecarboxylate_(prepared according to the procedure of Intermediate 2) (11.4 g, 42.0 mmol) in DCM (300 mL) cooled to 0°C was added DDQ (11g, 47 mmol) portion wise. The resultant mixture was stirred at 0°C for 1 hour. The reaction mixture was filtered through Celite® and the filter cake washed with additional DCM (2 x 500 mL). The filtrate was washed with saturated sodium bicarbonate solution (2 x 300 mL), dried over anhydrous sodium sulphate, filtered through a short pad of Celite® and concentrated in vacuo to provide the title compound as a dark solid (10.4 g, 92%) which was used without further purification.JH NMR (300 MHz, DMSO) 6 9.28 (s, 1H), 5.25 (s, 1H), 3.63 (s, 3H), 2.81 - 2.71 (m, 4H), 2.63 (s, 3H), 1.01 (s, 3H). LC-MS (ESI+) Method 1 RT 0.70 minutes m / z = 270.0 (M+H)+

[0157] INTERMEDIATE 4: Methyl 3-methyl-l-(3-methylsulfanyl-L2.4-triazin-5-yl)-3- trimethylsilyloxy-cyclobutanecarboxylate

[0158] To a stirred solution of methyl 3-hydroxy-3-methyl-l-(3-methylsulfanyl-l,2,4-triazin-5- yl)cyclobutanecarboxylate (prepared according to the procedure of Intermediate 3) (8.0 g, 30 mmol) in DCM (150 mL) cooled to 0°C was added di-zso-propylethylamine (13 mL, 75 mmol) followed by trimethylsilyltrifluoromethane sulphonate (8.0 mL, 39 mmol). The resulting solution was stirred at 0°C for 15 minutes before being warmed to ambient temperature and stirred for 17 hours. The resulting deep red reaction mixture was stirred at 0°C for 15 minutes, warmed to room temperature and stirred for 17 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2 x 150 mL), the combined organic extracts passed through a phase separator and concentrated in vacuo to a dark brown residue which was purified by chromatography on silica eluting with a gradient of 0% to 15% ethyl acetate in / .so-hexane to provide the title compound as a yellow oil (8.8 g, 87%). 'H NMR (300 MHz, DMSO) 6 9.31 (s, 1H), 3.63 (s, 3H), 2.93 - 2.81 (m, 4H), 2.63 (s, 3H), 1.10 (s, 3H), 0.12 (s, 9H). LC-MS (ESI+) Method 7 RT 1.35 minutes m / z = 342.0 (M+H).

[0159] INTERMEDIATE _ 5: _ Methyl _ l-(3-amino-1.2,4-triazin-5-yl)-3-methyl-3- trimethylsilyloxy-cyclobutanecarboxylate

[0160] To a stirred solution of methyl 3-methyl-l-(3-methylsulfanyl-l,2,4-triazin-5-yl)-3- trimethylsilyloxy-cyclobutanecarboxylate (prepared according to the procedure of Intermediate 4) (10 g, 29.3 mmol) in DCM (300 mL) cooled to 0°C was added 3- chloroperoxy benzoic acid (70 weight %, 18g, 73 mmol) and the resultant suspension stirred at 0°C for 90 minutes before warming to ambient temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 250 mL), 20% aqueous sodium bisulfite solution (250 mL), aqueous sodium bicarbonate solution (250 mL), dried over sodium sulfate and filtered under vacuum. To the filtrate was added anhydrous 1,4-dioxane (100 mL) and the mixture concentrated under vacuum (>250 mbar at 30 °C) to remove residual di chloromethane and afford a solution of the intermediate sulphone in 1,4-dioxane. The resultant solution was cooled to 0°C with stirring under nitrogen and a solution of ammonia (0.5M in 1,4-dioxane, 300mL, 150 mmol) added. The resultant suspension was warmed to ambient temperature and stirred for 15 hours. The reaction mixture was concentrated in vacuo and the resulting crude residue partitioned between ethyl acetate (300 mL) and saturated aqueous potassium carbonate solution (300 mL). The aqueous layer was extracted with additional ethyl acetate (300 mL), the combined organic extracts dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (7.5 g, 83%) as a pale-yellow solid. 'H NMR (300 MHz, DMSO) 6 8.67 (s, 1H), 7.28 (s, 2H), 3.61 (s, 3H), 2.85 - 2.75 (m, 4H), 1.11 (s, 3H), 0.11 (s, 9H). LC-MS (ESI+) Method 1 RT 1.07 minutes m / z = 311.2 (M+H).

