TW202440579A - Imidazotriazine derivatives as il-17 modulators - Google Patents

Abstract

N-[( S)-(4,4-Difluorocyclohexyl){3-[4-(2,2-difluoropropylcarbamoyl)-1-methoxy-carbonylpiperidin-4-yl]imidazo[1,2- b][1,2,4]triazin-6-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide, or a phar-maceutically acceptable salt thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatme-nt and/or prevention of various human ailments, including infla-mmatory and autoimmune disorders.

Description

Imidazolidinone derivatives as IL-17 modulators

The present invention relates to heterocyclic compounds and their use in therapy. More specifically, the present invention relates to pharmacologically active substituted imidazo[1,2- b ][1,2,4]triazolo ... These compounds act as modulators of IL-17 activity and are therefore useful as 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 founding member of the IL-17 family (Rouvier et al. , J. Immunol. , 1993, 150 , 5445-5456). Subsequently, five additional members of the family have been identified (IL-17B to IL-17F), 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-associated T helper cell subset Th17, which also expresses the 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 can also be expressed as IL-17A/F heterodimers (Wright et al. , J. Immunol. , 2008, 181 , 2799-2805). IL-17A and IL-17F signal through the receptors IL-17R, IL-17RC or IL-17RA/RC receptor complex (Gaffen, Cytokine , 2008, 43 , 402-407). Both IL-17A and IL-17F are associated with a variety of autoimmune diseases.

Compounds according to the present invention that are potent modulators of human IL-17 activity are therefore useful in the treatment and/or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

Furthermore, the compounds according to the invention may be useful as pharmacological standards for developing new biological tests and for finding new pharmacological agents. Thus, the compounds of the invention may be useful as radioligands in assays for detecting pharmacologically active compounds.

International patent applications PCT/EP2022/068165 (published as WO 2023/275301 on January 5, 2023) and WO 2020/261141, both of which are still pending, describe fused bicyclic imidazole derivatives that are shown to act as modulators of IL-17 activity, thereby being beneficial in treating pathological conditions including adverse inflammatory and autoimmune disorders.

However, the available prior art to date has not disclosed or suggested the substituted imidazo[1,2- b ][1,2,4]triazolidines as provided by the present invention. The exact structural class of the derivative.

In addition to being effective modulators of human IL-17 activity, the compounds according to the present invention also have other significant advantages. In particular, the compounds of the present invention show valuable metabolic stability, as measured in microsomes or hepatocyte cultures. The compounds of the present invention also show valuable permeability, as measured by standard tests, for example, the Caco-2 permeability test.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, .

The compounds according to the present invention are covered in the general scope of the international patent application PCT/EP2022/068165 (published as WO 2023/275301 on January 5, 2023), which is still under review. However, there is no specific disclosure of the compound of formula (I) as defined above or its pharmaceutically acceptable salt.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above 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 conditions for which 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 conditions for which administration of a modulator of IL-17 function is indicated.

The present invention also provides a method for treating and/or preventing a condition for which administration of a modulator of IL-17 function is indicated, comprising 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.

For use in medicine, salts of compounds of formula (I) will be pharmaceutically acceptable salts. However, other salts may be useful in the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof. Standard principles in the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use , ed. PH Stahl & CG Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts, which may be formed, for example, by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid.

Unless otherwise stated or presented, formula (I) and the chemical formulae described hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof. In addition, compounds of formula (I) may exist as tautomers, such as amide (NHC=O)↔hydroxyimine (N=COH) tautomers. Unless otherwise stated or presented, formula (I) and the chemical formulae described hereinafter are intended to represent all individual tautomers and all possible mixtures thereof.

It should be understood that each individual atom present in formula (I) or in the chemical formulae described below may in fact be present in the form of any of its naturally occurring isotopes, preferably the most abundant isotope. Thus, for example, each individual hydrogen atom present in formula (I) or in the chemical formulae described below may be present as a ¹ H, ² H (deuterium) or ³ H (tritium) atom, preferably ¹ H. Similarly, for example, each individual carbon atom present in formula (I) or in the chemical formulae described below may be present as a ¹² C, ¹³ C or ¹⁴ C atom, preferably ¹² C.

