US20200216413A1 - Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals - Google Patents

Substituted indazoles useful for treatment and prevention of allergic and/or inflammatory diseases in animals Download PDF

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US20200216413A1
US20200216413A1 US16/306,235 US201716306235A US2020216413A1 US 20200216413 A1 US20200216413 A1 US 20200216413A1 US 201716306235 A US201716306235 A US 201716306235A US 2020216413 A1 US2020216413 A1 US 2020216413A1
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trifluoromethyl
indazol
methyl
alkyl
carboxamide
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Gerald Beddies
Adrian FOSTER
Ulrich Bothe
Nicole Schmidt
Ulf Bömer
Reinhard Nubbemeyer
Maria De Lourdes MOTTIER
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Bayer Animal Health GmbH
Bayer Pharma AG
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Bayer Pharma AG
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present application relates to the use of novel substituted indazoles for treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals and to the use thereof for production of medicaments for treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals, especially of atopic dermatitis and/or Flea Allergy Dermatitis, and especially in domestic animals, particularly in dogs.
  • the present invention relates to the use of novel substituted indazoles of the general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4).
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • TLRs Toll-like receptors
  • IL-1 ⁇ family consisting of the IL-1R (receptor), IL-18R, IL-33R and IL-36R
  • IRAK4 knockout mice nor human cells from patients lacking IRAK4 react to stimulation by TLRs (except TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
  • TLR ligands or the ligands of the IL-I 3 family leads to recruitment and binding of MyD88 [Myeloid differentiation primary response gene (88)] to the receptor.
  • MyD88 interacts with IRAK4, resulting in the formation of an active complex which interacts with and activates the kinases IRAK1 or IRAK2 (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009).
  • NF nuclear factor
  • MAPK mitogen-activated protein kinase
  • cytokines cytokines
  • chemokines chemokines
  • COX-2 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • COX-2 cyclooxygenase-2
  • mRNA stability of inflammation-associated genes for example COX-2, IL-6 (interleukin-6), IL-8
  • COX-2 IL-6
  • IL-8 Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004
  • these processes may be associated with the proliferation and differentiation of particular cell types, for example monocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi, et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).
  • IRAK4 KDKI The central role of IRAK4 in the pathology of various inflammatory disorders had already been shown by direct comparison of wild-type (WT) mice with genetically modified animals having a kinase-inactivated form of IRAK4 (IRAK4 KDKI).
  • IRAK4 KDKI animals have an improved clinical picture in the animal model of multiple sclerosis, atherosclerosis, myocardial infarction and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012).
  • IRAK4 In addition, it was found that deletion of IRAK4 in the animal model protects against virus-induced myocarditis by an improved anti-viral reaction with simultaneously reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013). It has also been shown that the expression of IRAK4 correlates with the disease activity of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
  • IRAK4 immune complex-mediated IFN ⁇ (interferon-alpha) production by plasmacytoid dendritic cells, a key process in the pathogenesis of systemic lupus erythematosus (SLE), has been shown (Chiang et al., The Journal of Immunology, 2010). Furthermore, the signalling pathway is associated with obesity (Ahmad, R., P. Shihab, et al., Diabetology & Metabolic Syndrome, 2015). As well as the essential role of IRAK4 in congenital immunity, there are also hints that IRAK4 influences the differentiation of Th17 T cells, components of adaptive immunity.
  • IRAK4 kinase activity In the absence of IRAK4 kinase activity, fewer IL-17-producing T cells (Th17 T cells) are generated compared to WT mice.
  • the inhibition of IRAK4 enables the prophylaxis and/or treatment of atherosclerosis, type 1 diabetes mellitus, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, chronic inflammatory bowel disorder and viral disorders, for example HIV (human immunodeficiency virus), hepatitis virus (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal of Inflammation, 2014
  • IRAK4 Due to the central role of IRAK4 in the MyD88-mediated signal cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be utilized for the prophylaxis and/or treatment of disorders mediated by the receptors mentioned.
  • U.S. Pat. No. 8,293,923 and US20130274241 disclose IRAK4 inhibitors having a 3-substituted indazole structure. There is no description of 2-substituted indazoles.
  • WO2013106254 and WO2011153588 disclose 2,3-disubstituted indazole derivatives.
  • WO2007091107 describes 2-substituted indazole derivatives for the treatment of Duchenne muscular dystrophy. The compounds disclosed do not have 6-hydroxyalkyl substitution.
  • WO2015091426 describes indazoles, such as Example 64, substituted at the 2 position by a carboxamide side chain.
  • WO2015104662 discloses 2-substituted indazoles of the following general formula:
  • R 2 is an alkyl or cycloalkyl group.
  • 2-substituted indazoles having a methyl, 2-methoxyethyl and cyclopentyl group at the 2 position (Examples 1, 4 and 76).
  • Example 117 is an indazole derivative having a hydroxyethyl substituent at the 1 position. However, no indazole derivatives having a 3-hydroxy-3-methylbutyl substituent at the 1 position or 2 position are described.
  • Indazoles having a hydroxyl-substituted alkyl group in the 2 position are encompassed generically by the general formula, but are not disclosed explicitly in WO2015104662.
  • Indazoles having an alkyl group in the 2 position where the alkyl group is additionally substituted by a methylsulphonyl group are not encompassed by the general formula and the definitions of the R 2 substituents in WO2015104662.
  • WO2015104662 describes indazoles having substitution at the 6 position for which R 1 is defined as follows: alkyl, cyano, —NR a R b or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl, where the substituents are independently alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCOCH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 .
  • R 1 is an optionally substituted alkyl group
  • substituents at the 6 position described in WO2015104662 for R 1 are cyclopropyl, cyclohexyl, cyano, 3-fluorophenyl and saturated heterocyclic substituents. Indazoles having a hydroxyl-substituted alkyl group at position 6 are not described explicitly in WO2015104662.
  • the problem addressed by the present invention is that of providing a better treatment option for inflammatory and/or allergic diseases in animals.
  • the present IRAK4 inhibitors are especially suitable for treatment and for prevention of inflammatory disorders in animals characterized by an overreacting immune system.
  • Atopic dermatitis for example, is a common disease in companion animals, particularly in cats and dogs.
  • CAD Canine atopic dermatitis
  • FAD Flea Allergy Dermatitis
  • Canine atopic dermatitis can be defined as a ‘genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with IgE, most commonly directed against environmental allergens’ (Halliwell, Veterinary Immunology and Immunopathology, 2006), like dust mites and pollen, which are incredibly difficult for pets to avoid, since dust mites are virtually everywhere and pollen permeates the air outdoors.
  • Canine atopic dermatitis is a complex and multifactorial disease involving immune dysregulation, allergic sensitisation, skin barrier defects, microbial colonization and environmental factors.
  • IgE is not a prerequisite for the development of the clinical signs in all cases, and a separate clinical entity known as atopic-like dermatitis was defined as ‘an inflammatory and pruritic skin disease with clinical features identical to those seen in Canine Atopic Dermatitis in which an IgE response to environmental or other allergens cannot be documented’ (Nuttall et al., Vet. Record, 2013).
  • Canine Atopic Dermatitis include itching, excessive scratching, rubbing on the carpet, hair loss, greasy or flaky skin with a foul odor, excessive chewing on the paws and areas such as the groin and armpits. Over time, the skin that is scratched can develop hot spots—raw, inflamed areas—that may become infected.
  • the treatment of acute flares of atopic dermatitis should involve the search for, and then elimination of, the cause of the flares, bathing with mild shampoos, and controlling pruritus and skin lesions with interventions that include topical and/or oral glucocorticoids or oclacitinib.
  • the first steps in management are the identification and avoidance of flare factors, as well as ensuring that there is adequate skin and coat hygiene and care; this might include more frequent bathing and possibly increasing essential fatty acid intake.
  • the medications currently most effective in reducing chronic pruritus and skin lesions are topical and oral glucocorticoids, oral ciclosporin, oral oclacitinib, and, where available, injectable recombinant interferons. Allergen-specific immunotherapy and proactive intermittent topical glucocorticoid applications are the only interventions likely to prevent or delay the recurrence of flares of AD. (Olivry et al., BMC Veterinary Research, 2015)
  • Flea allergy dermatitis or flea bite hypersensitivity is the most common dermatologic disease of domestic dogs (Scott et al., In: Muller and Kirk's Small Animal Dermatology, 2001), caused by the by far most prevalent flea on dogs and cats: Ctenocephalides felis (Beresford-Jones, J Small Animal Practice, 1981; Chesney, Veterinary Record, 1995). Cats also develop FAD, which is one of the major causes of feline miliary dermatitis.
  • fleas When feeding, fleas inject saliva that contains a variety of histamine-like compounds, enzymes, polypeptides, and amino acids that span a wide range of sizes (40-60 kD) and induce Type I, Type IV, and basophil hypersensitivity.
  • Flea-naive dogs exposed intermittently to flea bites develop either immediate (15 min) or delayed (24-48 hr) reactions, or both, and detectable levels of both circulating IgE and IgG antiflea antibodies. Dogs exposed continuously to flea bites have low levels of these circulating antibodies and either do not develop skin reactions or develop them later and to a considerably reduced degree. This could indicate that immunologic tolerance may develop naturally in dogs continually exposed to flea bites. Although the pathophysiology of FAD in cats is poorly understood, similar mechanisms may exist.
  • the cat flea Ctencephalides felis ) causes severe irritation in animals and people, and is responsible for Flea Allergy Dermatitis. Typical symptoms are: pruritus, inflammation of the skin and skin lesions (erythema, scales, papules, crusts and lichenification). These lesions are most commonly seen along the back and at the base of the tail.
  • sores can be very painful.
  • the skin becomes thickened and dark, predominantly in the area on the dog's back at the base of the tail.
  • the dog itself, causes the damage with self mutilation due to the severe itching.
  • the present invention provides compounds of the general formula (I)
  • any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process.
  • names and structural formulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF 3 COOH”, “x Na + ” should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.
  • Present compounds are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds that are encompassed by formula (I) and are of the formulae mentioned below and the salts, solvates and solvates of the salts thereof and the compounds that are encompassed by the formula (I) and are mentioned below as embodiments and the salts, solvates and solvates of the salts thereof if the compounds that are encompassed by the formula (I) and are mentioned below are not already salts, solvates and solvates of the salts.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the present compounds.
  • the present disclosure also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the present compounds.