[0161] INTERMEDIATE 6: Methyl l-(3-amino-L2.4-triazin-5-yl)-3-hydroxy-3-methyl- cyclobutanecarboxylate To a stirred solution of methyl l-(3-amino-l,2,4-triazin-5-yl)-3-methyl-3- trimethylsilyloxy-cyclobutanecarboxylate (prepared according to the procedure of Intermediate 5) (4.0 g, 13 mmol) in DCM (65 mL) was added 4M HC1 in 1,4-di oxane (16 mL, 64 mmol). The resulting suspension was stirred at room temperature for 30 minutes before the reaction mixture was concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (200 mL) and saturated aqueous potassium carbonate solution (150 mL). The aqueous phase was extracted with further ethyl acetate (2 x 150 mL), the combined organic extracts dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound (3.1g, 96%) as an off-white solid.JH NMR (300 MHz, DMSO) 6 8.64 (s, 1H), 7.27 (s, 2H), 5.18 (s, 1H), 3.61 (s, 3H), 2.78 - 2.62 (m, 4H), 1.02 (s, 3H). LC-MS (ESI+) Method 1 RT 0.29 minutes m / z = 239.0 (M+H).

[0162] INTERMEDIATE 7: l-(3-Amino-L2.4-triazin-5-yl)-JV-(2.2-difluoropropyl)-3-hydroxy- 3 -methyl-cyclobutanecarboxamide

[0163] A stirred mixture of 2,2-difluoropropylamine hydrochloride (110 mg, 0.803 mmol) and methyl l-(3-amino-l,2,4-triazin-5-yl)-3-hydroxy-3-methyl-cyclobutanecarboxylate (prepared according to the procedure of Intermediate 6) (120 mg, 0.504 mmol) in anhydrous THF (5 mL) under nitrogen was cooled to 0 °C and a solution of lithium bis- trimethylsilylamide in THF (1.0M, 5 mL, 5 mmol) added drop wise. The reaction mixture was stirred at 0 °C for 1 hour, before being warmed to ambient temperature and stirred for 20 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and water (5 mL), ethyl acetate (5 mL) was added and the mixture stirred for 10 minutes. The separated aqueous layer was extracted with ethyl acetate (3 x 10 mL), the combined organic phases passed through a phase separator and concentrated in vacuo to afford the title compound (152 mg, 95%), as a light brown solid. 'H NMR (300 MHz, DMSO) 6 8.63 (s, 1H), 8.12 (t, J = 6.3 Hz, 1H), 7.19 (s, 2H), 5.11 (s, 1H), 3.49 (td, J = 13.6, 6.2 Hz, 2H), 2.70 - 2.58 (m, 4H), 1.46 (t, J = 19.1 Hz, 3H), 1.04 (s, 3H). LC-MS (ESI+) Method 1 RT 0.30 minutes m / z = 302.2 (M+H). INTERMEDIATE 8: Benzyl A-[(<S)-[3-[l-(2.2-difluoropropylcarbamoyl)-3-hydroxy-3- methyl-cyclobutyl]imidazo|T.2-6][1.2.4]triazin-6-yl]-[4-

