WO2023025783A1 - Modulateurs à petites molécules d'il-17 - Google Patents

Modulateurs à petites molécules d'il-17 Download PDF

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Publication number
WO2023025783A1
WO2023025783A1 PCT/EP2022/073457 EP2022073457W WO2023025783A1 WO 2023025783 A1 WO2023025783 A1 WO 2023025783A1 EP 2022073457 W EP2022073457 W EP 2022073457W WO 2023025783 A1 WO2023025783 A1 WO 2023025783A1
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Prior art keywords
methyl
oxo
difluorocyclohexyl
pyridazin
ate
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PCT/EP2022/073457
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English (en)
Inventor
Mark Andrews
Jimmi Gerner Seitzberg
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Leo Pharma A/S
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Publication of WO2023025783A1 publication Critical patent/WO2023025783A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This invention relates to novel am ino-acid anilides and derivatives thereof, to said compounds for use in therapy and to pharmaceutical compositions comprising said compounds.
  • I L-17 (also known as I L-17 A or CTLA8) is a pro- inflam mat ory cytokine involved in antimicrobial defense at epithelial surfaces.
  • I L-17 is comprised of two covalently joined I L-17A subunits (I L-17AA) with an approximate mass of 32 kDa, and signals through a receptor comprising I L17RA and I L17 RC subunits. This receptor is predominantly expressed in epithelial and mesenchymal cells.
  • the I L17RA/I L17RC receptor is also used by I L-17 variants I L-17AF and I L-17FF, which both are successively weaker, partial agonists on this receptor (Monin, L., Gaffen, S.L. ; 2018, Cold Spring Harb. Perspect. Biol. 10.
  • Crucial for signaling is the assembly of signaling complexes containing the m ultifunctional protein ACT1 /CI KS, which in turn can recruit TRAF and other proteins.
  • I L-17 induces cytokines, chemokines, antimicrobial peptides and growth factors via activation of transcription factor NFkB or via MAP kinase-dependent pathways (e.g. I L-6, I L-8, CXCL1 , CXCL2, CXCL5, CCL20, G-CSF, BD4) and stabilizes the m RNAs of certain inflammatory cytokines, such as CXCL1 . This leads to amplification of their effects. Further, I L-17 acts in concert with I L-1 beta, I L-22 and I FNgamma (Amatya, N. et al., Trends in I m munology, 2017, 38, 310-322.
  • I L-17 is secreted by a variety of imm une cells, such as Th17 helper cells, Tc17 cytotoxic cells, I LC3 innate cells, NKT cells, TCRbeta+ natural T cells and gam ma-deltaT-cells (Monin, L., Gaffen, S.L. ; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10.1 101 /csh perspect. a028522) .
  • imm une cells such as Th17 helper cells, Tc17 cytotoxic cells, I LC3 innate cells, NKT cells, TCRbeta+ natural T cells and gam ma-deltaT-cells (Monin, L., Gaffen, S.L. ; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10.1 101 /csh perspect. a028522) .
  • I L-17 is a significant therapeutic target.
  • diseases such as psoriasis, ankylosing spondylitis, spondyloarthritis and psoriatic arthritis.
  • Other diseases where deregulation of I L-17 is observed are rheumatoid arthritis, systemic lupus erythematosus, asthma, inflam matory bowel disease, autoimm une uveitis, multiple sclerosis and certain cancers (Gaffen, S.L. et al., Nat Rev I mm unol., 2014, 14, 585-600. doi: 10.1038/nri3707; Monin, L., Gaffen, S.L. ; 2018, Cold Spring Harb. Perspect. Biol. 10. doi: 10.1 101 / csh perspect. a028522) .
  • I L-17 is a significant therapeutic target.
  • Orally available, highly efficacious small molecule I L-17 modulators which bind to I L-17 to decrease its functional ability to activate the I L- 17 receptor complex may have a number of advantages compared to monoclonal antibodies.
  • Oral administration and flexible treatment regimen may be two significant aspects in favor of patient convenience and the compounds may exhibit improved safety due to the possibility of faster withdrawal of the drug should adverse events occur.
  • small molecule modulators of I L-17 particularly small molecules suitable for oral adm inistration.
  • some patients may be treated by topical application of small molecule modulators of I L-17. This can be particularly suitable for patients with skin lesions that are readily accessible and lim ited in body surface area. Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the I L-17 pathway, for example when undergoing treatment for infections or gastrointestinal problems.
  • novel compounds of the present invention exhibit modulating effects on the I L-17 signalling pathway.
  • Compounds of the present invention may have advantageous properties such as high metabolic stability and/or membrane permeability properties that make them suitable for oral adm inistration.
  • Other compounds of the present invention may have advantageous properties for local topical therapy, such as high skin permeability and high metabolic instability.
  • Compounds of the present invention may be beneficial in preventing, treating or ameliorating a variety of diseases which involve up-regulation or de- regulation of I L-17, such as for example psoriasis, ankylosing spondylitis and psoriatic arthritis.