  • Physiologically acceptable salts of the present compounds include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid
  • Physiologically acceptable salts of the present compounds also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to
  • Solvates in the context of the invention are described as those forms of the present compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
  • the present compounds may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else, if appropriate, of conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
  • the present invention therefore encompasses the use of enantiomers and diastereomers, and the respective mixtures thereof.
  • the stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this purpose, especially HPLC chromatography on an achiral or chiral phase.
  • the present invention encompasses the use of all the tautomeric forms.
  • the present invention also encompasses the use of all suitable isotopic variants of the present compounds.
  • An isotopic variant of an present compound is understood here as meaning a compound in which at least one atom within the present compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into an present compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I.
  • isotopic variants of an present compound such as, in particular, those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; because of the comparative ease of preparability and detectability, particularly compounds labelled with 3H or 14C isotopes are suitable for this purpose.
  • the incorporation of isotopes, for example of deuterium may lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the present compounds may therefore in some cases also constitute a preferred embodiment of the use of the present invention.
  • Isotopic variants of the present compounds can be prepared by the processes known to those skilled in the art, for example by the methods described further below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.
  • the present invention further provides the use of all the possible crystalline and polymorphous forms of the present compounds, where the polymorphs may be present either as single polymorphs or as a mixture of a plurality of polymorphs in all concentration ranges.
  • the present invention additionally also encompasses the use of prodrugs of the present compounds.
  • prodrugs in this context refers to compounds which may themselves be biologically active or inactive but are converted (for example metabolically or hydrolytically) to present compounds during their residence time in the body.
  • Alkyl in the context of the invention represents a straight-chain or branched alkyl group having the particular number of carbon atoms specified. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. Preference is given to methyl, ethyl, n-propyl, n-butyl, 2-methylbutyl, 3-methylbutyl and 2,2-dimethylpropyl.
  • Cycloalkyl in the context of the invention is a monocyclic saturated alkyl group having the number of carbon atoms specified in each case.
  • Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Alkoxy in the context of the invention represents a straight-chain or branched alkoxy group having the particular number of carbon atoms specified. 1 to 6 carbon atoms are preferred. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Particular preference is given to a linear or branched alkoxy group having 1 to 4 carbon atoms. Examples which may be mentioned as being preferred are methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy.
  • Halogen in the context of the invention is fluorine, chlorine and bromine. Preference is given to fluorine.
  • Hydroxyl in the context of the invention is OH.
  • a monocyclic saturated heterocycle is a monocyclic saturated heterocycle which has 4 to 6 ring atoms and contains a heteroatom or a heterogroup from the group of O, S, SO and SO 2 .
  • a heterocycle having a heteroatom or a heterogroup from the group of O, SO and SO 2 is preferred.
  • Examples include: oxetane, tetrahydrofuran, tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-2-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl.
  • Particular preference is given here to oxetane and tetrahydrofuran.
  • Very particular preference is given to oxetan-3-yl.
  • a symbol * at a bond denotes the bonding site in the molecule.
  • groups in the present compounds When groups in the present compounds are substituted, the groups may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all groups which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.
  • R 1 is a C 2 -C 6 -alkyl group substituted by 1, 2 or 3 fluorine atoms.
  • R 1 is a C 2 -C 6 -alkyl group substituted by one or two hydroxyl group(s) or one C 1 -C 3 -alkoxy or a tri-fluorine-substituted C 1 -C 3 -alkoxy.
  • Particular preference is given to a C 2 -C 5 -alkyl group substituted by hydroxyl or C 1 -C 3 -alkoxy or trifluoromethoxy or 2,2,2-trifluoroethoxy.
  • Very particular preference is given to 3-hydroxy-3-methylbutyl, 3-methoxypropyl, 3-hydroxypropyl, 3-trifluoromethoxypropyl, 2-methoxyethyl or 2-hydroxyethyl.
  • Especially preferred is the 3-hydroxy-3-methylbutyl group.
  • R 1 is a C 2 -C 6 -alkyl group substituted by a C 1 -C 6 -alkyl-SO 2 group.
  • a methyl-SO 2 -substituted C 2 -C 4 -alkyl group is particularly preferred.
  • R 1 are 2-(methylsulphonyl)ethyl or 3-(methylsulphonyl)propyl. From the latter group, 2-(methylsulphonyl)ethyl is particularly preferred.
  • R 1 is a C 1 -C 3 -alkyl group substituted by oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-2-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl. Particular preference is given to a C 1 -C 3 -alkyl group substituted by an oxetane group. Especially preferred for R 1 is an oxetan-3-ylmethyl group.
  • R 2 and R 3 which always have the same definition, hydrogen or methyl are preferred. Methyl is particularly preferred.
  • R 4 preference is given to an unsubstituted or mono- or poly-halogen-substituted C 1 -C 3 -alkyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group or a C 1 -C 3 -alkyl group substituted by one hydroxyl group and three fluorine atoms.
  • R 4 particular preference is given to the following groups: methyl, ethyl, trifluoro-C 1 -C 3 -alkyl, difluoro-C 1 -C 3 -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl and 2,2,2-trifluoro-1-hydroxyethyl.
  • R 4 particular preference is given to the methyl, trifluoromethyl and difluoromethyl groups. Particular preference is given here to a trifluoromethyl group.
  • R 5 is hydrogen, fluorine, chlorine or C 1 -C 3 -alkyl. More preferably, R 5 is hydrogen, fluorine or methyl. Most preferably, R 5 is hydrogen or fluorine.
  • R 4 is methyl or trifluoromethyl and R 5 is fluorine.
  • R 4 is methyl and R 5 is fluorine, where R 5 is in the ortho position to R 4 .
  • preferred embodiments include oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyran-4-yl, 1,1-dioxidotetrahydro-2H-thiopyran-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-2-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 1,1-dioxidotetrahydrothiophen-2-yl, 1,1-dioxidothietan-2-yl or 1,1-dioxidothietan-3-yl.
  • Particular preference is given here to oxetanyl.
  • Very particular preference is given to oxetan-3-yl.
  • R 7 is exclusively connected to the functional groups —SO 2 — and —SO—, i.e. is an R 7 -substituted —SO 2 — or SO group.
  • R 7 is preferably C 1 -C 4 -alkyl, where the C 1 -C 4 -alkyl group is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms.
  • R 7 is a cyclopropyl group.
  • Particularly preferred for R 7 are methyl, ethyl or hydroxyethyl. Very particular preference is given to methyl for R 7 .
  • R 8 preference is given to an unsubstituted C 1 -C 4 -alkyl group or a tri-fluorine-substituted C 1 -C 4 -alkyl group. Particular preference is given to methyl, ethyl, trifluoromethyl or 2,2,2-trifluoroethyl. Very particular preference is given to methyl, trifluoromethyl or 2,2,2-trifluoroethyl.
  • interleukin-1 receptor-associated kinase 4 plays an integral part in the signaling pathway of receptors activated by cytokines and TLR ligands that are implicated in inflammatory processes. Besides inflammation, IRAK4 is also involved in the signaling of allergic processes. Such allergic processes play an important role in the pathogenesis of allergic skin diseases, like atopic dermatitis.
  • IL-33 a recent addition to the IL-1 family of cytokines that also includes IL-18 and IL-1, binds to and activates IL-33 receptors (IL-33R) that then associate with MyD88, IRAK4 and TRF6 (Schmitz et al, Immunity, 2005).
  • IRAK4 is an essential component of this signaling pathway.
  • IL-33R are strongly expressed on T helper cell type 2 (Th2) cells, mast cells and eosinophils. IL-33 activates these cells and promotes Th2 immune responses (Schmitz et al, Immunity, 2005). These cell types are each involved in the pathogenesis of atopic dermatitis.
  • IL-33 levels in the serum correlate with the severity of atopic dermatitis in man and decrease on treatment with topical steroids & calcineurin inhibitor (Tamagawa-Mineoka et al, J American Academy Dermatology, 2014).
  • topical steroids & calcineurin inhibitor Tamagawa-Mineoka et al, J American Academy Dermatology, 2014.
  • the IL-33 gene was significantly up-regulated in skin lesions (Schamber et al., G3 (Bethesda), 2014; Olivry et al, Journal of Investigative Dermatology, 2016).
  • IL-18 has been implicated in atopic dermatitis. Serum levels of IL-18 increase with severity of atopic dermatitis in children (Sohn et al, Allergy and Asthma Proceedings, 2004). In models of acute Canine Atopic Dermatitis it has been shown that the IL-18 gene was significantly up-regulated in skin lesions (Schamber et al., G3 (Bethesda), 2014; Olivry et al, Journal of Investigative Dermatology, 2016).
  • atopic dermatitis-like inflammation & itching were initiated by over-release of IL-18 and accelerated by IL-1 in mice (Konishi et al, Proceedings of the National Academy of Sciences, 2002).
  • IRAK4 has been shown to be an essential component of the IL-18 signaling cascade (Suzuki et al, J Immunology, 2003).
  • IRAK4 is critical for the signaling of IL-1 and TLR ligands (Suzuki et al, Nature, 2002).
  • TLR agonists are known to induce itch (Liu et al, Neuroscience bulletin, 2012), an important symptom of atopic dermatitis, and anti-IL-1 therapies are used off-label to treat atopic dermatitis.
  • polymorphisms in IRAK4 are associated with elevated total IgE in allergic diseases such as asthma and chronic rhinosinusitis (Tewfik et al, Allergy, 2009). IgE levels are also elevated in atopic dermatitis.
  • IRAK4 is a critical part of the signaling pathways that are activated by a number of cytokine, TLR ligands and IRAK4 has polymorphisms associated with increased IgE level
  • inhibition of IRAK4 is an important therapeutic strategy for the treatment of allergic skin diseases such as atopic dermatitis.
  • atopic dermatitis and Flea Allergy Dermatitis are appropriate indications since both diseases are comprised of Type I hypersensitivity that involves IgE antibodies, Th2 cells, mast cells and eosinophils.
  • FAD can be comprised of Type IV hypersensitivity in which IL-1 and IL-18 are involved.
  • the present compounds act as inhibitors of IRAK4 kinase and therefore have an unforeseeable useful pharmacological activity spectrum in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals.
  • the present invention especially provides the following compounds:
  • the invention further provides compounds of the general formula (III)
  • the compounds of the general formula (III) are suitable for preparation of a portion of the compounds of the general formula (I).
  • the compounds of the general formula (III) are inhibitors of interleukin-1 receptor associated kinase-4 (IRAK4).