[0164] (trifluoromethyl)cyclohexyllmethyll carbamate

[0165] A mixture of l-(3-amino-l,2,4-triazin-5-yl)-N-(2,2-difluoropropyl)-3-hydroxy-3-methyl- cyclobutanecarboxamide (prepared according to the procedure of Intermediate 7) (2.46 g, 8.16 mmol), benzyl N-[(l<S)-3-bromo-2-oxo-l-[4-(trifluoromethyl)cyclohexyl]propyl] carbamate (prepared according to the procedure of Intermediate 16) 4.6 g, 11 mmol) and activated 4 molecular sieves (4.5g) was suspended in 1 -butanol (50 mL) and 2,6- lutidine (2.1 mL, 18 mmol) added with stirring. The mixture was heated to 65 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite® and concentrated in vacuo. The residue was dissolved in ethylacetate (300 mL) and the organic phase washed with water (2 x 300mL), brine (300mL), separated and dried over anhydrous sodium sulphate. The mixture was filtered and concentrated in vacuo to provide a crude residue that was purified by column chromatography on silica eluting with / .so-hexanes and ethylacetate to provide the title compound as a yellow / orange solid (3.95g, 73%). 'H NMR (400 MHz, DMSO) 6 8.59 (s, 1H), 8.23 (t, J = 6.3 Hz, 1H), 8.13 (s, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.45 - 7.12 (m, 5H), 5.23 (s, 1H), 5.03 (d, J = 2.5 Hz, 2H), 4.67 (dd, J = 9.2, 7.1 Hz, 1H), 3.50 (td, J = 13.7, 6.2 Hz, 2H), 2.80 (q, J = 12.4 Hz, 4H), 2.17 (m 1H), 1.86 (m 4H), 1.62 (d, J = 12.3 Hz, 1H), 1.50 (t, J = 19.1 Hz, 3H), 1.27 - 1.11 (m, 4H), 1.08 (s, 3H). LCMS: Method 1 RT 1.46 minutes m / z 639 (M+H)+

[0166] INTERMEDIATE 9: l-[6-[(5)-amino-[4-

[0167] (trifluoromethyl)cyclohexyl]methyl1imidazo[L2-b1[l,2.41triazin-3-yl1-N-(2.2- difluoropropyl)-3-hvdroxy-3-methyl-cvclobutanecarboxamide

[0168] To a solution of benzyl JV-[(S)-[3-[l-(2,2-difluoropropylcarbamoyl)-3-hydroxy-3-methyl- cyclobutyl]imidazo[l,2-b][l,2,4]triazin-6-yl]-[4-(trifluoromethyl)cyclohexyl]methyl] carbamate (prepared according to the procedure of Intermediate 8) (3.05g 4.78 mmol) in 2 -propanol (70 mL) under an atmosphere of nitrogen was added ammonium formate (6g, 94 mmol). Under a stream of nitrogen was added a slurry of 10% palladium on carbon, type 487 50% water (1g) in 2-propanol (5 mL) to the reaction mixture. The reaction was allowed to stir at ambient temperature for 18 hours. The reaction mixture was diluted with DCM (200 mL) and filtered through Celite® eluting with DCM. The organic phase was washed with saturated aqueous sodium bicarbonate solution (200 mL) and brine (2 x 200mL). The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The resultant crude residue was purified by column chromatography on silica eluting with a gradient of 0 to 30% methanol in DCM to provide the title compound (believed to be in the desired syn configuration) as a pale yellow solid (1.67g, 69%). 'H NMR (400 MHz, DMSO) 6 8.57 (s, 1H), 8.25 (t, J = 6.3 Hz, 1H), 8.15 (s, 1H), 5.23 (s, 1H), 3.80 (d, J = 5.5 Hz, 1H), 3.50 (td, J = 13.7, 6.3 Hz, 2H), 2.90 - 2.71 (m, 4H), 2.15 (d, J = 10.3 Hz, 1H), 2.03 - 1.78 (m, 5H), 1.78 - 1.58 (m, 2H), 1.49 (t, J = 19.1 Hz, 3H), 1.29 - 1.11 (m, 4H), 1.07 (s, 3H). LCMS: Method 1 RT 1.16 minutes m / z 505 (M+H)+