  • the present invention relates to a compound according to formula (I ) wherein Ri is selected from (C3-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(CH2)-, (C3- C7)heterocycloalkyl, (C3-C7)heterocycloalkyl(CH2)- and 5-membered heteroaryl(CH2)- wherein said (C3-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(CH2)-, (C3- C7)heterocycloalkyl, (C3-C7)heterocycloalkyl(CH2)- and 5-membered heteroaryl(CH2)- is optionally substituted with one or more substituents independently selected from R a ;
  • R a represents deuterium , halogen, cyano, ( Ci - C3) alky I , and halo(Ci-C3)alkyl;
  • R2 is hydrogen or methoxymethyl; or pharmaceutically acceptable salts, thereof.
  • the present invention relates to compounds of form ula (l a) wherein Ri and R2 are as defined in claim 1 or pharmaceutically acceptable salts thereof.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I ) as defined herein together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s), optionally together with one or more other therapeutically active compound(s) .
  • the invention relates to the use of a compound according to formula (I) as defined herein for use in therapy, for example for use in treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of I L- 17, for example for use in treatment of autoim mune diseases.
  • Figure 1 A XRPD pattern for form A (3-45° 2theta)
  • Figure 1 B XRPD pattern for form A (3-30° 2theta)
  • Figure 2A XRPD pattern for form B (3-45° 2theta)
  • FIG. 3 DSC and TGA curve of form A.
  • the DSC curve consists of two endotherm ic events with an onset value at 146.9 ⁇ 2°C and 192.5 ⁇ 2° C followed by decomposition of the sample.
  • the first event is a solid solid transition from form A to form B and the second event is melting of form B.
  • the TGA reveal no weight loss event corresponding to the two endotherm ic events.
  • (Ca-Cb)alkyl is intended to indicate a hydrocarbon radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon.
  • Said alkyl comprises (a- b) carbon atoms, such as 1 -6, such as 1 -4, such as 1 -3, such as 2-3 or such as 1 -2 carbon atoms.
  • the term includes the subclasses normal alkyl (n-alkyl) , secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert. -butyl, n- pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.
  • cyano is intended to indicate a -CN group attached to the parent molecular moiety through the carbon atom .
  • (Ca-Cb)cycloalkyl is intended to indicate a saturated (Ca-Cb)cycloalkane hydrocarbon radical, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, comprising a-b carbon atoms, such as 3-10 carbon atoms, such as 3-8 carbon atoms, such as 3-7 carbon atoms, such as 3-6 carbon atoms, such as 3-5 carbon atoms or such as 3-4 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3] hexanyl, bicyclo[3, 1 ,0] hexanyl.
  • polycyclic radicals such as bicyclic or tricyclic radicals
  • spirocyclic radicals comprising a-b carbon atoms, such as 3-10 carbon atoms, such as 3-8 carbon atoms, such as 3-7 carbon
  • (C a -Cb)cycloalkyl(CH2) is intended to indicate an (CH2) group substituted with one (Ca-Cb)cycloalkyl as defined herein, suitably the (Ca-Cb)alkyl group is substituted with one (Ca-Cb)cycloalkyl group.
  • halo(C a -Cb)alkyl is intended to indicate an (Ca-Cb)alkyl group as defined herein substituted with one or more halogen atoms as defined herein, e.g. fluoro or chloro, such as difluoromethyl or trifluoromethyl.
  • halogen is intended to indicate a substituent from the 7 th main group of the periodic table, such as fluoro, chloro and bromo.
  • 5-membered heteroaryl is intended to indicate radicals of 5-membered monocyclic heteroaromatic ring which contains from 1 -4 carbon atoms and from 1 -4 heteroatoms selected from oxygen, sulphur and nitrogen; such as 2-4 carbon atoms and 1 - 3 heteroatoms, such as 3-4 carbon atoms and 1 -2 heteroatoms, such as 4 carbon atoms and 1 heteroatom selected from oxygen, sulphur and nitrogen; such as furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl and triazolyl.
  • the term ”5-membered heteroaryl includes compounds wherein a ring member is a C(O) or carbonyl group.
  • (5 heteroaryl)-(CH2)alkyl is intended to indicate a 5-membered heteroaryl appended to the parent molecular moiety through a (CH2) group.
  • (Ca-Cb)heterocycloalkyl is intended to indicate a cycloalkane radical as described herein, including polycyclic radicals such as bicyclic or tricyclic radicals, including spirocyclic radicals, wherein one or more carbon atoms of said cycloalkane radical are replaced by heteroatoms, i.e. the (Ca-Cb)heterocycloalkyl comprise from a to b carbon- or heteroatoms.
  • Such (Ca-Cb)heterocycloalkyl could comprise for example 2-9 carbon atoms and 1 -6 heteroatoms selected from O, N, or S, such as 3-8 carbon atoms and 1 -4 heteroatoms, such as 3-7 carbon atoms and 1 -3 heteroatoms, such as 3-6 carbon atoms and 1 -2 heteroatom .
  • the heterocycloalkyl radical may be connected to the parent molecular moiety through a carbon atom or a nitrogen atom contained anywhere within the heterocycloalkyl group.
  • heterocycloalkyl groups include, but are not limited to azepanyl, azetidinyl, aziridinyl, dioxolanyl, dioxolyl, im idazolidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thietanyl, 2,6- diazaspiro[3.3] heptane, 2,6-diazaspiro[3.3] heptanyl, 2,5-diazabicyclo[2.2.1 ] heptanyl, 2- oxa-5-aza-[2.2.1 ] heptanyl, 6-oxa-2-azaspiro[3.3] heptanyl, and 2-oxaspiro[3.3] heptanyl.