  • the present compounds act as inhibitors of IRAK4 kinase and have an unforeseeable useful pharmacological activity spectrum.
  • domestic animals in this context includes, for example, mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets or in particular dogs, cats; cage birds; reptiles; amphibians or aquarium fish.
  • compounds of the formula (I), or the compounds particularly mentioned above for use in the treatment and/or prophylaxis of allergic dermatitis in domestic animals, particularly canine and feline allergic dermatitis, and more particularly canine allergic dermatitis.
  • compounds of the formula (I), or the compounds particularly mentioned above for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in farm animals, particularly in sheep, goats, horses, cattle and pigs, and more particularly in cattle and pigs.
  • farm animals in this context includes, for example, mammals, such as horses, sheep, goats, buffaloes, reindeers, fallow deers or in particular cattle or pigs.
  • compounds of formula (III) for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in domestic animals, particularly in cats and dogs, and more particularly in dogs.
  • compounds of the formula (III) for use in the treatment and/or prophylaxis of allergic dermatitis in domestic animals, particularly canine and feline allergic dermatitis, and more particularly canine allergic dermatitis.
  • compounds of the formula (III) for use in the treatment and/or prophylaxis of allergic and/or inflammatory diseases in farm animals, particularly in sheep, goats, horses, cattle and pigs, and more particularly in cattle and pigs.
  • compounds of the formula (III) for use in a method for treatment and/or prophylaxis of atopic dermatitis, Flea Allergy Dermatitis, inflammatory bowel disease, osteoarthritis and inflammatory pain, non-infectious recurrent airway disease, insect hypersensitivity, asthma, respiratory disease, mastitis and endometritis in animals, particularly of atopic dermatitis and Flea Allergy Dermatitis.
  • compounds of the formula (III) for use in a method for treatment and/or prophylaxis of Canine Atopic Dermatitis, Flea Allergy Dermatitis in dogs or cats, inflammatory bowel disease in dogs or cats, osteoarthritis and inflammatory pain in dogs, cats, horses or cattle, non-infectious recurrent airway disease in horses, insect hypersensitivity in horses, feline asthma, bovine respiratory disease, mastitis in cattle, endometritis in cattle, and swine respiratory disease.
  • compound examples 11, 12, 13, 19 have been evaluated in an in vitro IRAK4 TR-FRET assay detailed below using recombinant canine IRAK4 enzyme.
  • IC50 values of each compound have been calculated for the inhibition of canine IRAK4.
  • Example Compounds (11, 12, 13, 19) have been identified as being useful in the treatment of allergic skin diseases in animals, particularly dogs and cats, such as atopic dermatitis and Flea Allergy Dermatitis.
  • Example compounds 11, 12, 13, 19 were each potent inhibitors of canine IRAK4 with IC50 values of 1.7, 9.2, 2.2, 7.6 nM, respectively.
  • the IC50 values for each of these compound examples were also similar to the IC50 values calculated for inhibition of human IRAK4.
  • example compound 12 has also been evaluated in an in vitro assay to establish the effects of compounds on lipopolysaccharide (LPS)-induced cytokine production by canine peripheral blood mononuclear cells (PBMCs).
  • LPS lipopolysaccharide
  • Example compound 12 inhibited the production of the pro-inflammatory cytokine Tumor Necrosis factor alpha (TNF ⁇ ) by canine PBMCs induced by LPS, in a concentration-related manner.
  • PBMCs include cell types such as dendritics cells, T and B lymphocytes, as well as monocytes each of which are implicated in atopic dermatitis and TNF ⁇ is elevated in atopic dermatitis patients (Sumimoto et al, Archives of Disease in Childhood, 1992). This example is also illustrated by FIG. 7 .
  • the present compounds demonstrate inhibition of recombinant canine IRAK4 enzyme and cytokine production by canine PBMCs indicating the potential therapeutic benefit of such compound examples in Canine Atopic Dermatitis and Flea Allergy Dermatitis.
  • example compound 12 has also been evaluated in vivo in a further study to establish the effects of compounds in the treatment of clinical signs associated with canine allergic dermatitis, particularly Canine Atopic Dermatitis (CAD), in a House Dust Mite model.
  • Example compound 12 significantly reduced clinical signs of CAD like skin edema and erythema. This example is also illustrated by FIGS. 11 and 12 .
  • example compound 12 has been evaluated in an in vivo model of canine Flea Allergy Dermatitis (FAD) to establish the anti-pruritic effects of compounds. Treatment with Example compound 12 substantially reduced pruritus associated with allergic diseases like Flea Allergy Dermatitis. This example is also illustrated by FIG. 13 .
  • the present compounds demonstrate reduction of associated pathognomonic clinical signs of allergic dermatitis as skin inflammation and pruritus therefore indicating a therapeutic benefit of such compound examples in canine allergic dermatitis, particularly in Flea Allergy Dermatitis (FAD) and Canine Atopic Dermatitis (CAD).
  • FAD Flea Allergy Dermatitis
  • CAD Canine Atopic Dermatitis
  • canine allergic dermatitis in this context includes particularly Canine Atopic Dermatitis (CAD) and Flea Allergy Dermatitis (FAD).
  • CAD Canine Atopic Dermatitis
  • FAD Flea Allergy Dermatitis
  • example compound 12 has also been evaluated in an ex vivo assay to establish the effects of compounds on lipopolysaccharide (LPS)-induced cytokine production by bovine peripheral blood mononuclear cells (PBMCs).
  • LPS lipopolysaccharide
  • Example compound 12 inhibited the production of the pro-inflammatory cytokine Tumor Necrosis factor alpha (TNF ⁇ ) by bovine PBMCs induced by LPS, in a concentration-related manner.
  • TNF ⁇ tumor Necrosis factor alpha
  • PBMCs include cell types such as dendritic cells, T and B lymphocytes, as well as monocytes each of which are implicated in inflammatory and infectious diseases with overshooting pro-inflammatory immune response such as respiratory diseases (Sterner-Kock, Haider, et al., Tropical Animal Health and Production, 2016), enteric diseases (Pan, Rostagnio, et al., Veterinary Immunology and Immunopathology, 2015), and mastitis (Zheng, Xu, et al., Free Radical Biology and Medicine, 2016) in which TNF ⁇ is elevated in these patients. This example is also illustrated by FIGS. 8 and 9 .
  • the present compounds demonstrate inhibition of cytokine production by bovine PBMCs indicating the potential therapeutic benefit of such compound examples in inflammatory and/or infectious diseases such as respiratory diseases, enteric diseases and mastitis.
  • example compound 12 has also been evaluated in an ex vivo assay to establish the effects of compounds on lipopolysaccharide (LPS)-induced cytokine production by porcine peripheral blood mononuclear cells (PBMCs).
  • LPS lipopolysaccharide
  • Example compound 12 inhibited the production of the pro-inflammatory cytokine Tumor Necrosis factor alpha (TNF ⁇ ) by porcine PBMCs induced by LPS.
  • PBMCs include cell types such as dendritic cells, T and B lymphocytes, as well as monocytes each of which are implicated in inflammatory and infectious diseases with overshooting pro-inflammatory immune response such as respiratory diseases and enteric diseases in which TNF ⁇ is elevated in these patients. This example is also illustrated by FIG. 10 .
  • the present compounds demonstrate inhibition of cytokine production by porcine PBMCs indicating the potential therapeutic benefit of such compound examples in inflammatory and/or infectious diseases such as respiratory diseases and enteric diseases.
  • the prophylaxis and/or treatment of pruritus and pain, especially of acute, chronic, inflammatory and neuropathic pain in animals, is also provided by the present compounds.
  • the present compounds are suitable for the treatment and/or prophylaxis of pain disorders, especially of acute, chronic, inflammatory and neuropathic pain in animals.
  • This preferably includes hyperalgesia, allodynia, pain from arthritis (such as osteoarthritis, rheumatoid arthritis and spondyloarthritis), premenstrual pain, endometriosis-associated pain, post-operative pain, pain from interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain from prostatitis, pain caused by spinal cord injuries, inflammation-induced pain, lower back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain and chronic pain.
  • arthritis such as osteoarthritis, rheumatoid arthritis and spondyloarthritis
  • premenstrual pain endometriosis-associated pain
  • post-operative pain pain from interstitial cystitis
  • CRPS complex regional pain syndrome
  • the present invention further also provides a method for treatment and/or prevention of disorders in animals, especially the disorders mentioned above, using an effective amount of at least one of the presented compounds.
  • treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states.
  • therapy is understood here to be synonymous with the term “treatment”.
  • prevention is used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.
  • the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
  • the present compounds can be used alone or, if required, in combination with other active ingredients.
  • the present invention further provides medicaments containing at least one of the present compounds and one or more further active ingredients, for treatment and/or prevention of allergic and/or inflammatory diseases in animals.
  • active ingredients suitable for combinations include:
  • active ingredients such as antibacterial (e.g. penicillins, vancomycin, ciprofloxacin), antiviral (e.g. aciclovir, oseltamivir) and antimycotic (e.g. naftifin, nystatin) substances and gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporin, Methotrexat®, TNF antagonists (e.g. Humira®, Etanercept, Infliximab), IL-I inhibitors (e.g. Anakinra, Canakinumab, Rilonacept), phosphodiesterase inhibitors (e.g.
  • active ingredients such as antibacterial (e.g. penicillins, vancomycin, ciprofloxacin), antiviral (e.g. aciclovir, oseltamivir) and antimycotic (e.g. naftifin, nystatin) substances and gam
  • Jak/STAT inhibitors e.g. Tofacitinib, Baricitinib, GLPG0634
  • leflunomid e.g. tofacitinib, Baricitinib, GLPG0634
  • leflunomid e.g. tofacitinib, Baricitinib, GLPG0634
  • leflunomid e.g. tofacitinib, Baricitinib, GLPG0634
  • leflunomid e.g. Tofacitinib, Baricitinib, GLPG0634
  • leflunomid e.g. Tofacitinib, Baricitinib, GLPG0634
  • prednisone prednisolone, methylprednisolone, hydrocortisone, betamethasone
  • cyclophosphamide azathioprine and sulfasalazine
  • paracetamol non-steroidal anti-inflammatory substances (NSAIDS) (aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).