[0169] INTERMEDIATE 10: (7VE)-2-Methyl-A-l[trans-4-

[0170] (trifluoromethyl)cvclohexyl1methylene}propane-2-sulfinamide

[0171] To a solution of trans-4-(trifluoromethyl)cyclohexanecarboxaldehyde (16.1 g, 74.2 mmol) in DCM (500 mL) was added (S)-(-)-2-methyl-2-propanesulfmamide (8.70 g, 70.0 mmol), followed by titanium(IV) ethoxide (52 mL, 223.2 mmol). The mixture was heated under reflux for 2 h, then cooled to r.t. and treated with water (50 mL). After vigorous stirring, the fine suspension was filtered through Celite®. The filtrate was passed through a hydrophobic frit and concentrated in vacuo to afford the title compound (18.8 g, 89%) as an off-white solid. [a]25D +145° (c 1.00, DCM). 8H (300 MHz, CDCh) 8.00 (d, J 4.3 Hz, 1H), 2.57-2.40 (m, 1H), 2.17-1.96 (m, 5H), 1.54-1.28 (m, 4H), 1.21 (s, 9H).19F fH} NMR (282 MHz, CDCh) 8 -73.84 (s, 3F).

[0172] INTERMEDIATE 11: A-{(M-Cvano[trans-4-(trifluoromethyl)cvclohexyl]methyl}-2- methylpropane-2-sulfmamide

[0173] To a solution of (AE)-2-Methyl-A-{[trans-4-(trifluoromethyl)cyclohexyl ]methylene} propane-2-sulfmamide (prepared according to the procedure according to Intermediate 10) (18.8 g, 66.3 mmol) in DCM (180 mL) at 25°C was added cesium fluoride (1.00 g, 6.58 mmol), followed by trimethylsilyl cyanide (18.0 mL, 134 mmol). The mixture was stirred for 17 h at 25°C. Saturated aqueous sodium bicarbonate solution (150 mL) was added, and the mixture was stirred for 1 h. The biphasic mixture was separated and the organic layers were concentrated in vacuo. The resulting pale yellow oil was purified by flash column chromatography (0-100% EtOAc / isohexane), then recrystallised from EtOAc:isohexane (1:2; 90 mL), to afford the title compound (single diastereoisomer) (7.20 g, 35%) as a white solid. 8H (400 MHz, CDCh) 4.05 (dd, J 8.0, 6.4 Hz, 1H), 3.66 (d, J 8.0 Hz, 1H), 2.15-1.99 (m, 5H), 1.91-1.74 (m, 1H), 1.45-1.32 (m, 2H), 1.28 (s, 9H), 1.26-1.11 (m, 2H).19F fH} NMR (282 MHz, CDCh) 8 -73.80 (s, 3F).

[0174] INTERMEDIATE 12: -2-Amino-2-rtrans-4-(trifluoromethyl)cvclohexyllacetonitrile hydrochloride

[0175] To a solution of A-{(S)-cyano[trans-4-(trifluoromethyl)cyclohexyl]methyl}-2- methylpropane-2-sulfmamide (prepared according to the procedure of Intermediate 77) (7.00 g, 22.6 mmol) in MeOH (17 mL) was added HC1 in 1,4-dioxane (4N, 12 mL), resulting in a white precipitate. After 4 h, the mixture was concentrated under reduced pressure. To the resulting oily slurry was added isohexane (100 mL). After vigorous stirring, the resultant white solid was filtered out, to afford the title compound (5.20 g, 95%). 8H (300 MHz, DMSO-d6) 9.15 (s, 3H), 4.57 (d, J 5.5 Hz, 1H), 2.39-2.20 (m, 1H), 2.11-1.79 (m, 5H), 1.40-1.01 (m, 4H).