  • the term includes compounds wherein a ring member of said ” (C a -Cb) membered heterocycloalkyl” is a C(O) or carbonyl group and S(O) group.
  • (C a -Cb) eterocycloalkyl)-(CH2)-” is intended to indicate an a-b membered heterocycloalkyl radical appended to the parent molecular moiety through an (CH2) group.
  • hydrocarbon radical is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties.
  • Said hydrocarbon comprises 1 -6 carbon atoms, e.g. 1 -5, e.g. 1 -4, e.g. 1 -3, e.g. 1 -2 carbon atoms.
  • the term includes alkyl and cycloalkyl as indicated herein.
  • the first mentioned radical is a substituent on the latter mentioned radical, where the point of attachment to the parent molecular moiety is on the latter radical.
  • each substituent is selected independent of the other. Each substituent may therefore be identical or different from the other substituent(s).
  • optionally substituted means “unsubstituted or substituted”, and therefore the general form ulas described herein encompasses compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s) .
  • a suitable inorganic or organic acid such as hydrochloric, hydrobromic, hydroiodic, sulfur
  • Pharmaceutically acceptable salts of compounds of formula I comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, barium hydroxide, am monia or the like, or suitable non-toxic am ines, such as lower alkylam ines (such as diethylamine, tetraalkylam monium hydroxide) , hydroxy-lower alkylamines (such as diethanolamine, 2-(diethylam ino)-ethanol, ethanolam ine, triethanolamine, trometham ine, deanol) , cycloalkylamines, ethylene diam ine, or benzylamines, (such as benetham ine and benzathine) , betaine, choline hydroxide, N-methyl-glucam ine, hydrabam ine, 1 H-imidazole, 4-(2-hydroxyethyl)-morpholine,
  • solvate is intended to indicate a species formed by interaction between a compound, e.g. a compound of form ula I , and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a crystalline form .
  • a solvent e.g. alcohol, glycerol or water
  • water is the solvent
  • said species is referred to as a hydrate.
  • compositions of form ula (I ) and hydrates or solvates thereof includes compound of form ula (I ) and hydrates or solvates thereof, and pharmaceutically acceptable salts of the compounds of form ula(l) as well as hydrates or solvates thereof.
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the amelioration, alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the term may also include prevention of the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference, regardless of any separately provided incorporation of particular documents made elsewhere herein.
  • the invention relates to a compound of formula (I) or (la), wherein Ri is selected from (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(CH2)-, wherein said (C3- Cs)cycloalkyl and (C3-Cs)cycloalkyl(CH2)- is optionally substituted with one or more substituents independently selected from R a .
  • the invention relates to a compound of formula (I) or (la), wherein R1 is selected from (C3-C4)cycloalkyl and (C3-C4)cycloalkyl(CH2)-, wherein said (C3- C4)cycloalkyl or (C3-C4)cycloalkyl(CH2)- is optionally substituted with one or more flouro.
  • the invention relates to a compound of formula (I) or (la), wherein R1 is cyclopropyl.
  • the invention relates to a compound of formula (I) or (la), wherein R1 is cyclobutyl substituted with one or more fluoro.
  • the invention relates to a compound of formula (I) or (la), wherein R1 is cyclopropyl(CH2)- substituted with one or more fluoro.
  • the invention relates to a compound of formula (I) or (la), wherein R1 is 5-membered heteroaryl(CH2)- optionally substituted with one or more substituents independently selected from Ra.
  • the invention relates to a compound of formula (I) or (la), wherein R2 is methoxymethyl.
  • the invention relates to a compound of formula (I) or (la), selected from cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(4S)-2-oxo-4-
  • the invention relates to a compound of formula (I) or (la), selected from cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1 -[(4S)-2-oxo-4- ( t r if I u orom et hy I) i m id azo I id i n - 1 -yl] ethyl] i mid azo[ 1 ,2-b] pyridazin -2-yl] methyl] carbarn ate, (2,2-difluorocyclopropyl) methyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S) -2- m ethoxy- 1 - [(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1 -y
  • the compounds of general formula I have an (ECso) value in a HEK-BlueTM IL-17 assay of less than 1 micromolar, or of less than 100 nanomolar.
  • the compounds of formula I may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent that may be organic or inorganic, such as water.
  • the crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate.
  • the invention covers all crystalline forms, such as polymorphs and pseudopolymorphs, and also mixtures thereof.
  • Compounds of formula I comprise asymmetrically substituted (chiral) carbon atoms which give rise to the existence of isomeric forms, e.g. enantiomers and possibly diastereomers.
  • the present invention relates to all such isomers, either in optically pure form or as mixtures thereof (e.g. racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of procedures known in the art.
  • the various isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. high pressure liquid chromatography using chiral stationary phases.
  • Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts which may be formed with optically active amines, or with optically active acids. Optically purified compounds may subsequently be liberated from said purified diastereomeric salts. Enantiomers may also be resolved by the formation of diastereomeric derivatives. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occur stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials.
  • geometric isomers may be formed. Any geometric isomer, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atom ic mass or mass number found in nature.
  • the present invention includes all suitable isotopic variations of the compounds of general Form ula I .