  • NSAIDS non-steroidal anti-inflammatory substances
  • inventive IRAK4 inhibitors can also be combined with the following active ingredients:
  • beta-2-sympathomimetics e.g. salbutamol
  • anticholinergics e.g. glycopyrronium
  • methylxanthines e.g. theophylline
  • leukotriene receptor antagonists e.g. montelukast
  • PDE-4 phosphodiesterase type 4 inhibitors
  • methotrexate IgE antibodies, azathioprine and cyclophosphamide, cortisol-containing preparations
  • substances for treatment of osteoarthritis such as non-steroidal anti-inflammatory substances (NSAIDs).
  • NSAIDs non-steroidal anti-inflammatory substances
  • methotrexate and biologics for B-cell and T-cell therapy should be mentioned for rheumatoid disorders, for example rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis.
  • Neurotrophic substances such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoaminooxidase) inhibitors (e.g. selegiline), interferons und anticonvulsives (e.g. gabapentin); active ingredients for treatment of cardiovascular disorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g.
  • angiotensin receptor blockers e.g. losartan, valsartan
  • diuretics e.g. hydrochlorothiazide
  • calcium channel blockers e.g. nifedipine
  • statins e.g. simvastatin, fluvastatin
  • anti-diabetic drugs for example metformin, glinides (e.g. nateglinide), DPP-4 (dipeptidyl peptidase-4) inhibitors (e.g.
  • linagliptin saxagliptin, sitagliptin, vildagliptin
  • SGLT2 sodium/glucose cotransporter 2
  • inhibitors/gliflozin e.g. dapagliflozin, empagliflozin
  • incretin mimetics hormonee glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptid 1 (GLP-1) analogues/agonists
  • GIP glucose-dependent insulinotropic peptide
  • GLP-1 glucagon-like peptid 1
  • exenatide liraglutide
  • lixisenatide ⁇ -glucosidase inhibitors
  • acarbose miglitol, voglibiose
  • sulphonylureas e.g. glibenclamide, tolbutamide
  • insulin sensitizers e.g. pioglitazone
  • insulin therapy e.g. NPH insulin, insulin lispro
  • Active ingredients such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL #3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L.
  • Bifidobacterium infantis 35624 Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics, for example ciprofloxacin and metronidazole, anti-diarrhoea drugs, for example loperamide, or laxatives (bisacodyl) for treatment of chronic inflammatory bowel diseases.
  • antibiotics for example ciprofloxacin and metronidazole
  • anti-diarrhoea drugs for example loperamide
  • laxatives bisacodyl
  • Immunosuppressants such as glucocorticoids and non-steroidale anti-inflammatory substances (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for treatment of lupus erythematosus.
  • Vitamin D3 analogues for example calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, ciclosporine, methotrexate, efalizumab for dermatological disorders.
  • medicaments comprising at least one of the present compounds and one or more further active ingredients for the inventive use, especially EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKR1C3 inhibitors (aldo-keto reductase family 1 member C3 inhibitors), for treatment and/or prevention of the aforementioned disorders.
  • EP4 inhibitors prostaglandin E2 receptor 4 inhibitors
  • P2X3 inhibitors P2X purinoceptor 3
  • PTGES inhibitors prostaglandin E synthase inhibitors
  • AKR1C3 inhibitors aldo-keto reductase family 1 member C3 inhibitors
  • the present compounds can act systemically and/or locally.
  • they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal or conjunctival route, via the ear or as an implant or stent.
  • the present compounds can be administered in administration forms suitable for these administration routes.
  • Suitable administration forms for oral administration are those which work according to the prior art and release the present compounds rapidly and/or in a modified manner and which contain the present compounds in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the present compound), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, chewables (for example soft chewables), granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the present compound
  • tablets or films/oblates which disintegrate rapidly in the oral cavity
  • films/lyophilizates capsules (for example hard or soft gelatin capsules), sugar
  • Parenteral administration can be accomplished with avoidance of a resorption step (for example by an intravenous, intraarterial, intracardiac, intraspinal or intralumbar route) or with inclusion of a resorption (for example by an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal route).
  • Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films/oblates or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, pour-ons, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.
  • inhalable medicament forms including powder inhalers, nebulizers
  • nasal drops including tablets, films/oblates or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, pour-ons, transdermal therapeutic systems (e.g. patches), milk, paste
  • the present compounds can be converted to the administration forms mentioned. This can be accomplished in a manner known per se by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), colorants (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecyl
  • the present invention further provides medicaments which comprise at least one present compound, typically together with one or more inert, nontoxic, pharmaceutically suitable excipients, for use in a method for treatment and/or prophylaxis of allergic and/or inflammatory diseases in animals.
  • parenteral administration amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effective results.
  • the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 10 mg/kg of body weight.
  • carboxylic acids V3 can be prepared proceeding from carboxylic esters (Intermediate V2) by hydrolysis (cf., for example, the reaction of ethyl 6-(hydroxymethyl)pyridine-2-carboxylate with aqueous sodium hydroxide solution in methanol, WO2004113281) or—in the case of a tert-butyl ester—by reaction with an acid, for example hydrogen chloride or trifluoroacetic acid (cf., for example, Dalton Transactions, 2014, 43, 19, 7176-7190).
  • the carboxylic acids V3 can also be used in the form of their alkali metal salts.
  • the Intermediates V2 can optionally also be prepared from the Intermediates V1 which bear a chlorine, bromine or iodine as substituent X 1 by reaction in a carbon monoxide atmosphere, optionally under elevated pressure, in the presence of a phosphine ligand, for example 1,3-bis(diphenylphosphino)propane, a palladium compound, for example palladium(II) acetate, and a base, for example triethylamine, with addition of ethanol or methanol in a solvent, for example dimethyl sulphoxide (for preparation methods see, for example, WO2012112743, WO 2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948-1949, WO200661715).
  • a phosphine ligand for example 1,3-bis(diphenylphosphino)propane
  • a palladium compound for example palladium(II) acetate
  • a base for example triethy
  • the Intermediates V1 are either commercially available or can be prepared by routes known from the literature. Illustrative preparation methods are detailed in WO 2012061926, European Journal of Organic Chemistry, 2002, 2, 327-330, Synthesis, 2004, 10, 1619-1624, Journal of the American Chemical Society, 2013, 135, 32, 12122-12134, Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039-4043, US2007185058, WO2009117421.
  • X 1 is chlorine, bromine or iodine.
  • R d is methyl, ethyl, benzyl or tert-butyl.
  • R 4 , R 5 are each as defined in the general formula (I).
  • Methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 2) can be obtained proceeding from methyl 1H-indazole-6-carboxylate (Intermediate 0) according to Synthesis Scheme 2 by nitration and reduction of the nitro group of Intermediate 1 with hydrogen in the presence of palladium on charcoal analogously to WO 2008/001883.
  • Synthesis Scheme 2 For preparation of the Intermediates 3 proceeding from Intermediate 2, it is possible to use various coupling reagents known from the literature (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3—Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12—Peptide-Coupling Reagents, 407-442; Chem. Soc.
  • R 4 , R 5 are each as defined in the general formula (I).
  • alkyl halides or alkyl 4-methylbenzenesulphonates used are commercially available or can be prepared analogously to routes known from literature (for the preparation of alkyl 4-methylbenzenesulphonates, one example is the reaction of an appropriate alcohol with 4-methylbenzenesulphonyl chloride in the presence of triethylamine or pyridine; see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12 4277-4294).
  • an alkali metal iodide such as potassium iodide or sodium iodide.
  • Bases used may, for example, be potassium carbonate, caesium carbonate or sodium hydride.
  • reactive alkyl halides it is also possible in some cases to use N-cyclohexyl-N-methylcyclohexanamine.
  • Useful solvents include, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF.
  • the alkyl halides or alkyl 4-methylbenzenesulphonates used may have functional groups which have optionally been protected with a protecting group beforehand (see also P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis , Fourth Edition, ISBN: 9780471697541).
  • alkyl halides or alkyl 4-methylbenzenesulphonates having one or more hydroxyl groups may optionally be protected by a tert-butyl(dimethyl)silyl group or a similar silicon-containing protecting group familiar to those skilled in the art.
  • the hydroxyl groups may also be protected by the tetrahydro-2H-pyran (THP) group or by the acetyl or benzoyl group.
  • THP tetrahydro-2H-pyran
  • the protecting groups used can then be detached subsequently to the synthesis of Intermediate 4, or else after the synthesis of (I).
  • a tert-butyl(dimethylsilyl) group is used as protecting group, it can be detached using tetrabutylammonium fluoride in a solvent such as THF, for example.
  • a THP protecting group can be detached, for example, using 4-methylbenzenesulphonic acid (optionally in monohydrate form).
  • Acetyl groups or benzoyl groups can be detached by treatment with aqueous sodium hydroxide solution.
  • the alkyl halides or alkyl 4-methylbenzenesulphonates used may contain functional groups which can be converted by oxidation or reduction reactions known to those skilled in the art (see, for example, Science of Synthesis , Georg Thieme Verlag). If, for example, the functional group is a sulphide group, this can be oxidized by methods known in the literature to a sulphoxide or sulphone group. In the case of a sulphoxide group, this can likewise be oxidized to a sulphone group.
  • 3-chloroperbenzoic acid (CAS 937-14-4) (in this regard, see also, for example, US201094000 for the oxidation of a 2-(methylsulphanyl)ethyl-1H-pyrazole derivative to a 2-(methylsulphinyl)ethyl-1H-pyrazole derivative and the oxidation of a further 2-(methylsulphanyl)ethyl-1H-pyrazole derivative to a 2-(methylsulphonyl)ethyl-1H-pyrazole derivative).
  • alkyl halides or tosylates used contain a keto group, this can be reduced by reduction methods known to those skilled in the art to an alcohol group (see, for example, Chemische Berichte, 1980, 113, 1907-1920 for the use of sodium borohydride). These oxidation or reduction steps can be effected subsequently to the synthesis of Intermediate 4, or else after the synthesis of the present compounds of the general formula (I).
  • Intermediate 4 can be prepared via Mitsunobu reaction (see, for example, K. C. K. Swamy et. al. Chem. Rev. 2009, 109, 2551-2651) of Intermediate 3 with optionally substituted alkyl alcohols.
  • phosphines such as triphenylphosphine, tributylphosphine or 1,2-diphenylphosphinoethane in combination with diisopropyl azodicarboxylate (CAS 2446-83-5) or further diazene derivatives mentioned in the literature (K. C. K. Swamy et. al. Chem. Rev. 2009, 109, 2551-2651). Preference is given to the use of triphenylphosphine and diisopropyl azodicarboxylate.