[0176] INTERMEDIATE 13: (25)-2-Amino-2-|trans-4-(trinuoromethyl)cvclohexyl lacetic acid hydrochloride

[0177] Acetic acid (35 mL) and HC1 in H2O (33%, 50 mL) were added to (2S)-2-amino-2-[trans- 4-(trifluoromethyl)cy cl ohexyl] acetonitrile hydrochloride (prepared according to the procedure of Intermediate 12) (5.20 g, 21.0 mmol). The mixture was heated under reflux for 4 h, then cooled with stirring to 20°C. After 18 h, the white precipitate was filtered off, and dried under a flow of air, to afford the title compound (4.40 g, 74%) as a white solid. [a]25D +22.1° (c 1.0, MeOH). 6H (300 MHz, DMSO-d6) 13.81 (s, 1H), 8.46 (s, 3H), 3.75 (d, J 4.3 Hz, 1H), 2.34-2.05 (m, 1H), 2.03-1.66 (m, 5H), 1.47-1.04 (m, 4H).19F fH} NMR (282-MHz, DMSO-d6) 6 -72.33 (s, 3F).

[0178] INTERMEDIATE 14: (2<S)-2-(Benzyloxycarbonylamino)-2-(4- (trifluoromethyl)cyclohexyllacetic acid

[0179] To a suspension of (2S)-2-Amino-2-[tra«s-4-(trifluoromethyl)cyclohexyl]acetic acid hydrochloride (prepared according to the procedure of Intermediate 13) (5.00 g, 19.1 mmol) and triethylamine (10 mL, 71.7 mmol) in DCM (100 mL) at 0°C was added N- (benzyloxycarbonyloxy)succinimide (4.47 g, 17.6 mmol) in three portions. The reaction mixture was allowed to warm to r.t. overnight. The reaction mixture was diluted with DCM (10 mL), washed with 5% hydrochloric acid (2 x 15 mL) and water (15 mL), then dried (Na2SO4) and concentrated in vacuo, to give the title compound (6.34 g, 92%) as a white solid. 6H (300 MHz, DMSO-d6) 12.65 (s, 1H), 7.54 (d, J 8.4 Hz, 1H), 7.40-7.28 (m, 5H), 5.04 (s, 2H), 3.89 (dd, J 8.4, 5.9 Hz, 1H), 2.26-2.05 (m, 1H), 1.96-1.80 (m, 2H), 1.80-1.59 (m, 3H), 1.32-1.07 (m, 4H).

[0180] INTERMEDIATE 15: Benzyl A-{(lS)-3-(dimethyl(oxo)-X6-sulfanylidene1-2-oxo-l-(4- (trifluoromethyl)-cyclohexyllpropyl} carbamate

[0181]

[0182] Trimethyl sulfoxonium iodide (70.00 g, 0.318 mol) was dissolved in THF (350 mL) and IM potassium tert-butoxide in THF (300 mL, 0.300 mol) was added. The resulting mixture was stirred at 70°C (external temperature) under nitrogen for 2 h, then cooled to - 5°C in an ice / salt bath under nitrogen, to provide an ylide. Meanwhile, in a separate flask, (2S)-2-(benzyloxycarbonylamino)-2-[4-(trifluoromethyl)cyclohexyl]acetic acid (prepared according to the procedure of Intermediate 14) (37.00 g, 0.103 mol) was dissolved in THF (350 mL) and HATU (49.00 g, 0.129 mol) was added, followed by DIPEA (24 mL, 0.137 mol). The reaction mixture was stirred under nitrogen for 150 minutes, then added dropwise over ~50 minutes to the cooled solution of the ylide, maintaining internal temperature below 1°C. The reaction mixture was stirred at -4°C under nitrogen for 5 minutes, then quenched at -4°C by addition of water (700 mL) and saturated aqueous NaHCCL solution (700 mL). The resulting suspension was extracted with TBME (3 L). The organic layer was washed with brine (500 mL) and concentrated to dryness under vacuum. The residue was suspended in TBME (500 mL) and water (50 mL), then heated to 50°C and cooled to r.t., then filtered, then washed with TBME (100 mL) and heptane (100 mL). An additional three crops were obtained as more solid precipitated from solution in the filtrate each time. The four crops of solid were combined, then water (400 mL) was added. The mixture was sonicated to break up big lumps, then cooled to 0°C, filtered and washed with water (150 mL). the residue was dried in a vacuum oven overnight to afford the title compound (36.15 g, 81%) as a colourless solid. 6H (400 MHz, DMSO-d6) 7.42-7.27 (m, 5H), 7.06 (d, J 9.2 Hz, 1H), 5.01 (s, 2H), 4.87 (s, 1H), 3.67 (dd, J 9.1, 6.6 Hz, 1H), 3.43 (s, 6H), 2.20-2.03 (m, 1H), 1.92-1.78 (m, 2H), 1.76-1.54 (m, 3H), 1.26-0.99 (m, 4H). LCMS (Method 6): [M+H]+434.2, RT 2.70 minutes. INTERMEDIATE 16: Benzyl A-l(lS)-3-bromo-2-oxo-l-(4-