The compounds according to the invention are useful in the treatment and/or prevention of a variety of human diseases, including inflammatory and autoimmune disorders.

The compounds according to the invention are useful for the treatment and/or prevention of pathological abnormalities mediated by pro-inflammatory IL-17 cytokines or pathological abnormalities associated with increased levels of pro-inflammatory IL-17 cytokines. Generally, the pathological condition is selected from the group consisting of infection (viral, bacterial, fungal and parasitic), endotoxin shock associated with infection, arthritis, rheumatoid arthritis, psoriasis arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway 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, spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie's disease, coeliac disease, gallbladder 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-Barré syndrome), syndrome), other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrotic disorders (including pulmonary fibrosis, hepatic fibrosis, renal fibrosis, scleroderma or systemic sclerosis), cancer (both solid tumors (such as melanoma, hepatoblastoma, sarcoma, squamous cell carcinoma, transitional cell carcinoma, ovarian cancer) and hematological malignancies, especially acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, gastric cancer and colorectal cancer), heart disease (including ischemic disease such as myocardial infarction) as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydria, and pain (especially pain related to inflammation).

WO 2009/089036 discloses that modulators of IL-17 activity can be administered to inhibit or reduce the severity of ocular inflammatory disorders, especially ocular surface inflammatory disorders, including dry eye syndrome (DES). Therefore, the compounds according to the present invention are useful for treating and/or preventing IL-17-mediated ocular inflammatory disorders, especially IL-17-mediated ocular surface inflammatory disorders, including dry eye syndrome. Inflammatory ocular surface disorders include dry eye syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, inflammatory conditions of the corneal ocular surface, conjunctival scarring disorders, ocular autoimmune conditions, pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergies, severe allergic (ectopic) eye disease, conjunctivitis, and microbial keratitis. Specific categories of dry eye syndromes include keratoconjunctivitis sicca (KCS), Sjögren syndrome, Sjögren syndrome-related keratoconjunctivitis sicca, non-Sjögren syndrome-related keratoconjunctivitis sicca, keratitis sicca, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), tetanus gland dysfunction, and evaporative loss.

Illustratively, the compounds of the present invention may be useful for treating and/or preventing a pathological abnormality selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriasis arthritis, systemic juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive respiratory disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, pulmonary fibrosis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), axial spondylitis, ankylosing spondylitis and other spondyloarthropathies, cancer, and pain (particularly pain associated with inflammation).

Suitably, the compounds of the invention are useful for the treatment and/or prevention of psoriasis, psoriasis arthritis, hidradenitis suppurativa, axial spondyloarthritis or ankylosing spondylitis.

The present invention also provides a pharmaceutical composition comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof as described above and one or more pharmaceutically acceptable carriers.

The pharmaceutical composition according to the present invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, intraocular or rectal administration; or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets, lozenges or capsules, which are prepared by conventional means with pharmaceutically acceptable: a binder such as pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose; a filler such as lactose, microcrystalline cellulose or calcium hydrogen phosphate; a lubricant such as magnesium stearate, talc or silica; a disintegrant such as potato starch or sodium glycolate; or a wetting agent such as sodium lauryl sulfate. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of solutions, syrups or suspensions, for example; or they may be present as dry products to be constituted with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifiers, non-aqueous vehicles or preservatives. If appropriate, the preparations may also contain buffer salts, flavoring agents, coloring agents or sweeteners.

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

For buccal administration, the composition may take the form of tablets or lozenges formulated in known manner.

The compounds according to the invention may be formulated for parenteral administration by injection, for example by bolus injection or infusion. Formulations for injection may be in unit dosage form, for example in glass ampoules or multi-dose containers (e.g., glass vials). Compositions for injection may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents, such as suspending agents, stabilizers, preservatives and/or dispersants. 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 above-mentioned formulations, the compounds according to the present invention may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer, using a suitable propellant, e.g., dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.