  • alkyl alcohol bears a functional group it is possible—as in the case of the abovementioned reactions with alkyl halides—for known protecting group strategies (further pointers can be found in P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) and—as in the case of the abovementioned reactions with alkyl halides—for oxidation or reduction steps to be effected correspondingly to the synthesis of Intermediate 4, or else after the synthesis of the present compounds of the general formula (I).
  • present compounds of the general formula (I) where R 2 and R 3 are defined as C 1 -C 6 -alkyl may be obtained by a Grignard reaction (cf., for example, the reaction of a methyl 1H-indazole-6-carboxylate derivative with methylmagnesium bromide in EP 2489663).
  • a Grignard reaction cf., for example, the reaction of a methyl 1H-indazole-6-carboxylate derivative with methylmagnesium bromide in EP 2489663
  • alkylmagnesium halides Particular preference is given to methylmagnesium chloride or methylmagnesium bromide in THF or diethyl ether, or else in mixtures of THF and diethyl ether.
  • present compounds of the general formula (I) where R 2 and R 3 are defined as C 1 -C 6 -alkyl may be obtained by a reaction with an alkyllithium reagent (cf., for example, the reaction of a methyl 2-amino-4-chloro-1-methyl-1H-benzimidazole-7-carboxylate derivative with isopropyllithium or tert-butyllithium in WO2006116412).
  • R 1 , R 2 , R 3 , R 4 , R 5 are each as defined in the general formula (I).
  • R 1 in the compounds of the formula (I-a) includes a suitable functional group, it is optionally possible subsequently, in analogy to Synthesis Scheme 3, to use oxidation or reduction reactions for preparation of further present compounds.
  • R 1 , R 4 , R 5 are each as defined in the general formula (I).
  • R 2 and R 3 always have the same definition and are both C 1 -C 6 -alkyl.
  • Intermediate 6 can then be converted to Intermediate 7 by reduction of the nitro group.
  • the nitro group can be reduced with palladium on carbon under a hydrogen atmosphere (cf., for example, WO2013174744 for the reduction of 6-isopropoxy-5-nitro-1H-indazole to 6-isopropoxy-1H-indazol-5-amine) or by the use of iron and ammonium chloride in water and ethanol (see, for example, also Journal of the Chemical Society, 1955, 2412-2419), or by the use of tin(II) chloride (CAS 7772-99-8). The use of iron and ammonium chloride in water and ethanol is preferred.
  • the preparation of Intermediate 4 from Intermediate 7 can be effected analogously to Synthesis Scheme 2 (preparation of Intermediate 3 from Intermediate 2).
  • Synthesis Scheme 3 it is optionally possible to use protecting group strategies in the case of Synthesis Scheme 5 as well.
  • R 1 , R 4 , R 5 are each as defined in the general formula (I).
  • sodium chloride solution always means a saturated aqueous sodium chloride solution.
  • the present compounds and precursors and/or intermediates thereof were analysed by LC-MS.
  • Instrument Waters Acquity; column: Kinetex (Phenomenex), 50 ⁇ 2 mm; eluent A: water+0.05% by vol. of formic acid, eluent B: acetonitrile+0.05% by vol. of formic acid; gradient: 0-1.9 min 1-99% B, 1.9-2.1 min 99% B; flow rate 1.5 ml/min; temperature: 60° C.; injection: 0.5 ⁇ l; DAD scan: 200-400 nm.
  • the present compounds and the precursors and/or intermediates thereof were purified by the following illustrative preparative HPLC methods:
  • Method P1 system: Waters Autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBridge C18 5 ⁇ m 100 ⁇ 30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow: 50 ml/min; temperature: room temperature; solution: max. 250 mg/max. 2.5 ml DMSO or DMF; injection: 1 ⁇ 2.5 ml; detection: DAD scan range 210-400 nm; MS ESI+, ESI ⁇ , scan range 160-1000 m/z.
  • Method P2 system: Waters Autopurification system: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100; column: XBridge C18 5 ⁇ m 10 ⁇ 30 mm; eluent A: water+0.2% by vol. of ammonia (32%), eluent B: methanol; gradient: 0-8 min 30-70% B; flow: 50 ml/min; temperature: room temperature; detection: DAD scan range 210-400 nm; MS ESI+, ESI ⁇ , scan range 160-1000 m/z; ELSD.
  • Method P3 system: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C18 5 ⁇ m 100 ⁇ 30 mm; eluent A: water+0.2% by vol. of ammonia (25%), eluent B: acetonitrile; gradient: 0-1 min 15% B, 1-6.3 min 15-55% B, 6.3-6.4 min 55-100% B, 6.4-7.4 min 100% B; flow: 60 ml/min; temperature: room temperature; solution: max. 250 mg/2 ml DMSO; injection: 2 ⁇ 2 ml; detection: UV 218 nm; Software: SCPA PrepCon5.
  • Method P4 system: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: Chromatorex RP C18 10 ⁇ m 125 ⁇ 30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-15 min 65-100% B; flow: 60 ml/min; temperature: room temperature; solution: max. 250 mg/2 ml DMSO; injection: 2 ⁇ 2 ml; detection: UV 254 nm; Software: SCPA PrepCon5.
  • Method P5 system: Sepiatec: Prep SFC100, column: Chiralpak IA 5 ⁇ m 250 ⁇ 20 mm; eluent A: carbon dioxide, eluent B: ethanol; gradient: isocratic 20% B; flow: 80 ml/min; temperature: 40° C.; solution: max. 250 mg/2 ml DMSO; injection: 5 ⁇ 0.4 mL; detection: UV 254 nm.
  • Method P6 system: Agilent: Prep 1200, 2 ⁇ prep pump, DLA, MWD, Gilson: Liquid Handler 215; column: Chiralcel OJ-H 5 ⁇ m 250 ⁇ 20 mm; eluent A: hexane, eluent B: ethanol; gradient: isocratic 30% B; flow: 25 ml/min; temperature: 25° C.; solution: 187 mg/8 ml ethanol/methanol; injection: 8 ⁇ 1.0 ml; detection: UV 280 nm.
  • Method P7 system: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C18 5 ⁇ m 100 ⁇ 30 mm; eluent A: water+0.1% by vol. of formic acid, eluent B: acetonitrile; gradient: 0-3 min: 65% B isocratic, 3-13 min: 65-100% B; flow: 60 ml/min; temperature: room temperature; solution: max. 250 mg/2 ml DMSO; injection: 2 ⁇ 2 ml; detection: UV 254 nm.
  • Method P8 system: Agilent: Prep 1200, 2 ⁇ prep pump, DLA, MWD, Gilson: Liquid Handler 215; column: Chiralpak IF 5 ⁇ m 250 ⁇ 20 mm; eluent A: ethanol, eluent B: methanol; gradient: isocratic 50% B; flow: 25 ml/min; temperature: 25° C.; solution: 600 mg/7 ml N,N-dimethylformamide; injection: 10 ⁇ 0.7 ml; detection: UV 254 nm.
  • substance mixtures were purified by column chromatography on silica gel.
  • Flash chromatography For preparation of some of the present compounds and the precursors and/or intermediates thereof, a column chromatography purification (“flash chromatography”) was conducted on silica gel using Isolera® devices from Biotage. This was done using cartridges from Biotage, for example the “SNAP Cartridge, KP_SIL” cartridge of different size and “Interchim Puriflash Silica HP 15UM flash column” cartridges from Interchim of different size.
  • the reaction mixture was admixed with water, and the precipitate was filtered off with suction and washed repeatedly with water and dichloromethane. This gave 1.53 g (27% of theory) of the title compound.
  • the phases of the filtrate were separated, the organic phase was concentrated, admixed with a little dichloromethane and suspended in an ultrasound bath, and the precipitate was filtered off with suction. This gave a further 1.03 g of the title compound.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • the combined organic phases were filtered through a hydrophobic filter and concentrated.
  • the residue was purified by column chromatography on silica gel (hexane/ethyl acetate). 400 mg of the title compound were obtained.
  • the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml of DMSO and purified by preparative HPLC. The product-containing fractions were freeze-dried. 20 mg of the title compound were obtained.
  • the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, filtered through a hydrophobic filter and concentrated. The residue was dissolved in 3 ml of DMSO and purified by preparative HPLC. The product-containing fractions were freeze-dried. 25 mg of the title compound were obtained.
  • the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The residue was dissolved in 2.0 ml of DMSO and purified by preparative HPLC. The product-containing fractions were freeze-dried. 30 mg of the title compound were obtained.
  • Example 11 Analogously to the preparation of Example 11 (Preparation Method 1), 3.00 g of methyl 5-( ⁇ [6-(difluoromethyl)pyridin-2-yl]carbonyl ⁇ amino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-carboxylate (Intermediate 4-11) were reacted with 3M methylmagnesium bromide solution (in diethyl ether). After purification of the crude product by stirring with diethyl ether, filtering followed by preparative HPLC, 1.37 g of the title compound were obtained.
  • Example 11 Analogously to the preparation of Example 11 (Preparation Method 1), 52 mg (0.10 mmol) of methyl 2-[3-(2,2,2-trifluoroethoxy)propyl]-5-( ⁇ [6-(trifluoromethyl)pyridin-2-yl]carbonyl ⁇ amino)-2H-indazole-6-carboxylate (Intermediate 4-10) in 3 ml of THF were reacted with 2 ⁇ 171 ⁇ l of 3M magnesium bromide solution in diethyl ether. Purification by preparative HPLC gave 12 mg of the title compound.
  • the mixture was admixed with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate, and the extracts were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC. 111 mg of the title compound were obtained.
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • the substrate used for the kinase reaction was the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in amide form) which can be purchased, for example, from Biosyntan GmbH (Berlin-Buch).
  • the concentration of the IRAK4 was adjusted to the respective activity of the enzyme and set such that the assay was carried out in the linear range. Typical concentrations were in the order of about 0.2 nM.
  • the reaction was stopped by addition of 5 ⁇ l of a solution of TR-FRET detection reagents [0.1 ⁇ M streptavidin-XL665 (Cisbio Bioassays; France, catalogue No. 610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, “STK Antibody”, catalogue No. 35-002] and 0.6 nM LANCE EU-W1024-labelled anti-mouse-IgG antibody (Perkin-Elmer, product No.
  • TR-FRET detection reagents 0.1 ⁇ M streptavidin-XL665 (Cisbio Bioassays; France, catalogue No. 610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, “STK Antibody”, catalogue No. 35-002] and 0.6 nM LANCE EU-W1024-labelled anti-mouse-IgG antibody (Perkin-Elmer, product No.