  • different isotopic forms of hydrogen include 1 H, 2 H and 3 H
  • different isotopic forms of carbon include 12 C, 13 C and 14 C
  • different isotopic forms of nitrogen include 14 N and 15 N.
  • Enriching for deuterium ( 2 H) may for example increase in-vivo half-life or reduce dosage regimens, or may provide a compound useful as a standard for characterization of biological samples.
  • I sotopically enriched compounds within general form ula I can be prepared by conventional techniques well known to a person skilled in the art or by processes analogous to those described in the general procedures and examples herein using appropriate isotopically enriched reagents and/or intermediates.
  • the compounds of the present invention may be useful for preventing, treating or ameliorating any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjogren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE) , m ultiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum , hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyo
  • the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of any of the following diseases: psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, lichen planus, lupus nephritis, Sjogren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE) , m ultiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum , hidradenitis suppurativa, discoid lupus erythemat
  • the invention relates to the use of a compound of general formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of autoim mune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis.
  • autoim mune diseases such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis.
  • the invention relates to a method of preventing, treating or ameliorating autoim mune diseases, such as psoriatic arthritis, lichen planus, lupus nephritis, Sjogren’s syndrome, acne, vitiligo, alopecia areata, ichthyosis, acute and chronic liver diseases, gout, osteoarthritis, SLE (besides LN and DLE) , m ultiple sclerosis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, pityriasis rubra pilaris, pyoderma gangrenosum , hidradenitis suppurativa, discoid lupus erythematosus, Papulopustolar rosacea, atopic dermatitis, Ichthyosis, bullous pemphigoid, scleroderma, tendinopathy,
  • the invention relates to a method of preventing, treating or ameliorating autoim mune diseases, such as psoriasis, ankylosing spondylitis, spondyloarthritis or psoriatic arthritis, the method comprising administering to a person suffering from at least one of said diseases an effective amount of one or more compounds according to general form ula (I ) , optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.
  • the compounds of the present invention may also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats.
  • compositions of the I nvention are provided.
  • compounds of the present invention are typically in the form of a pharmaceutical composition.
  • the invention therefore relates to a pharmaceutical composition comprising a compound of form ula I , optionally together with one or more other therapeutically active compound(s) , together with a pharmaceutically acceptable excipient, vehicle or carrier(s) .
  • the excipient m ust be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the active ingredient comprises from 0.0001 -99.9% by weight of the form ulation.
  • a dosage unit of a formulation contain between 0.001 mg and 1000 mg, preferably between 0.01 mg and 300 mg of a compound of formula I .
  • a suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician.
  • the compound may be administered either orally, parenterally, topically, transdermally or intradermally and other routes according to different dosing schedules, e.g. daily, weekly or with monthly intervals. I n general, a single dose will be in the range from 0.001 to 400 mg/kg body weight.
  • the administration of a compound of the present invention with one or more other active compounds may be either concom itantly or sequentially.
  • the formulations include e.g. those in a form suitable for oral, rectal, parenteral transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal administration.
  • the formulations may conveniently be presented in dosage unit form and may be prepared by but not restricted to any of the methods well known in the art of pharmacy, e.g. as disclosed in Rem ington, The Science and Practice of Pharmacy, 21 ed ed., 2005. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. I n general, the formulations are prepared by uniform ly and intimately bringing the active ingredient into association with a liquid carrier, sem isolid carrier or a finely divided solid carrier or combinations of these, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral and buccal administration may be in the form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each containing a predeterm ined amount of the active ingredient.
  • a tablet may be made by compressing, moulding or freeze drying the active ingredient optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form ; for example with a lubricant, a disintegrating agent or a dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a m ixture of the powdered active ingredient and suitable carrier. Freeze dried tablets may be formed in a freeze-dryer from a solution of the drug substance.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Liposomal form ulations are also suitable for parenteral administration.
  • Transdermal formulations may be in the form of a plaster, patch, microneedles, liposomal or nanoparticulate delivery systems or other cutaneous form ulations applied to the skin.
  • Formulations suitable for ophthalmic adm inistration may be in the form of a sterile aqueous preparation of the active ingredients. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for ophthalmic adm inistration. Formulations suitable for topical, such as dermal, intradermal or ophthalm ic adm inistration include liquid or sem i-solid preparations, solutions or suspensions.
  • Formulations suitable for nasal or buccal administration include powder, self-propelling and spray form ulations, such as aerosols and atomisers.
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis.
  • the compounds of the invention could for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chem istry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not lim ited to, those described below.
  • the reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. Not all compounds falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.
  • the compounds of the present invention or any intermediate could be purified, if required, using standard methods well known to a synthetic organist chem ist, e.g. methods described in “ Purification of Laboratory Chemicals”, 6 th ed. 2009, W. Amarego and C. Chai, But terworth -Heinemann.
  • Mass spectra were obtained on a Waters Quattro micro API I Waters SQD2 I Waters Quattro Premier Spectrometer using electrospray ionization and atmospheric-pressure chem ical ionization with the colum n and solvents indicated.
  • Solid forms were characterised using the following methods: a. X-Ray Powder Diffraction (XRPD) (room temperature) :
  • XRPD patterns were collected with a PANalytical X’pert PRO MPD diffractometer using an incident Cu K « radiation and operating at 45 kV and 40 mA.