[0183] (trifluoromethyl)cvclohexyllpropyl} carbamate

[0184] Benzyl JV-{(l<S)-3-[dimethyl(oxo)-X6-sulfanylidene]-2-oxo-l-[4-(trifluoromethyl)- cyclohexyl]propyl}carbamate (prepared according to the procedure of Intermediate 15) (28.08 g, 64.8 mmol) was dissolved in THF (300 mL) and cooled to 0°C (external temperature) under nitrogen. LiBr (5.69 g, 64.8 mmol) was added, and the mixture was stirred until it fully dissolved (~2 minutes). Methanesulfonic acid (4.2 mL, 64.7 mmol) was added and the mixture was stirred at 0°C under nitrogen for 5 minutes, then allowed to warm to r.t. and stirred for 30 minutes under nitrogen. The resulting suspension was warmed to 58°C (internal temperature; heating block at 65°C) over approximately 30 minutes, and stirred under nitrogen at this temperature for 1 h. The reaction mixture was allowed to cool to r.t. and quenched by the addition of saturated aqueous NaHCCL solution (450 mL). The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (600 mL). The organic layer was washed with saturated aqueous NaBr solution (400 mL), then dried (Na2SO4) and concentrated to dryness under vacuum. The residue was purified by FCC (750 g Biotage KP-Sil cartridge, wet loaded in 150 mL DCM, eluting with 10-20% EtOAc in heptane), and the product fractions were concentrated to dryness under vacuum, to afford the title compound (19.80 g, 68%) as a colourless solid. A mixed fraction was isolated and concentrated to dryness under vacuum, then re-purified by FCC (100 g Biotage Sfar Duo cartridge, wet loaded in 20 mL DCM, eluting with 10-20% EtOAc in heptane), and the product fractions were concentrated to dryness under vacuum, to afford a second crop of the title compound (4.90 g, 17%) as a colourless solid. 6H (500 MHz, CDCh) 7.44-7.29 (m, 5H), 5.31 (d, J 8.7 Hz, 1H), 5.11 (s, 2H), 4.66 (dd, J 8.7, 4.6 Hz, 1H), 4.03 (q, J 13.3 Hz, 2H), 2.03-1.92 (m, 3H), 1.92-1.83 (m, 2H), 1.63 (d, J 13.0 Hz, 1H), 1.42-1.18 (m, 3H), 1.06 (qd, J 13.0, 3.2 Hz, 1H). LCMS (Method 4): [M+H]+436.0 / 438.0, RT 3.27 minutes. IV. EXAMPLES

[0185] EXAMPLE 1: 3-Cvclopropyl-A-[(M-[3-H-(2.2-difluoropropylcarbamoyl)-3-hvdroxy-3- methyl-cvclobutyl]imidazo|T.2-blH.2.4]triazin-6-yl]-[4-