  • AD0077 alternatively, it is possible to use a terbium cryptate-labelled anti-mouse-IgG antibody from Cisbio Bioassays) in aqueous EDTA solution (100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5).
  • aqueous EDTA solution 100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5.
  • the resulting mixture was incubated at 22° C. for 1 h to allow formation of a complex of the biotinylated phosphorylated substrate and the detection reagents.
  • the amount of the phosphorylated substrate was then evaluated by measuring the resonance energy transfer from europium chelate-labelled anti-mouse-IgG antibody to streptavidin-XL665. To this end, the fluorescence emissions at 620 nm and 665 nm were measured after excitation at 350 nm in a TR-FRET measuring instrument, for example a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • the ratio of the emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate.
  • the test substances were tested on the same microtitre plates at 11 different concentrations in the range from 20 ⁇ M to 0.073 nM (20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM).
  • the dilution series were prepared prior to the assay (2 mM to 7.3 nM in 100% DMSO) by serial dilutions.
  • the IC 50 values were calculated by a 4-parameter fit.
  • the inhibitory activity of the present substances of the general formula (III) with respect to IRAK4 was likewise measured in the IRAK4 TR-FRET assay described above.
  • TNF- ⁇ tumor necrosis factor alpha
  • THP-1 cells human monocytic acute leukaemia cell line
  • TNF- ⁇ secretion is triggered by incubation with bacterial lipopolysaccharide (LPS).
  • LPS bacterial lipopolysaccharide
  • THP-1 cells were kept in continuous suspension cell culture [RPMI 1460 medium with L-Glutamax (Gibco, Cat. No. 61870-044) supplemented with foetal calf serum (FCS) 10% (Invitrogen, Cat. No. 10082-147), 1% penicillin/streptomycin (Gibco BRL, Cat. No. 15140-114)] and should not exceed a cell concentration of 1 ⁇ 10 6 cells/ml.
  • FCS foetal calf serum
  • the assay was carried out in cell culture medium (RPMI 1460 medium with L-Glutamax supplemented with FCS 10%).
  • the plates were centrifuged at 80 g for 30 s and incubated at 37° C., 5% CO 2 and 95% atmospheric humidity for 17 h.
  • the amount of TNF- ⁇ was determined using the TNF-alpha HTRF Detection Kit (Cisbio, Cat. No. 62TNFPEB/C).
  • 2 ⁇ l of the detection solution in each case consisting of anti-TNF- ⁇ -XL665 conjugate and anti-TNF- ⁇ -cryptate conjugate dissolved in the reconstitution buffer in accordance with the manufacturer's instructions, were added for the HTRF (Homogeneous Time-Resolved Fluorescence) test. After the addition, the mixture was incubated either at room temperature for 3 h or at 4° C. overnight.
  • the signals were then read at 620/665 nm using an HTRF-enabled measuring instrument such as the BMG PheraStar.
  • the activity of the substances is expressed as the ratio between neutral and inhibitor control in percent.
  • the IC 50 values were calculated using a 4-parameter fit.
  • the human PBMCs were obtained from anti-coagulated human whole blood. For this purpose, 15 ml of Ficoll-Paque (Biochrom, Cat. No. L6115) were initially pipetted in Leucosep tubes and 20 ml of human blood were added. After centrifugation of the blood at 800 g for 15 min at room temperature, the plasma including the platelets was removed and discarded. The PBMCs were transferred into centrifugation tubes and made up with PBS (phosphate-buffered saline) (Gibco, Cat. No. 14190). The cell suspension was centrifuged at room temperature at 250 g for 10 min and the supernatant was discarded.
  • PBS phosphate-buffered saline
  • the PBMCs were resuspended in complete medium (RPMI 1640, without L-glutamine (PAA, Cat. No. E15-039), 10% FCS; 50 U/ml penicillin, 50 ⁇ g/ml streptomycin (PAA, Cat. No. P11-010) and 1% L-glutamine (Sigma, Cat. No. G7513)).
  • complete medium RPMI 1640, without L-glutamine (PAA, Cat. No. E15-039), 10% FCS; 50 U/ml penicillin, 50 ⁇ g/ml streptomycin (PAA, Cat. No. P11-010) and 1% L-glutamine (Sigma, Cat. No. G7513)).
  • the assay was also carried out in complete medium.
  • the PBMCs were seeded in 96-well plates at a cell density of 2.5 ⁇ 10 5 cells/well.
  • the present compounds were subjected to serial dilution in a constant volume of 100% DMSO and used in the assay at 8 different concentrations in the range from 10 ⁇ M to 3 nM such that the final DMSO concentration was 0.4% DMSO.
  • the cells Prior to the actual stimulation, the cells were then pre-incubated therewith for 30 min.
  • the cells were stimulated with 0.1 ⁇ g/ml LPS (Sigma, Escherichia coli 0128:B12, Cat. No. L2887) for 24 hours.
  • Example Compound 11 and Example Compound 12 have activity ⁇ 1 ⁇ M.
  • TH-17 cells play a crucial role in the pathogenesis of disorders such as rheumatoid arthritis, psoriatic arthritis, Bekhterev's disease (ankylosing spondylitis) or else multiple sclerosis (Lubberts, Nat. Rev. Rheumatol., 2015; Marinoni et al., Auto. Immun. Highlights, 2014; Isailovic et al., J.
  • human primary monocytes isolated from human PBMCs using magnetic separation [Miltenyi Biotech, Monocyte Isolation Kit, Cat. No. 130-091-153] and by the addition of growth factors (recombinant human GM-CSF [PeproTech, Cat. No. 300-03] and IL-4 [PeproTech, Cat. No. 200-04]) in complete medium (VLE (very low endotoxin) RPMI 1640 [Biochrom AG, Cat. No. FG1415], 10% Fetal Bovine Serum (FBS) [Gibco, Cat-No.
  • VLE very low endotoxin
  • the DMSO concentration present was always 0.1% DMSO for each of the 9 concentrations used.
  • the obtained pDCs were resuspended in complete medium (RPMI 1640+GlutaMax [Gibco, Cat. No. 61870-010] supplemented with 10% FBS [Gibco, Cat. No. 10493-106] and 50 U penicillin/streptomycin [Gibco, Cat. No. 15140-114]) and seeded at a cell density of 5 ⁇ 10 4 cells/well in a 96-well microtitre plate (Costar, Cat. No. 3599).
  • the present compounds were subjected to serial dilution in a constant volume of 100% DMSO and used in the assay at 9 different concentrations in the range from 10 ⁇ M to 1 nM.
  • DMSO concentration present was always 0.1% DMSO for each of the 9 concentrations tested.
  • the pDCs were stimulated either with a TLR7/8 ligand (imiquimod, R837, Invivogen, Cat. No. tlrl-imq) or with a TLR-9 ligand (CPG-A, ODN2216, Invivogen, Cat. No. tlrl-2216-1) and this led to activation of the IRAK4-mediated signalling pathways.
  • Example Compound 12 After incubation for 24 hours, the cell culture supernatants were removed and analysed using a commercially available human IFN ⁇ ELISA (IFNalpha Multi-Subtype ELISA Kit, pbl Assay Science, Cat. No. 41105-1). The results of the inhibition of IFN ⁇ in human plasmacytoid DCs are shown by way of example for Example Compound 12 in FIG. 2 .
  • the present compounds of the general formula (I) were examined for their in vivo efficacy in a model of in vivo TLR-mediated inflammation.
  • This mechanistic model particularly shows the potential effect of the present compounds on TLR4-mediated disorders, since an LPS-mediated inflammation model was used.
  • female Balb/c mice (about 8 weeks old; Charles River Laboratories, Germany) were divided into groups of 5 animals each.
  • the control group was treated with the vehicle in which the substance had been dissolved (substance vehicle) and also with the vehicle in which the LPS had been dissolved.
  • the substance treatment groups as well as the positive control group received 0.2 mg LPS/kg body weight (Sigma, Cat. No. L4391) (lipopolysaccharides from E.
  • FIG. 3 shows the amount of TNF- ⁇ in the plasma, which is reduced in a dose-dependent manner by administration of Example Compound 11 in comparison with the LPS-induced concentration.
  • IL-1 ⁇ was administered i.p. to female Balb/c mice (about 8 weeks old, Charles River Laboratories, Germany) and the effect of the present compounds on IL-1 ⁇ -mediated cytokine secretion was examined. There were 5 animals in each group.
  • the control group was treated with the vehicles used for dissolving the substance and the IL-1 ⁇ .
  • the substance treatment groups and the positive control group were each administered 90 ⁇ g IL-1 ⁇ /kg body weight i.p. (R&D, Cat. No. 401-ML/CF).
  • the substance or its vehicle in the positive control group was administered 6 hours before the administration of IL-1 ⁇ .
  • TNF- ⁇ was determined in the plasma isolated from the blood using the Mouse ProInflammatory 7-Plex Tissue Culture Kit (MSD, Cat. No. K15012B) in accordance with the manufacturer's instructions.
  • MSD Mouse ProInflammatory 7-Plex Tissue Culture Kit
  • FIG. 4 This is illustrated by FIG. 4 .
  • the treatment only with the vehicle of the test substance was conducted in a preventative manner, i.e. starting from day 0, by oral administration.
  • the starting condition of the animals was additionally determined in terms of the disease activity scores (rating of the severity of arthritis based on a points system).
  • the disease activity of the animals was scored by means of disease activity scoring starting from day 8, when the animals first exhibit signs of arthritis, and subsequently 3 times per week, until the end (day 20).
  • Statistical analysis was performed using single-factor variance analysis (ANOVA) and by comparison with the control group by means of multiple comparative analysis (Dunnett's test).
  • a collagen antibody cocktail (10 mg/ml; ArthritoMab, MD Bioproducts
  • the treatment with different dosages of the test substance was conducted in a preventative manner, i.e. starting from day 0, by oral administration.
  • the extent of disease was scored on the basis of a point award system for the disease activity score on all four paws. In this awarding of points, no points are awarded for a healthy paw, whereas points from 1 [mild inflammation, for example, of the toe(s)] to 4 [severe inflammation extending over the entire paw] are awarded in each case for the particular extent of joint inflammation that has arisen from the toes through the metatarsal joint to the ankle joint, as explained as follows:
  • the starting condition was determined beforehand one day before the start of the experiment (day ⁇ 1) and this disease activity score was subsequently scored three times per week from day 8 onwards.