  • the XRPD patterns were collected in the 2 theta range from 3 to 45 degrees with a stepsize of 0.0066° , counting time of 148.93 s and in transm ission geometry.
  • I n the incident beam path, an elliptically graded multilayer mirror together with a 4 m m fixed mask, fixed anti-scatter slit 1 ° and fixed divergence slits of 1 /a° were placed to line focus the Cu K « X-rays through the sample and onto the detector.
  • XRPD X-Ray Powder Diffraction
  • XRPD patterns were collected with a PANalytical Empyrean diffractometer using an incident Cu K « radiation and operating at 45 kV and 40 mA.
  • the XRPD patterns were collected in the 2 theta range from 5 to 45 degrees with a stepsize of 0.0130°, counting time of 273.87 s and in reflection geometry through the x-ray transparence windows in the CHC+ temperature chamber from Anton Paar.
  • the sample was placed on a zero-background plate.
  • the diffraction patterns were collected using a PIXel RTMS detector with an active length of 3.347° and located 240 m m from the sample.
  • TGA Thermo gravimetric analysis
  • TGA experiments were conducted using a TGA550 instrument from TA I nstruments. About 1 -10 mg of sample was loaded into a ceramic pan for the measurements. The sample temperature was ramped from 25 to 500 e C at 10 e C/min. Nitrogen was used as the purge gas at a flow rate of 50 mL/m in.
  • DSC Differential Scanning Calorimetry
  • DSC The sample was run in modulated mode with an amplitude of 2°C, a period of 80 s and a heating rate of 2 « C/ min under a nitrogen atmosphere. About 1 -2 mg of sample was loaded into an open aluminum pan for the measurements. I nstrument X3 from TA I nstruments.
  • Compounds of general formula (I) can be prepared, as shown in Scheme 1 .
  • Compounds of form ula (I nt 1 ) which are synthesized, are reacted with compounds of general formula (I nt 2) in a suitable solvent such as THF, in the presence of a suitable base such as sodium bicarbonate or DI PEA at between 65 and 80°C, and optionally in the presence of trimethyl borate, to form compounds of general formula (I nt 3) .
  • the protecting group can be removed by methods known to those skilled in the art.
  • alcohols of general formula (I nt 5) can be reacted with reagents such as phosgene, diphosgene, triphosgene, CDI , 4-nitrophenyl chloroformate or bis(2,5- d ioxopy r rol id i n - 1 -yl) carbonate, optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DCM to form a reactive intermediate that is subsequently reacted with amines of general formula (I nt 4) , optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DMF, to give compounds of general formula (I) .
  • reagents such as phosgene, diphosgene, triphosgene, CDI , 4-nitrophenyl chloroformate or bis(2,5- d ioxopy r rol id i n
  • the amines of general formula (I nt 4) can be reacted with reagents such as phosgene, diphosgene, triphosgene, CDI , 4-nitrophenyl chloroformate or bis( 2 , 5 - d ioxopy r rol id i n - 1 -yl) carbonate, optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DCM to form a reactive intermediate that is subsequently reacted with alcohols of general formula (I nt 5) , optionally in the presence of a suitable base, such as TEA, in a suitable solvent, such as MeCN or DMF, to give compounds of general formula (I ) .
  • reagents such as phosgene, diphosgene, triphosgene, CDI , 4-nitrophenyl chloroformate or bis( 2 , 5 - d ioxopy r
  • the compound of form ula (I nt 10) can react with (2S)-3,3,3-trifluoropropane-1 ,2-diamine;dihydrochloride (I nt 1 1 , see W02020146194 A for preparation), to form an im ine that can be reduced with sodium cyanoborohydride in MeOH/AcOH to form the compound of form ula (I nt 12) .
  • Cyclisation to the compound of formula (I nt 13) can be effected with CDI in THF at 65°C. Removal of the pivaloyl protecting group can be achieved by methods known to those skilled in the art to give the compound of form ula (I nt 2) wherein R2 and X are H.
  • the compound of formula (I nt 22) can be prepared as shown in Scheme 3.
  • the am ine of form ula (I nt 14) can be protected by methods known to those skilled in the art, preferably using pivaloyl chloride in a solvent such as NMP or DMF, with a suitable base such as pyridine.
  • Reaction of the compound of form ula (I nt 15) with 1 ,1 -diethoxy-N.N.dimethyl- methanam ine in DMF at 120° C gives rise to the compound of formula (I nt 16).
  • Conversion of the enamine with sodium periodate in aqueous THF affords the compound of formula (Int 17).
  • the compound of formula (Int 25) can be accessed by the treatment of the compound of formula (Int 24) with (2S)-3,3,3-trifluoropropane-1 ,2- diamine ; dihydrochlor ide (Int 11, see W02020146194 A for preparation) in acetonitrile in the presence of sodium iodide and DIPEA. Cyclisation to the compound of formula (Int 26) is as for the formation of the compound of formula (Int 13).
  • Compounds of formula (Int 2), wherein R2 is H and Xis Cl, can be made by removal of the pivaloyl protecting group with aqueous hydrochloric acid at 70°C.
  • the compound of formula (Inf 33) can be prepared as shown in Scheme 5.