[0186] (trifluoromethyl)cvclohexyl]methyl]isoxazole-4-carboxamide

[0187] (desired syn stereoisomer)

[0188] To a mixture of l-[6-[(<S)-amino-[4-(trifluoromethyl)cyclohexyl]methyl]imidazo[l,2- b][l,2,4]triazin-3-yl]-N-(2,2-difluoropropyl)-3-hydroxy-3-methyl- cyclobutanecarboxamide (believed to be syn stereoisomer, prepared according to the procedure of Intermediate 9) (60 mg, 0.12 mmol) and 3-cyclopropyl-4- isoxazolecarboxylic acid (39 mg, 0.24 mmol) in acetonitrile (0.7 Ml) and DIPEA (85 pL, 0.49 mmol) was added HATU (70 mg, 0.18 mmol) at room temperature and the reaction was stirred for Ih at room temperature.The reaction mixture was concentrated in vacuo to provide a crude residue which was purified by column chromatography on silica eluting in a gradient from 0 to 100% EtOAc in iso-hexanes to provide the title compound as a pale yellow solid (60 mg, 79%). 'H NMR (400 MHz, DMSO) 6 9.38 (s, IH), 8.69 (d, J = 9.0 Hz, IH), 8.60 (s, IH), 8.26 - 8.22 (m, 2H), 5.24 (s, IH), 5.12 (t, J= 8.4 Hz, IH), 3.50 (td, J= 13.8, 6.3 Hz, 2H), 2.89 - 2.72 (m, 4H), 2.70 (m, IH), 2.45 (td, J= 8.5, 4.3 Hz, IH), 2.24 (s, IH), 2.04 - E82 (m, 3H), E66 (d, J= 11.7 Hz, IH), E50 (t, J= 19.1 Hz, 3H), E26 - El l (m, 5H), 1.08 (s, 3H), 1.04 - 0.81 (m, 3H). LCMS: Method 2 RT 1.92 minutes; m / z 640 (M+H)+ V. BIOLOGICAL ASSAYS

[0189] V.I: Inhibition of IL-17 A induced IL-6 release from primary Dermal Fibroblast Cells

[0190] The purpose of this assay is to test the neutralising ability to IL- 17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal but in combination with certain other cytokines, such as TNFa, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6.

[0191] HDFs were stimulated with IL-17A (50 pM) in combination with TNF-a (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).

[0192] The ability of a compound to inhibit IL- 17 induced IL-6 release from human dermal fibroblasts is measured in this assay.

[0193] 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 104cells / mL before being added to the 384 well assay plate (Coming #3701) at 40 pL per well. The cells were left for a minimum of three hours, at 37°C / 5% CO2, to adhere to the plate.

[0194] The compound of formula (I) was serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 pL from the titration plate was transferred to 45 pL of complete media and mixed to give a solution containing 10% DMSO.

[0195] Mixtures of TNFa and IL- 17 cytokine were prepared in complete media to final concentrations of TNFa 25 pM / IL-17A 50 pM, then 30 pL of the solution was added to a 384 well reagent plate (Greiner #781281).

[0196] 10 pL from the aqueous dilution plate was transferred to the reagent plate containing 30 pL 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 pL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C / 5% CO2.

[0197] From the 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. To a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 pL). then supernatant (10 pL) 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).

[0198] When tested in the primary HDF cell assay as described above, the compound of formula (I), believed to be (IA’) (desired syn stereoisomer), was found to exhibit a pICso value of about 9.0.

[0199] V.II: Thl 7-Human Dermal Fibroblast Co-culture cell assay

[0200] Peripheral blood monocytes were isolated from healthy donors, CD4+ T cells enriched and then CD4+CCR6+ T cells (Thl7 cells) were sorted using a BD FACS Aria. Human dermal fibroblasts (HDF) were allowed to adhere and grow in a 384-well assay plate for 24 hours at 37°C.