  • Statistical analysis was performed using single-factor variance analysis (ANOVA) and by comparison with the control group by means of multiple comparative analysis (Dunnett's test).
  • streptozotocin (STZ; Sigma-Aldrich, USA) is each injected subcutaneously in 45 male 2-day-old C57BL/6 mice. Starting at 4 weeks of age, these animals are fed ad libitum with a high-fat diet (HFD; 57 kcal % fat, # HFD32 from CLEA, Japan). At an age of 6 weeks, the animals are randomized into 3 groups (15 animals per group). While one of the groups does not receive any treatment, the other 2 groups are daily orally treated either with vehicle or the test substance over 4 weeks. After the 4-week treatment, all animals are sacrificed painlessly under anaesthesia, and the livers are removed and fixed for the histological study in Bouin's solution (H.
  • the NAFLD activity score is determined in the haematoxylin-eosin sections on the basis of the criteria recommended by D. E. Kleiner et al., Hepatology 41 (2005), 1313-1321 (Table 1). For the histological quantification of fibrotic areas, 5 digital photos (DFC280; Leica, Germany) are taken for each section under 200-fold microscope enlargement and the percentage of fibrosis is determined using the ImageJ Software (National Institute of Health, USA).
  • mice 30 male 8-week-old db/db mice are used.
  • This model is a well accepted model for obesity, insulin resistance and type 2 diabetes (Aileen J F King; The use of animal models in diabetes research; British Journal of Pharmacology 166 (2012), 877-894).
  • the animals receive a standard diet (RM1(E) 801492, SDS) and tap water ad libitum.
  • the animals are randomized into 3 groups (10 animals per group) and treated orally with the test substance over 6 weeks.
  • blood is taken from the animals at different time points (before start of treatment, 3 weeks after start of treatment and 2 days before the end of treatment) to determine insulin sensitivity parameters (e.g. HbA1c, glucose content, insulin content).
  • an OGTT oral glucose tolerance test
  • HOMA-IR index fasting insulin level (mU/l)*fasting glucose level (mmol/l)/22.5
  • the anti-tumour activity of the present compounds of the general formula (I) is studied in murine xenotransplantation models.
  • female C.B-17 SCID mice are implanted subcutaneously with human B-cell lymphoma cell lines, e.g. TMD-8.
  • human B-cell lymphoma cell lines e.g. TMD-8.
  • oral monotherapeutic treatment is started with an present compound or by administration of an present compound in combination with a standard therapy, each administered orally.
  • the animals are randomized beforehand.
  • the treatment is ended as soon as the untreated control group has large tumours.
  • the tumour size and body weight are determined three times per week.
  • tumour weight is detected by an electronic caliper gauge [length (mm) ⁇ width (mm)].
  • the anti-tumour efficacy defines the ratio of tumour weight of treatment vs. control (T/C) [tumour weight of the treatment group on day x/tumour weight of the control group on day x] or the ratio of the tumour area of treatment vs. control [tumour area of the treatment group on day x/tumour area of the control group on day x].
  • T/C ratio of tumour weight of treatment vs. control
  • a compound having a T/C greater than 0.5 is defined as active (effective).
  • Statistical analysis is preformed using single-factor ANOVA and by comparison with the control group by means of pair-by-pair comparative analysis (Dunnett's test).
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • the substrate used for the kinase reaction was the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in amide form) which can be purchased, for example, from Biosyntan GmbH (Berlin-Buch).
  • the concentration of the Irak4 was adjusted to the respective activity of the enzyme and set such that the assay was carried out in the linear range. Typical concentrations were in the order of about 0.1 nM.
  • the reaction was stopped by addition of 5 ⁇ l of a solution of TR-FRET detection reagents [0.1 ⁇ M streptavidin-XL665 (Cisbio Bioassays; France, catalogue No. 610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, “STK Antibody”, catalogue No. 35-002] and 0.6 nM LANCE EU-W1024-labelled anti-mouse-IgG antibody (Perkin-Elmer, product No.
  • TR-FRET detection reagents 0.1 ⁇ M streptavidin-XL665 (Cisbio Bioassays; France, catalogue No. 610SAXLG)] and 1.5 nM anti-phosphoserine antibody [Merck Millipore, “STK Antibody”, catalogue No. 35-002] and 0.6 nM LANCE EU-W1024-labelled anti-mouse-IgG antibody (Perkin-Elmer, product No.
  • AD0077 alternatively, it is possible to use a terbium cryptate-labelled anti-mouse-IgG antibody from Cisbio Bioassays) in aqueous EDTA solution (100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5).
  • aqueous EDTA solution 100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5.
  • the resulting mixture was incubated at 22° C. for 1 h to allow formation of a complex of the biotinylated phosphorylated substrate and the detection reagents.
  • the amount of the phosphorylated substrate was then evaluated by measuring the resonance energy transfer from europium chelate-labelled anti-mouse-IgG antibody to streptavidin-XL665. To this end, the fluorescence emissions at 620 nm and 665 nm were measured after excitation at 350 nm in a TR-FRET measuring instrument, for example a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • the ratio of the emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate.
  • the test substances were tested on the same microtitre plates at 11 different concentrations in the range from 20 ⁇ M to 0.073 nM (20 ⁇ M, 5.7 ⁇ M, 1.6 ⁇ M, 0.47 ⁇ M, 0.13 ⁇ M, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM).
  • the dilution series were prepared prior to the assay (2 mM to 7.3 nM in 100% DMSO) by serial dilutions.
  • the IC 50 values were calculated by a 4-parameter fit.
  • the canine PBMCs were obtained from anti-coagulated dog whole blood.
  • canine leucocyte rich plasma was prepared from 15 ml dog blood by centrifugation at 400 g for 15 min at 4° C., followed by harvest and then suspension of the canine PBMC buffy coat in plasma.
  • Seven (7) ml Ficoll-Paque Plus (Fischer Scientific, Cat. No. 11778538) were pipetted in a centrifugation tube and 7 ml canine leucocyte rich plasma then layered on top of the Ficoll-Paque Plus. After centrifugation of the tube at 400 g for 20 min at 4° C., canine PBMCs were harvested from the interface of the canine plasma and Ficoll-Paque Plus.
  • PBMCs were transferred into a fresh centrifugation tube and made up with Hanks' Balanced Salt Solution 1 ⁇ (HBSS) without Ca 2+ /Mg 2+ (Sigma-Aldrich, Cat. No. H9394).
  • HBSS Hanks' Balanced Salt Solution 1 ⁇
  • the cell suspension was centrifuged at 400 g for 5 min at 4° C. and the supernatant was discarded.
  • the cell pellet was then re-suspended in 0.2% hypotonic saline to lyse any remaining red blood cells. After 30 seconds the cell suspension was made isotonic and centrifuged at 400 g for 5 min at 4° C.
  • the cell pellet was then re-suspended in HBSS without Ca 2 +/Mg 2+ for a final wash and centrifuged at 400 g for 5 min at 4° C.
  • the PBMCs were then re-suspended in complete medium (RPMI 1640 with GlutaMAX (Sigma-Aldrich, Cat. No. R0883), 10% FCS; 50 U/ml penicillin, 50 ⁇ g/ml streptomycin (Sigma-Aldrich, Cat. No. P4333)).
  • the assay was also carried out in complete medium.
  • the PBMCs were seeded in 96-well plates at a cell density of 2.5 ⁇ 10 5 cells/well.
  • the present compounds were dissolved in DMSO and subjected to serial dilution in complete medium.
  • the compound examples were used in the assay at 8 different concentrations in the range from 3 nM to 10 ⁇ M such that the final DMSO concentration was 0.0003-0.4%.
  • To induce cytokine secretion the cells were stimulated with 0.1 ⁇ g/ml LPS (Sigma-Aldrich, Escherichia coli 0111:B4, Cat. No. L3024) for 24 hours. Cell viability was determined using 0.2% trypan blue (Sigma-Aldrich, Cat. No.
  • Example Compound 12 inhibited the production of TNF ⁇ by canine PBMCs stimulated with LPS. This is illustrated by FIG. 7 .
  • bovine PBMCs were obtained from anti-coagulated cattle whole blood.
  • bovine leucocyte rich plasma was prepared from 500 ml cattle blood by centrifugation at 1000 g for 20 min at room temperature (RT), followed by harvest and then suspension of the bovine PBMC buffy coat in equal volume of PBS/5 mM EDTA (RT).
  • RT room temperature
  • Ficoll-Paque Plus Fischer Scientific, Cat. No. 11778538
  • bovine PBMCs were harvested from the interface of the bovine plasma and Ficoll-Paque Plus. PBMCs were transferred into a fresh centrifugation tube and made up with cold PBS/5 mM EDTA. The cell suspension was centrifuged at 350 g for 10 min at 4° C. and the supernatant was discarded. The cell pellet was then re-suspended in 0.2% hypotonic saline to lyse any remaining red blood cells. After 30 seconds the cell suspension was made isotonic and centrifuged at 500 g for 5 min at 4° C.
  • the PBMC cell pellet was then resuspended in complete medium (DMEM with GlutaMAX (ThermoFisher, Cat. No. 32430100), 10% horse serum (ATCC® 30-2040TM), 20 ⁇ M ⁇ -mercaptoethanol (ThermoFisher Cat. No. 31350010 [stock solution: 50 mM]).
  • DMEM with GlutaMAX ThermoFisher, Cat. No. 32430100
  • 10% horse serum ATCC® 30-2040TM
  • 20 ⁇ M ⁇ -mercaptoethanol ThermoFisher Cat. No. 31350010 [stock solution: 50 mM]
  • the assay was also carried out in complete medium.
  • the PBMCs were seeded in 24-well plates at a cell density of 1 ⁇ 10 6 cells/well.
  • the present compounds were dissolved in DMSO and subjected to serial dilution in complete medium.
  • the compound examples were used in the assay at 8 different concentrations in the range from 0.003 ⁇ M to 10 ⁇ M such that the final DMSO concentration was 0.5%.
  • To induce cytokine secretion the cells were stimulated with 1 ⁇ g/ml ( FIG. 8 ) and 0.1 ⁇ g/ml LPS ( FIG. 9 ) (LPS from E. coli K12; Invivogen # tlrl-eklps) for 24 hours. Cell viability was determined using Monocyte solution (Merck Millipore #1092770100).
  • the amount of secreted TNF ⁇ in the cell culture supernatant of LPS-exposed bovine PBMCs was determined using a rabbit anti-bovine TNF ⁇ antibody based ELISA read-out.