If desired, the compositions may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispenser device may be accompanied by instructions for administration.

For topical administration, the compounds according to the present invention can be conveniently formulated in suitable ointments containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, liquid wax, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention can be formulated in suitable lotions containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Specific carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetearyl wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.

For intraocular administration, the compounds according to the invention may be conveniently formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for intraocular administration, the compounds according to the invention may be formulated in an ointment such as petroleum grease.

For rectal administration, the compounds according to the invention may conveniently be formulated as suppositories. These may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

The amount of a compound according to the invention required to prevent or treat a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. However, in general, for oral or buccal administration, the daily dose may be in the range of about 10 ng/kg to 1000 mg/kg body weight, typically from 100 ng/kg to 100 mg/kg body weight, e.g., about 0.01 mg/kg to 40 mg/kg body weight; for parenteral administration, from about 10 ng/kg to 50 mg/kg body weight; and for nasal administration or administration by inhalation or insufflation, from about 0.05 mg to about 1000 mg, e.g., from about 0.5 mg to about 1000 mg.

If desired, the compounds according to the invention may be co-administered with another pharmaceutically active agent, such as an anti-inflammatory molecule.

The compound of formula (I) can be prepared by a process comprising reacting a compound of formula (II) with methyl chloroformate. .

The reaction is ideally carried out in the presence of a base. Suitable bases include organic amines, for example trialkylamines, such as N,N -diisopropylethylamine. The reaction is conveniently carried out at a temperature of about 0°C in a suitable solvent, for example a chlorinated solvent, such as dichloromethane.

The intermediate of formula (II) can be prepared by removing the N -protecting group ^Rq from the compound of formula (III). wherein ^Rq represents an N -protecting group.

The N -protecting group ^Rq may suitably be tertiary butoxycarbonyl (BOC), in which case its removal may conveniently be effected by treatment with an acid, for example a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

The intermediate of formula (III) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) in the presence of a transition metal catalyst. wherein ^Rq is as defined above.

Suitable transition metal catalysts for the reaction include [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridyl- N 1, N 1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl- N ]phenyl-C}iridium(III) hexafluorophosphate; ^{and tris[2-phenylpyridinato-C 2 ,} N ] iridium(III). The reaction can generally be carried out by exposing the reactants to a bright light source. Suitable bright light sources can generally include an "integrated photoreactor" described in ACS Cent. Sci. , 2017, 3 , 647-653; or a Penn photoreactor M2 system. The reaction is conveniently carried out at ambient temperature in the presence of trifluoroacetic acid in a suitable solvent, for example a dipolar aprotic solvent such as N , N -dimethylformamide or an organic disulfide such as dimethyl sulfoxide.

The intermediate of formula (V) can be prepared by including 4-methyl-1,2,5- The process for reacting oxadiazole-3-carboxylic acid with a compound of formula (VI) is prepared. .

The reaction is conveniently carried out 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-oxide hexafluorophosphate (HATU); and 2,4,6-tripropyl-1,3,5,2,4,6-trioxotriphosphorus. -2,4,6-trioxide (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, for example: trialkylamines such as N , N -diisopropylethylamine; or pyridine. The reaction is conveniently carried out at ambient temperature or at an elevated temperature in a suitable solvent, for example: a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as N , N -dimethylformamide or N , N -dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.

The intermediate of formula (VI) can be prepared by removing the N -protecting group R ^p from the compound of formula (VII). wherein R ^p represents an N -protecting group.

The N -protecting group ^R may suitably be benzyloxycarbonyl, in which case its removal may be conveniently effected by catalytic hydrogenation, typically by treatment with hydrogen or ammonium formate in the presence of a hydrogenation catalyst such as palladium on carbon, or palladium hydroxide on carbon. In a variant process, where the N -protecting group ^R is benzyloxycarbonyl, its removal may be effected by treatment with hydrogen bromide and acetic acid.