  • the Weinreb amide of formula (Inf 28) can be formed by reacting acetyl chloride of formula (Int 27) with A/,0-dimethylhydroxylamine in a solvent such as DCM using a base such as TEA.
  • the amine of formula (Int 29) can be protected by methods known to those skilled in the art, preferably using pivaloyl chloride in a solvent such as THF, NMP or DMF, with a suitable base such as TEA or pyridine, to give the compound of formula (Int 30).
  • A/,0-dimethylhydroxyiamine (253 g, 4.14 mol) was added dropwise to a solution of 2- methoxyacetyl chloride (254 mL, 2.76 mol) in DCM (3.0 L) over 20 m inutes at 0°C.
  • TEA (1 .2 L, 8.29 mol
  • the resulting reaction mixture was stirred at room temperature for 16 hours before it was quenched with water (1 .5 L) and extracted with DCM (2 x 2.0 L) .
  • the combined organic phases were washed with 1 M HCI (1 .5 L), sat.
  • TEA 6-chloropyridazin-3-amine
  • THF 2.5 L
  • Pivaloyl chloride 945 mL, 7.72 mol
  • the combined organic phases were washed with water (2.0 L) , brine (1 .5 L) , dried over Na2SC>4, filtered and concentrated in vacuo.
  • Preparation 17 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(difluoromethyl)-4H-isoxazol-5- ol Hydroxylamine hydrochloride (683 mg, 9.18 mmol) and sodium bicarbonate (771 mg, 9.18 mmol) were dissolved in water (2.3 mL) and stirred at room temperature for 30 min. This solution was then added to a solution of the compound of preparation 16 (1.90 g, 7.65 mmol) in THF (19 mL) at 0°C and stirred at room temperature for 3 days.
  • 2,2-difluorocyclopropanecarboxylic acid (2.5 g, 20 mmol) was added to a solution of (1 R)- 1 -(4-methoxyphenyl)ethanam ine (3.0 mL, 20 mmol) in MeCN (20 mL) and stirred at room temperature for 3 hours. The reaction mixture was then cooled to 0°C and left for 1 hour while crystallization was observed. The crystalline material was filtered and recrystallized 3 times from MeCN affording the title compound (1.49 g, 27% yield).
  • the compound of preparation 22 (434 mg, 3.55 mmol) in THF (4 mL) was added dropwise to a solution of Li AIH4 in THF (1 M, 3.9 mL, 3.9 mmol) and stirred over night at room temperature before the reaction mixture was quenched with 5 drops of water. 10 drops of 4M NaOH was added, and the organic phase was dried over MgSC and filtered to afford a THF solution containing the title compound (0.24M, 15 mL, assume 100% yield) which was used without further purification.
  • Example 1 cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[[(4S)-2-oxo-4-
  • Example 1 The following Examples were prepared as for Example 1 from the appropriate alcohol and the amine of Preparation 3.
  • Example 24 cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1 -[(4S)-2- oxo- 4- ( t r if I u orom et hy I) i m id azol id i n - 1 -y I] ethyl] imidazo[ 1 ,2-b] py rid azin -2- yl] methyl]carbamate and
  • Example 25 cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7- [(1 R) -2- m ethoxy- 1 -[ (4S)-2-oxo-4- (trifluoromet hy I) i mid azol id in- 1 -y I] ethyl] im idazo[ 1,2- b
  • the reaction mixture was concentrated in vacuo, then dissolved in DMF (0.25 mL) and purified directly by prep, basic HPLC to afford the title compounds as a mixture of diastereomers (14.2 mg).
  • the diastereomeric mixture was purified by silica gel chromatography, eluting with DCM/MeOH (0.5-2%), to afford the separated title compounds.
  • Example 24 Alternative Preparation of Example 24: cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7- [(1 S)- 2- meth oxy-1 - [ (4S) - 2- oxo- 4- (trifluoro m ethyl) im id azol id i n - 1 -yl] ethyl] i mid azo[ 1,2- b] pyridazin -2-yl] methyl] carbarn ate
  • Example 26 (2,2-difluorocyclopropyl)methyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1S)-2- m ethoxy- 1 -[(4S)-2-oxo-4-(trifluoromethyl)imidazolidin-1 -y I] ethyl] imidazo[ 1 ,2-b] pyridazin- 2-y I] methyl] carbarn ate.
  • Example 27 (3,3-difluorocyclobutyl) N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy- 1 -[ (4S)-2-oxo-4- (trifluoromet hy I) im id azol id i n - 1 -yl] ethyl] i mid azo[ 1 ,2-b] pyridazin-2- y I] methyl] carbarn ate.
  • Example 263-difluorocyclobutanol 38 mg, 0.35 mmol was reacted with CDI (57 mg, 0.35 mmol) and the resulting imidazolide was reacted with (4S)- 1 - [ (1 S)-1 -[2-[ (S)-amino-(4,4-difluorocyclohexyl)methyl] im idazo[ 1 ,2-b] pyridazin-7-yl] - 2- methoxy-ethyl] -4-(trifluoromethyl)imidazolidin-2-one; hydrochloride (45 mg, 0.088 mmol) to give the title compound (7.1 mg, 13% yield) as a white solid.