  • the ELISA assay was performed in 384 well ELISA plates, which were coated with 5 ⁇ g/ml rabbit anti-bovine TNF ⁇ antibody (BioRad, AHP2383) in 50 mM Na 2 CO 3 /NaHCO 3 pH 9.6 buffer in 10 ⁇ l/well overnight at 4° C. After removal of antibody and rinsing of wells for three times with 50 ⁇ l of wash buffer (PBS, 0.05% (v/v) Tween 20), the wells were incubated for 90 min at 37° C.
  • wash buffer PBS, 0.05% (v/v) Tween 20
  • blocking buffer PBS, 0.05% (v/v) Tween 20, 1% (w/v) bovine serum albumin. Thereafter, blocking buffer was removed and culture supernatant samples were added (20 ⁇ l/well). After an incubation for 90 min at 37° C., the samples were removed and the wells were rinsed for three times with 50 ⁇ l wash buffer. A 1 ⁇ g/ml rabbit anti-bovine TNF ⁇ -biotin conjugated antibody (BioRad, AHP2383B) in blocking buffer was added to the plates (20 ⁇ l/well) which were incubated for 60 min at 37° C.
  • PBS 0.05% (v/v) Tween 20, 1% (w/v) bovine serum albumin
  • Example Compound 12 inhibited the production of TNF ⁇ by bovine PBMCs stimulated with LPS. This is illustrated by FIGS. 8 and 9 .
  • porcine PBMCs were obtained from anti-coagulated porcine whole blood.
  • porcine leucocyte rich plasma was prepared from 36 ml pig blood by centrifugation at 1000 g for 20 min at room temperature (RT), followed by harvest and then suspension of the porcine PBMC buffy coat in equal volume of PBS/5 mM EDTA (RT).
  • RT room temperature
  • Ficoll-Paque Plus Fischer Scientific, Cat. No. 11778538
  • porcine PBMCs were harvested from the interface of the porcine plasma and Ficoll-Paque Plus. PBMCs were transferred into a fresh centrifugation tube and made up with cold PBS/5 mM EDTA. The cell suspension was centrifuged at 350 g for 10 min at 4° C. and the supernatant was discarded. The cell pellet was then re-suspended in 0.2% hypotonic saline to lyse any remaining red blood cells. After 30 seconds the cell suspension was made isotonic and centrifuged at 500 g for 5 min at 4° C.
  • the PBMC cell pellet was then resuspended in complete medium (DMEM with GlutaMAX (ThermoFisher, Cat. No. 32430100), 10% horse serum (ATCC® 30-2040TM), 20 ⁇ M 1-mercaptoethanol (ThermoFisher Cat. No. 31350010 [stock solution: 50 mM]).
  • DMEM with GlutaMAX ThermoFisher, Cat. No. 32430100
  • 10% horse serum ATCC® 30-2040TM
  • 20 ⁇ M 1-mercaptoethanol ThermoFisher Cat. No. 31350010 [stock solution: 50 mM]
  • the assay was also carried out in complete medium.
  • the PBMCs were seeded in 24-well plates at a cell density of 1 ⁇ 10 6 cells/well.
  • the present compounds were dissolved in DMSO and subjected to serial dilution in complete medium.
  • the compound examples were used in the assay at 8 different concentrations in the range from 0.003 ⁇ M to 10 ⁇ M such that the final DMSO concentration was 0.5%.
  • LPS LPS from E. coli K12; Invivogen # tlrl-eklps
  • Cell viability was determined using Monocyte solution (Merck Millipore #1092770100).
  • the amount of secreted TNF ⁇ in the cell culture supernatant of LPS-exposed porcine PBMCs was determined using a rabbit anti-porcine TNF ⁇ antibody based ELISA read-out.
  • the ELISA assay was performed in 384 well ELISA plates, which were coated with 3 ⁇ g/ml rabbit anti-porcine TNF ⁇ antibody (BioRad, AHP2397) in 50 mM Na 2 CO 3 /NaHCO 3 pH 9.6 buffer in 10 ⁇ l/well for 48 h at 4° C.
  • wash buffer PBS, 0.05% (v/v) Tween 20
  • the wells were incubated for 60 min at 37° C. with 50 ⁇ l blocking buffer (PBS, 0.05% (v/v) Tween 20, 1% (w/v) bovine serum albumin). Thereafter, blocking buffer was removed and culture supernatant samples were added (20 ⁇ l/well). After an incubation for 90 min at 37° C., the samples were removed and the wells were rinsed for three times with 50 ⁇ l wash buffer.
  • HDM-sensitization consisted of a series of subcutaneous injections of HDM antigen (10 ⁇ g, Greer Laboratories, Lenoir, N.C., USA) and Alhydrogel® (0.2 mL, InvivoGen, San Diego, Calif. 921221, USA) as adjuvant in time intervals of approximately two weeks. The sensitization process was monitored and confirmed by intradermal skin testing.
  • HDM antigen (135 ⁇ g) was topically applied and pricked into the skin (with 2 mm long micro needles) of the adult beagle dogs in the inner part of the posterior legs and the effect of the present compounds on signs of allergic dermatitis, e.g. erythema and edema, was examined.
  • the control group was orally treated with gelatin capsules containing micro cellulose while the group treated with Example Compound 12 was orally treated with gelatin capsules containing Example Compound 12 and micro cellulose.
  • Example Compound 12 The administration of Example Compound 12 or the placebo started 5 days before the challenge with HDM antigen and continued until 2 days after the challenge.
  • the treatment frequency was once daily, with a dose of 10 mg/kg body weight in the case of Example Compound 12.
  • erythema and edema were evaluated using VAS (Visual Analogue Scale) in the 2 groups. Plasma samples were analyzed to determine exposure to the compound in relationship to the clinical evaluations. Edema and erythema were significantly reduced after treatment with Example Compound 12. This is illustrated by Tables 4 and 5, and by FIGS. 11 and 12 .
  • the control group was orally treated with gelatin capsules containing micro cellulose while the group treated with Example Compound 12 was orally treated with gelatin capsules containing Example Compound 12 and micro cellulose.
  • the treatment frequency was once daily, with a dose of 20 mg/kg body weight in the case of Example Compound 12. Starting 1 day after treatment and at every third day, dogs were recorded for 4 hours and time spent in pruritic behavior was determined as seconds spent in scratching, licking, biting. Plasma samples were analyzed to determine exposure to the compound in relationship to the clinical evaluations. Pruritus was substantially reduced after 10 days of treatment with Example Compound 12. This is illustrated by Table 6 and FIG. 13 .
  • Example Compound 12 Compared to baseline after treatment with Example Compound 12 versus placebo (shown as percent-change from baseline at the listed day after treatment) Day 4 Day 7 Day 10 Day 13 Placebo Control ⁇ 12.0% ⁇ 9.9% 1.7% ⁇ 20.0%
  • Example Compound 12 ⁇ 26.7% 5.7% ⁇ 57.7% ⁇ 48.0%
  • FIG. 1 Inhibition of IL-23 in human monocyte-generated DCs for Example Compound 12. Data are shown as mean values with standard deviations.
  • FIG. 2 Inhibition of INF- ⁇ in (A) imiquimod (R837)- or (B) CpG-A-stimulated human plasmacytoid DCs for Example Compound 12. Data are shown as mean values with standard deviations.
  • FIG. 3 Treatment of an LPS-induced inflammation with Example Compound 11 leads to a reduced amount of secreted TNF- ⁇ . Data are shown as mean values with standard deviations.
  • FIG. 4 Treatment of an IL-1 ⁇ -induced inflammation with Example Compounds 11 (left) and 12 (right) leads to a dose-dependent reduction in the amount of secreted TNF- ⁇ . Data are shown as mean values with standard deviations.
  • FIG. 5 Anti-inflammatory effects of Example Compound 11 in an animal model of rheumatoid arthritis (adjuvant-induced rat model). Significant and dose-dependent inhibition of rheumatic joint inflammation measured on the basis of the disease activity score. The data corresponds to the mean values+standard deviations. Single-factor ANOVA variance analysis with subsequent multiple comparative analysis with the CFA control group by means of Dunnett's test; *p ⁇ 0.05; **p ⁇ 0.01;***p ⁇ 0.001; ****p ⁇ 0.0001.
  • FIG. 6 Anti-inflammatory effects of Example Compound 12 in an animal model of rheumatoid arthritis (collagen antibody-induced mouse model). Significant and dose-dependent inhibition of rheumatic joint inflammation measured on the basis of the disease activity score. The data corresponds to the mean values+standard deviations. The statistical significances between collagen antibody (AK) control and the treatment groups were calculated by means of single-factor ANOVA variance analysis with subsequent multiple comparative analysis (Dunnett's test) (*p ⁇ 0.05; **p ⁇ 0.01;***p ⁇ 0.001; ****p ⁇ 0.0001).
  • FIG. 7 Inhibition of LPS-induced TNF ⁇ production by canine PBMCs for Example Compound 12. Data are shown as mean values with standard deviations.
  • FIG. 8 Dose-dependent inhibition by Example Compound 12 of TNF ⁇ production by bovine PBMCs induced by 1 ⁇ g/ml LPS (kinetic measurement). Data show the mean values with standard deviations of biological triplicates each measured in duplicate. The IC50 value determined from this curve is 120 nM.
  • FIG. 9 Dose-dependent inhibition by Example Compound 12 of TNF ⁇ production by bovine PBMCs induced by 0.1 ⁇ g/ml LPS (kinetic measurement). Data show the mean values with standard deviations of biological triplicates each measured in duplicate. The IC50 value determined from this curve is 70.5 nM.
  • FIG. 10 Inhibition by 10 ⁇ M of Example Compound 12 of TNF ⁇ production by porcine PBMCs induced by 0.1 ng/ml LPS (kinetic measurement). Data show the mean values with standard deviations of biological triplicates each measured in duplicate.
  • FIG. 11 Treatment of a House Dust Mite induced Canine Allergic Dermatitis model with Example Compound 12 leads to reduction of erythema (a). Data are shown as mean values with standard deviations.
  • FIG. 12 Treatment of a House Dust Mite induced Canine Allergic Dermatitis model with Example Compound 12 leads to reduction of edema (b). Data are shown as mean values with standard deviations.
  • FIG. 13 Anti-pruritic effect of Example Compound 12 in an animal model of Flea Allergy Dermatitis. The data is expressed as Percent Change from Baseline corresponding to median values.

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