The intermediate of formula (VII) can be obtained by reacting 1,2,4-triazine -3-amine is reacted with a compound of formula (VIII) to prepare the wherein R ^p is as defined above, and L ¹ represents a suitable leaving group.

The ionizing group ^L1 is usually a halogen atom, such as bromine.

The reaction is usually carried out in the presence of a base. Suitably, the base may be an inorganic base, for example a bicarbonate, such as sodium bicarbonate, or an organic base, such as pyridine. The reaction is conveniently carried out at elevated temperature in a suitable solvent, for example _a C _{1 -4} alkanol, such as ethanol or isopropanol, or a cyclic ether, such as 1,4-dihydro-1- pyridine. alkyl.

The intermediate of formula (IV) can be prepared by a two-step process comprising: (i) saponifying the compound of formula (IX), wherein R ^q is as defined above, and Alk ¹ represents a C _1-4 alkyl group, such as methyl; and (ii) reacting the carboxylic acid derivative thus obtained with N -hydroxyphthalimide.

When Alk ¹ represents a methyl group, the saponification reaction in step (i) can usually be carried out by treatment with a base. Suitable bases include inorganic hydroxides, for example alkali metal hydroxides, such as lithium hydroxide or sodium hydroxide. The reaction is conveniently carried out at ambient temperature or at an elevated temperature in water and a suitable organic solvent, for example: a cyclic ether, such _as tetrahydrofuran; or _a C _1-4 alkanol, such as methanol or ethanol; or a chlorinated solvent, such as dichloromethane.

Step (ii) may conveniently be carried out in the presence of a coupling agent, such as N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride. The reaction is suitably carried out at ambient temperature in a suitable solvent, such as a dipolar aprotic solvent, such as N,N -dimethylformamide.

The intermediate of formula (IX) can be prepared by reacting the compound (VI) with 4-methyl-1,2,5- The method is prepared by reacting a carboxylic acid derivative of formula (X) with 2,2-difluoropropylamine or a salt thereof (e.g., hydrochloride) under the conditions of a reactant between oxadiazole-3-carboxylic acid and oxadiazole-3-carboxylic acid. wherein R ^q and Alk ¹ are as defined above.

Where they are not commercially available, the starting materials of formula (VIII) and (X) may be prepared by methods analogous to those described in the accompanying Examples or by standard methods well known in the art.

In the case where a mixture of products is obtained from any of the above-mentioned processes for preparing the compounds according to the present invention, the desired product can be separated therefrom at an appropriate stage by known methods, such as preparative HPLC or column chromatography using, for example, silica and/or alumina in combination with an appropriate solvent system.

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 involved. This may be achieved by means of known protecting groups, such as those described in Greene's Protective Groups in Organic Synthesis , ed. PGM Wuts, John Wiley & Sons, ^5th edition, 2014. Protecting groups may be removed at any convenient subsequent stage using methods known in the art.

The compounds according to the present invention effectively inhibit IL-17-induced IL-6 release from human dermal fibroblasts. Thus, when tested in the HDF cell line assay described below, the compounds of the present invention exhibit _pIC50 values exceeding 8.0 ( _pIC50 is equal to _-log10 [ _IC50 ], where _IC50 is expressed as molar concentration, and one of ordinary skill in the art will understand that higher _pIC50 values represent more active compounds).

Inhibition of IL - 17A- induced IL - 6 release from dermal fibroblast cell lines The purpose of this assay was to test the ability to neutralize the IL-17 protein in a human primary cell system. Stimulation of normal human dermal fibroblast cells (HDF) with IL-17 alone produces only a weak signal, but in combination with certain other cytokines (such as TNFα) a synergistic effect in the production of inflammatory cytokines (i.e., IL-6) is observed.

HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (25 pM). The resulting IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio. The kit utilizes two monoclonal antibodies, one labeled with Eu-Cryptate (donor) and the second labeled with d2 or XL665 (acceptor). The signal intensity is proportional to the concentration of IL-6 present in the sample (ratio calculated as 665/620 x 10 ⁴ ).

In this assay, the ability of compounds to inhibit IL-17-induced IL-6 release from human dermal fibroblasts is measured.

HDF cells (Sigma #106-05n) were cultured in complete medium (DMEM + 10% FCS + 2 mM L-glutamine) using standard techniques and maintained in tissue culture flasks. Cells were harvested from tissue culture flasks using TrypLE (Invitrogen #12605036) on the morning of the assay. TrypLE was neutralized with complete medium (45 mL) and cells were centrifuged at 300 x g for 3 minutes. Cells were resuspended in complete medium (5 mL), counted and adjusted to a concentration of 3.125 x 10 ⁴ cells/mL before being added to 384-well plates (Corning #3701) at 40 μL per well. Incubate the cells at 37°C/5% CO ₂ for a minimum of 3 hours to allow them to attach to the plate.

Compounds were serially diluted in DMSO and the aqueous dilutions were received in a 384-well dilution plate (Greiner #781281) where 5 μL was transferred from the plate into 45 μL of complete medium and mixed to give a solution containing 10% DMSO.

A mixture of TNFα and IL-17 cytokines was prepared in complete medium to a final concentration of TNFα 25 pM/IL-17A 50 pM, and 30 μL of this solution was added to a 384-well plate (Greiner #781281).

Transfer 10 μL from the aqueous dilution plate to the reagent plate containing 30 μL of diluted cytokine to obtain a 2.5% DMSO solution. Incubate the compound and cytokine mixture at 37°C for 5 hours. After incubation, transfer 10 μL to the assay plate to obtain a 0.5% DMSO solution and incubate at 37°C/5% _CO2 for 18-20 hours.

Europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1:1 from the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) according to the kit instructions. FRET reagent (10 μL) was added to a white low-volume 384-well plate (Greiner #784075), and the supernatant (10 μL) was transferred from the assay plate to the Greiner reagent plate. The mixture was incubated at room temperature for 3 hours with gentle shaking (<400 rpm) and then read on a Synergy Neo 2 plate reader (excitation: 330 nm; emission: 615/645 nm).

When tested in the HDF cell line assay as described above, the compound of Example 1 below was found to exhibit a _pIC50 value of 8.2.

The following examples illustrate the preparation of compounds according to the present invention.

Embodiment Abbreviation DCM: dichloromethane THF: Tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: N , N -diisopropylethylamine DMF: N , N -dimethylformamide EtOAc: ethyl acetate TFA: trifluoroacetic acid IPA: Isopropyl alcohol AcOH: acetic acid EDCI.HCl: N -(3-Dimethylaminopropyl)- N '-ethylcarbodiimide hydrochloride HATU: 1-[Bis(dimethylamino)methylene]-1H - 1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate {Ir[dF(CF ₃ )ppy] ₂ (dtbpy)} PF ₆ : [4,4'-Bis(1,1-dimethylethyl)-2,2'-bipyridine- N 1, N 1']bis-{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl- N ]phenyl-C} iridium(III) hexafluorophosphate h: hours rt: room temperature M: mass; mole RT: Retention time HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography-Mass Spectrometry HRMS: High Resolution Mass Spectrometry TOF-MS: Time of Flight Mass Spectrometry

Analysis and separation methods Method 1 Short pH 10 Stationary Phase: Phenomenex Gemini NX-C18 2 x 20 mm, 3 μm Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Shift phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow Rate: 1 mL/min Gradient Program: time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00

Method 2 Short pH 3 Stationary Phase: Phenomenex Gemini NX-C18 2 x 50 mm, 3 μm Column temperature: 40℃ Phase A: 10 mM ammonium formate in water + 0.1% formic acid Shift phase B: Acetonitrile + 5% water + 0.1% formic acid Flow Rate: 1 mL/min Gradient Program: time A% B% 0.00 95.00 5.00 1.80 5.00 95.00 2.10 5.00 95.00 2.30 95.00 5.00