  • Example 27 Alternative Preparation of Example 27: cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7- [(1 S)- 2- meth oxy-1 - [ (4S) - 2- oxo- 4- (trifluoro m ethyl) im id azol id i n - 1 - yl] ethyl] i mid azo[ 1,2- b] pyridazin -2-yl] methyl] carbarn ate
  • Example 28 (3,3-difluorocyclobutyl) A/-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy- 1 -[ (4S)-2-oxo-4- (trifluoromet hy I) im id azol id i n - 1 - yl] ethyl] i mid azo[ 1 ,2-b] pyridazin-1 -ium-2- y I] meth y I] car bam ate; ethanesulfonate
  • Example 27 A solution of ethanesulfonic acid (1.31 g, 0.967 mL, 11.9 mmol) in MTBE (33.9 mL) was added to a stirred solution of the compound of Example 27 (7.77 g, 11.3 mmol) in EtOAc (33.9 mL). Additional MTBE (35 ml) was added slowly to the point where precipitation is just occuring. Seed crystals of Example 27 esylate salt were added and the mixture was stirred for 2 hours before additional MTBE (35 mL) was added The mixture was stirred overnight and the precipitate was collected by filtration, washing with MTBE (2 x 10 mL), then dried under reduced pressure to give the title compound (7.54 g, 93%) as a crystalline solid.
  • Form A was heated to 175°C in an Aton Paar temperature chamber CHC+ for X-ray diffraction, and a XRPD patten for form B was recorded after equilibrium was obtained.
  • the XRPD pattern for form B is shown in figure 2A and 2B.
  • Example 29 (1 - cy clopropy I - 2 , 2 , 2- 1 r if I uo ro- et hy I) N-[(S)-(4,4-difluorocyclohexyl)-[7- [[ (4S)-2-oxo-4- (trifluoromethyl) i m idazo I id i n - 1 -y I] methyl] im idazo[ 1 ,2- b] py ridazineyl] meth y I] car bam ate
  • Example 29 The following Examples were prepared as for Example 29 from the appropriate alcohol and the amine of Preparation 3.
  • Example 34 [5-(difluoromethyl)isoxazol-3-yl] methyl N-[(S)-(4,4-difluorocyclohexyl)-[7- [(1 S)- 2- met oxy-1 - [(4S)-2-oxo-4-(trifluorom ethyl) im id azol id i n - 1 -yl] ethyl] i mid azo[ 1,2- b] pyridazin -2-yl] methyl] carbarn ate
  • Example 34 The following Examples were prepared as for Example 34 from the appropriate alcohol and the amine of Preparation 15.
  • DI PEA was used instead of TEA.
  • Example 51 I nhibition of human I L-17- induced SEAP reporter gene activity in H EK- BlueTM IL-17 cells
  • test compounds in 100% DMSO were added into each well reserved for test compounds in a 384-well ViewPlates (Perkin Elmer), by the use of acoustic pipetting.
  • the remaining wells received an equal volume of DMSO, as vehicle control, or VETRANAL® (Merck) in DMSO, as a positive control for cytotoxicity.
  • VETRANAL® Merck
  • 5 pl of an anti-IL-17A monoclonal antibody final concentration 150 ng/ml was added to the positive control wells.
  • All wells containing test compounds and wells prepared to yield maximum stimulation received 5 pL of human TH-17 supernatant corresponding to 2 ng/m L I L-17A final concentration (measured by IL-17A AlphaLisa® SureFire®, Perkin Elmer). Finally, 45 pl HEK-BlueTM IL-17 cells (Invivogen) were added to all the wells resulting in a density of 12500 cells/well and incubated in a humid incubator at 37°C, 5% CO2, overnight.
  • the HEK- BlueTM I L-17 cells, anti- 1 L-17A antibody and TH-17 supernatant were all diluted in DM EM with high glucose (Sigma) supplemented with 10% FBS, 1% P/S (Life technologies) and HEK-BlueTM selection (Invivogen).
  • Cytotoxicity was measured in the cellcontaining Viewplate following addition of 7 pL PrestoBlue (Thermo Fisher) and incubation for 2.5-3 hours at room temperature, by measuring fluorescence at 615 nm (excitation at 535 nm) . Fluorescence was directly proportional to the amount of metabolic activity.
  • Embodiment 1 A compound having the form ula ( I ) wherein R1 is selected from (C3-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(CH2)- , (C3- C7)heterocycloalkyl, (C3-C7)heterocycloalkyl(CH2)- and 5-membered heteroaryl(CH2)- wherein said (C3-Ce)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(CH2)- , (C3- C7)heterocycloalkyl, (C3-C7)heterocycloalkyl(CH2)- and 5-membered heteroaryl(CH2)- is optionally substituted with one or more substituents independently selected from R a ;
  • R a represents deuterium , halogen , cyano, ( Ci - C3) alky I , and halo(Ci-C3)alkyl ;
  • R2 is hydrogen or methoxymethyl; or pharmaceutically acceptable salts thereof.
  • Embodiment 2 The compound according to embodiment 1 having the formula (l a)
  • Embodiment 3 The compound according to any one of embodiments 1 or 2, wherein wherein R1 is selected from (C3-Cs)cycloalkyl and (C3-Cs)cycloalkyl(CH2)-, wherein said (C3- Cs)cycloalkyl and (C3-Cs)cycloalkyl(CH2)- is optionally substituted with one or more substituents independently selected from R a .