[0201] The following day, the compound of formula (I) was pre-diluted or anti-IL17 antibody or DMSO vehicle controls and T cell stimulants anti-CD3 / CD28 beads were added to the HDF 384-well assay plate. Finally, the CD4+CCR6+ cells (Thl7 cells) were added to the assay plate and incubation continued at 37 °C for 17-18 hours.

[0202] An aliquot of the cell supernatant was then diluted into a homogenous time- resolved fluorescence (HTRF from Cisbio) buffer reagent plus substrate to determine the concentration of IL6 cytokine produced.

[0203] The HTRF ratios were expressed as % inhibition relative to a minimum response in the presence of DMSO control and a maximum response in the presence of anti-IL17A antibody, and plotted as a function of log-transformed compound concentrations. A four- parameter fitting model was used to determine IC50 and IC90 values as a measure of compound potency.

[0204] The compound of formula (I) was tested in a minimum of 6 independent human blood donors and the composite data expressed as a geomean. When tested in the primary Thl7-HDF co-culture cell assay as described above, the compound of formula (I), believed to be (IA’) (desired syn stereoisomer), was found to exhibit a pICso value of about 6.8.

[0205] V.III Kinetic measurements of affinity by Surface Plasmon Resonance (SPR)

[0206] The SPR assay was performed on Biacore T200, S200 and 8K (Cytiva, Sweden) consisting of immobilizing human IL17AA on the surface of CM5 chip followed by titration of compound in the single cycle kinetics format.

[0207] Human IL17AA was diluted in lOmM sodium acetate and immobilized on a CM5 Series S Sensor Chip via amine coupling chemistry at 25°C to a level of -1200 response units (RU). The immobilisation was run in HBS P buffer (lOmM HEPES pH 7.4, 0.15M NaCl, 0.005 % Surfactant P20, (Cytiva, Sweden) at a flow rate of lOpL / min. A reference surface was prepared by activating and deactivating the appropriate flow cell. Binding assays were performed after equilibration at 37°C in HBS-P buffer with 5% DMSO at a flow rate of 50pL / min.

[0208] The assay was performed in the single cycle kinetics mode with compound titrated at 5 concentrations in the ascending order to 30pM over the immobilized human IL17AA and reference flow cell, followed by 17200s dissociation. After dissociation a second injection of the same IL17 NCE top concentration was added to confirm binding. Background subtraction binding curves for compound were analyzed using the Biacore Evaluation Software, Version (Cytiva, Sweden), using the 1:1 binding model fitted.

[0209] When tested in the SPR assay as described above, the compound of formula (I), believed to be (IA’) (desired syn stereoisomer), was found to exhibit an advantageous SPR on rate.

Claims

Claims:

1. A compound of formula (I)or a salt and / or solvate thereof.

2. A compound of formula (I) as claimed in claim 1, which is a compound of formula (IA’), namely 3-cyclopropyl-A-[(S)-[3-[l-(2,2-difluoropropylcarbamoyl)-3- hydroxy-3-methyl-cyclobutyl]imidazo[l,2-b][l,2,4]triazin-6-yl]-[4- (trifluoromethyl)cyclohexyl]methyl]isoxazole-4-carboxamide (syn isomer):or a salt and / or solvate thereof.

3. The compound of formula (I) or a salt and / or solvate thereof as claimed in claim 1 or claim 2, wherein the salt and / or solvate is a pharmaceutically acceptable salt and / or solvate.

4. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, for use in therapy.

5. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, for use in the treatment and / or prevention of disorders for which the administration of a modulator of IL- 17 function is indicated.

6. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, for use in the treatment and / or prevention of an inflammatory or autoimmune disorder.

7. A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, in association with a pharmaceutically acceptable carrier.

8. The use of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, 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.

9. The use of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3, for the manufacture of a medicament for the treatment and / or prevention of an inflammatory or autoimmune disorder.

10. 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 the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3.

11. A method for the treatment and / or prevention of an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as claimed in claim 3.

12. A compound of formula (II):or a salt and / or solvate thereof.

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