Method 3 MSDXT, pH 10 Stationary Phase: Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μm Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Shift phase B: Acetonitrile + 5% water + 0.1% ammonia solution Flow Rate: 1.5 mL/min Gradient Program: time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00

Method 4 HRMS was performed on a Waters UPLC system with a Xevo G2 QToF mass spectrometer. The mass spectrometer was calibrated using a solution of sodium iodide and cesium iodide in a 1:1 mixture of IPA and water, and leucine-enkephalin was used as an internal calibrant. The injection method was a 5-95% gradient of acetonitrile (+ 5% H ₂ O + 0.08% formic acid + 0.02% TFA) in water (+ 0.08% formic acid + 0.02% TFA) over 2 minutes using a Waters BioResolve RP mAb polyphenyl column (2.7 µm, 2.1 mm x 150 mm) maintained at 80°C. The flow rate was 1 mL/min.

Method 5 was analyzed on a Waters Acquity UPC² coupled to a QDa mass spectrometer using a Regis (R,R)-Whelk-O1 (150 x 4.6 mm, 5 µm) at a flow rate of 3.0 mL/min and a column temperature of 35°C with a 6.5 min elution gradient of 3.0 to 40.0% CO ₂ (120 bar).

Intermediate 1 N -[( S )-(4,4-difluorocyclohexyl)(imidazo[1,2- b ][1,2,4]triazine A mixture containing N -[(1 S )-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]-carbamic acid benzyl ester (300 mg, 0.74 mmol), 1,2,4-trifluoromethyl]-1-[(1 S )-3-bromo-1-(4,4-difluorocyclohexyl)-2-oxopropyl]-carbamic acid benzyl ester (300 mg, 0.74 mmol), A mixture of -3-amine (70.0 mg, 0.74 mmol) and NaHCO ₃ (75.0 mg, 0.89 mmol) in IPA (5 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated and the residue was purified twice by flash column chromatography, eluting with a gradient of 0-60% EtOAc in hexanes to give the title compound as a brown solid (111 mg, 36%). LCMS (Method 1): [M+H] ⁺ m/z 402.2, RT 1.27 min.

Intermediate 2 (S)-(4,4-difluorocyclohexyl)(imidazo[1,2-b][1,2,4]triazine To a solution of intermediate 1 (900 mg, 2.02 mmol) in AcOH (6 mL) was added AcOH (35%, 3.3 mL, 20.2 mmol) containing hydrogen bromide. The solution was stirred at room temperature for 2 hours. Diethyl ether (50 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was collected by vacuum filtration. The viscous residue was washed with diethyl ether (2 x 50 mL) and transferred from the filter paper to a separatory funnel by rinsing with water. The aqueous layer was washed with DCM (50 mL) and then alkalized with saturated aqueous NaHCO _3. The resulting material was extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL) and dried over MgSO ₄ , then filtered and concentrated under reduced pressure to give the title compound (435 mg, 78%). δ _H (500 MHz, CDCl ₃ ) 8.42 (d, J 2.0 Hz, 1H), 8.33 (d, J 2.0 Hz, 1H), 7.90 (s, 1H), 4.07 (d, J 6.3 Hz, 1H), 2.38-1.87 (m, 6H), 1.82-1.58 (m, 3H), 1.56-1.36 (m, 2H). LCMS (Method 2): [M+H] ⁺ 268.2, RT 1.26 min.