  • Embodiment 4 The compound according to any one of embodiments 1 to 3, wherein R2 is methoxymethyl.
  • Embodiment 5 The compound according to any one of embodiments 1 or 2, wherein R1 is selected from (C3-C4)cycloalkyl and (C3-C4)cycloalkyl(CH2)-, wherein said (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(CH2)- is optionally substituted with one or more flouro.
  • Embodiment 6 The compound according to embodiment 5, wherein R2 is methoxymethyl.
  • Embodiment 7 The compound according to any one of embodiments 1 or 2, wherein R1 is cyclopropyl.
  • Embodiment 8 The compound according to embodiment 7, wherein R2 is methoxymethyl.
  • Embodiment 9. The compound according to any one of embodiments 1 or 2, wherein Ri is cyclobutyl substituted with one or more fluoro.
  • Embodiment 10 The compound according to embodiment 9 wherein R2 is methoxymethyl.
  • Embodiment 1 1 The compound according to any one of embodiments 1 -2, wherein R1 is cyclopropyl(CH2)- substituted with one or more fluoro.
  • Embodiment 12 The compound according to embodiment 1 1 , wherein R2 is methoxymethyl.
  • Embodiment 13 The compound according to any one of embodiments 1 or 2, wherein R1 is selected from cycloalkyl, cyclopropyl(CH2)- and cyclobutyl, wherein said cycloalkyl, cyclopropyl(CH2)- and cyclobutyl is optionally substituted with one or more flouro and R2 is methoxymethyl.
  • Embodiment 14 The compound according to any one of embodiments 1 -2, wherein R1 is selected from cycloalkyl, cyclopropyl(CH2)- and cyclobutyl, wherein said cyclopropyl(CH2)- and cyclobutyl is substituted with one or more fluoro, and R2 is methoxymethyl.
  • Embodiment 15 The compound according to any one of embodiments 1 or 2, wherein R1 is 5-membered heteroaryl(CH2)- optionally substituted with one or more substituents independently selected from Ra.
  • Embodiment 16 The compound according to embodiment 15, wherein R2 is methoxymethyl.
  • Embodiment 17 The compound according to any one of embodiments 1 -2, wherein R1 is (C3-C6)heterocycloalkyl wherein the hetero atom in the (C3-C6)heterocycloalkyl is oxygen, wherein said (C3-C6)heterocycloalkyl is either unsubstituted or substituted with one or more substituents independently selected from R a .
  • Embodiment 18 The compound according to embodiment 17 wherein R2 is methoxymethyl.
  • Embodiment 19 The compound according to any one of embodiments 1 -2, wherein
  • R1 is 3-oxetanyl, wherein said 3-oxetanyl is either unsubstituted or substituted with one or more substituents independently selected from R a .
  • Embodiment 20 The compound according to embodiment 19 wherein R2 is methoxymethyl.
  • Embodiment 21 The compound according to embodiment 1 which is cyclopropyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1 -[(4S)-2-oxo-4- (trifluoromethyl)im id azol id i n - 1 -yl] ethyl] i mid azo[ 1 ,2-b] pyridazin -2-yl] methyl] carbarn ate, or pharmaceutically acceptable salts thereof.
  • Embodiment 22 The compound according to embodiment 1 which is (2,2- difluorocyclopropyl) methyl N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1 -[(4S)-2- oxo-4-(trifluoromethyl)imidazolidin-1 -y I] ethyl] imidazo[ 1 ,2-b] pyridazin -2- yl] methyl]carbamate, or pharmaceutically acceptable salts thereof.
  • Embodiment 23 The compound according to embodiment 1 which is (3,3- difluorocyclobutyl) N-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1 -[(4S)-2-oxo-4- (trifluoromethyl)im id azol id i n - 1 - yl] ethyl] i mid azo[ 1 ,2-b] pyridazin -2-yl] methyl] carbarn ate, or pharmaceutically acceptable salts thereof.
  • Embodiment 24 The compound according to embodiment 1 which is (3,3- difluorocyclobutyl) A/-[(S)-(4,4-difluorocyclohexyl)-[7-[(1 S)-2-methoxy-1-[(4S)-2-oxo-4- (trifluoromethyl)im id azol id i n - 1 - yl] ethyl] i mid azo[ 1 ,2-b] pyridazin- 1 -ium -2- y I] meth y I] car bam ate; ethanesulfonate.
  • Embodiment 29 The compound according to embodiment 24 wherein the compound is characterized by an XRPD pattern essentially sim ilar to the XRPD pattern shown in figure 1 A and/or 1 B.
  • Embodiment 34 The compound according to embodiment 24 wherein the compound is characterized by an XRPD pattern essentially similar to the XRPD pattern shown in figure 2A and/or 2B.
  • Embodiment 35 The compound according to embodiment 24 wherein the compound has an DSC and TGA curve essentially sim ilar to the DSC and TGA curve as shown in Figure.

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Abstract

La présente invention concerne un composé selon la formule (I) et ses sels, hydrates ou solvates pharmaceutiquement acceptables. L'invention concerne en outre lesdits composés à utiliser en thérapie, des compositions pharmaceutiques comprenant lesdits composés, des méthodes de traitement de maladies, par exemple des maladies dermiques, avec lesdits composés, et l'utilisation desdits composés dans la fabrication de médicaments.
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