Intermediate 3 N -[( S )-(4,4-difluorocyclohexyl)(imidazo[1,2- b ][1,2,4]triazine -6-yl)methyl]-4-methyl-1,2,5- The oxadiazole-3-carboxamide was used to synthesize the intermediate 2 (435 mg, 1.58 mmol), 4-methyl-1,2,5- To a solution of oxadiazole-3-carboxylic acid (222 mg, 1.74 mmol) and DIPEA (0.55 mL, 3.16 mmol) in anhydrous DMF (10 mL) was added HATU (720 mg, 1.89 mmol). The mixture was stirred at room temperature for 30 minutes, then diluted with EtOAc (25 mL) and washed with water (2 x 25 mL), followed by brine (10 mL). The organic layer was dried over MgSO ₄ , then filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane to give the title compound (460 mg, 77%). δ _H (500 MHz, CDCl ₃ ) 8.49 (d, J 1.9 Hz, 1H), 8.39 (d, J 1.9 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J 9.0 Hz, 1H), 5.35-5.28 (m, 1H), 2.60 (s, 3H), 2.31-2.21 (m, 1H), 2.21-2.11 (m, 1H), 2.11-1.98 (m, 2H), 1.85-1.61 (m, 3H), 1.58-1.46 (m, 1H), 1.44-1.32 (m, 1H). LCMS (Method 2): [M+H] ⁺ 378.2, RT 2.09 min.

Intermediate 4 4-(2,2-Difluoropropylaminomethyl)piperidine-1,4-dicarboxylic acid O ¹ -tert-butyl ester O ⁴ -methyl ester To a solution of 1-(tert-butyloxycarbonyl)-4-methoxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.48 mmol), 2,2-difluoropropylamine hydrochloride (572 mg, 4.18 mmol) and DIPEA (1.82 mL, 10.4 mmol) in DMF (17 mL) was added HATU (1.62 g, 4.18 mmol). The mixture was stirred at room temperature for 10 minutes, then diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to give the title compound as a colorless oil (1.26 g, 99%). LCMS (Method 1): [M-BOC+H] ⁺ m/z 265.2, RT 0.98 min.

Intermediate 5 1-(tert-Butyloxycarbonyl)-4-(2,2-difluoropropylaminocarbonyl)piperidine-4-carboxylic acid To a solution of intermediate 4 (1.26 g, 3.45 mmol) in THF (14 mL) was added a solution of lithium hydroxide monohydrate (294 mg, 6.89 mmol) in water (3.5 mL). The reaction mixture was stirred at room temperature for 72 hours. A second portion of lithium hydroxide monohydrate (294 mg, 6.89 mmol) was added and the reaction mixture was stirred for 2 hours, then acidified to pH 4 with 2.0 M aqueous HCl (7 mL) and diluted with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound as a colorless amorphous solid (1.12 g, 93%). LCMS (Method 1): [M-BOC+H] ⁺ m/z 251.2, RT 0.57 min.

Intermediate 6 4-(2,2-Difluoropropylaminomethyl)piperidine-1,4-dicarboxylic acid O ¹ -tert-butyl ester O ⁴ -(1,3-dioxoisoindol-2-yl) ester To a solution of intermediate 5 (1.12 g, 3.20 mmol) and N -hydroxyphthalimide (591 mg, 3.52 mmol) in DMF (16 mL) was added EDCI.HCl (681 mg, 3.52 mmol). The mixture was stirred at room temperature for 1.5 hours, then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-100% EtOAc in isohexane to afford the title compound as a colorless amorphous solid (1.22 g, 77%). LCMS (Method 1): [M-BOC+H] ⁺ m/z 396.2, RT 1.19 min.

Intermediate 7 4-(6-{( S )-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5- oxadiazole-3-carbonyl)-amino]methyl}imidazo[1,2- b ][1,2,4]triazol _N2 gas was bubbled through a solution of intermediate 3 (400 mg, 1.06 mmol), intermediate 6 (1050 mg, 2.12 mmol), {Ir[dF( _CF3 )ppy] ₂ (dtbpy)} _PF6 (24 mg, 0.02 mmol) and TFA (121 μL, 1.59 mmol) in DMSO (21 mL) for 5 min. The reaction mixture was placed under 450 nm irradiation at room temperature for 45 h, then quenched with saturated aqueous _NaHCO3 solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0-50% EtOAc in isohexane to afford the title compound as an orange amorphous solid (500 mg, 69%). LCMS (Method 1): [M+H] ⁺ m/z 682.4, RT 1.25 min.

Intermediate 8 N -[( S )-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylaminoformyl)piperidin-4-yl]-imidazo[1,2- b ][1,2,4]triazine -6-yl}methyl]-4-methyl-1,2,5- Oxadiazole-3-carboxamide To a solution of intermediate 7 (500 mg, 0.73 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 3.5 hours and then quenched with aqueous NaHCO ₃ (50 mL). The aqueous layer was extracted with DCM (3 x 25 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to give the title compound (316 mg, 74%) as a colorless amorphous solid. LCMS (Method 1): [M+H] ⁺ m/z 582.4, RT 0.92 min.

Embodiment 1 N -[( S )-(4,4-difluorocyclohexyl){3-[4-(2,2-difluoropropylaminomethyl)-1-methoxy-carbonylpiperidin-4-yl]imidazo[1,2- b ][1,2,4]triazol -6-yl}methyl]-4-methyl-1,2,5- Oxadiazole-3-carboxamide Intermediate 8 (135 mg, 0.2321 mmol) was dissolved in DCM (10 mL) and cooled using an external ice bath. DIPEA (0.10 mL, 0.58 mmol) was added followed by methyl chloroformate (25 mg, 0.26 mmol). After 1 h, the reaction mixture was diluted with DCM (20 mL) and partitioned between saturated aqueous NaHCO ₃ solution (50 mL). The mixture was phase separated using a hydrophobic frit and the organic layer was concentrated in vacuo. The crude residue was purified by column chromatography (Biotage SFAR HC DUO, 10 g, Isolera) eluting with a gradient of 1-100% EtOAc in isohexane to afford the title compound (100 mg, 67.9%) as a light yellow solid. δ _H (300 MHz, DMSO-d ₆ ) 9.52 (d, J 8.9 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.18 (t, J 6.3 Hz, 1H), 5.22 (t, J 8.5 Hz, 1H), 3.61 (s, 3H), 3.60-3.39 (m, 6H), 2.47 (s, 3H), 2.45-1.50 (m, 16H). ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 172.43, 157.34, 155.55, 154.54, 152.05, 149.82, 147.84, 140.95, 138.49, 127.02, 125.73, 124.63, 123.35, 122.25, 120.97, 113.01, 52.79, 52.43, 51.69, 44.66, 44.36, 44.05, 40.95, 39.27, 33.19, 33.07, 32.96, 32.83, 32.72, 32.60, 31.68, 26.24, 26.15, 25.54, 25.45, 22.08, 21.82, 21.56, 8.98. ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -90.21 (d, J 232.5 Hz, 1F), -93.21 to -93.98 (m, 2F), -97.21 to -100.53 (m, 1F). LCMS (Method 3): [M+H] ⁺ m/z 640.2, RT 1.87 min. TOF-MS (positive m / z ) (Method 4): [M+H] ⁺ calcd. for C ₂₇ H ₃₄ N ₉ O ₅ F ₄ : 640.2619; found: 640.2622. Chiral analysis (Method 5): [M+H] ⁺ m / z 640.0, RT 5.13 min.

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Claims (9)

A compound of formula (I) or a pharmaceutically acceptable salt thereof, . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 is used for treatment. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 is used for treating and/or preventing a disease for which administration of a modulator of IL-17 function is indicated. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 is used for treating and/or preventing inflammatory or autoimmune diseases. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the manufacture of a medicament for treating and/or preventing a disease for which administration of a modulator of IL-17 function is indicated. A use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for the manufacture of a medicament for treating and/or preventing inflammatory or autoimmune diseases. A method for treating and/or preventing a disease for which administration of a modulator of IL-17 function is indicated, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 to a patient in need of such treatment. A method for treating and/or preventing inflammatory or autoimmune diseases, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 to a patient in need of such treatment.