US20190125736A1 - Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases - Google Patents

Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases Download PDF

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US20190125736A1
US20190125736A1 US16/306,506 US201716306506A US2019125736A1 US 20190125736 A1 US20190125736 A1 US 20190125736A1 US 201716306506 A US201716306506 A US 201716306506A US 2019125736 A1 US2019125736 A1 US 2019125736A1
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alkyl
trifluoromethyl
indazol
carboxamide
methyl
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Alexandra RAUSCH
Stefan Joachim Jodl
Jörn KRÄTZSCHMAR
Ulrich Bothe
Nicole Schmidt
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Bayer Pharma AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present application relates to the use of 2-substituted indazoles for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of autoimmune disorders mediated by IRAK4, such as peripheral arthritides (psoriatic arthritis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), axial arthritis (in particular ankylosing spondylitis), systemic vasculitides such as giant cell arteritis and ANCA (anti-neutrophile cytoplasmic antibody)-associated vasculitides, gout and other crystal arthropathies or metabolic arthritides (hydroxyapatite arthropathy, chondrocalcinosis (calcium pyrophosphate dihydrate (CPPD), endocrine joint disorders such as in cases of hyperactivity of the parathyroid glands (hyperparathyroidism), of the thyroid gland (hyperthyroidism) in the case of diabetes me
  • the present invention relates to the use of substituted indazoles of the general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4), for use in the treatment of autoimmune disorders or dysfunctions.
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • TLR Toll-like receptors
  • IL interleukin-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 for TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., J Immunol, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
  • 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., J Biol Chem, 2004; Precious et al., J. Biol. Chem., 2009).
  • NF nuclear factor
  • MAPK mitogen-activated protein kinase
  • cytokines cytokines
  • chemokines cyclooxygenase-2
  • 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
  • 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, Br J Haematol, 2007).
  • Autoimmune disorders are diseases where the immune system is directed against the body itself (“auto”), thus attacking healthy endogenous tissue.
  • the immune system may be directed either selectively only against a certain organ (e.g. the intestine in the case of ulcerative colitis, the skin in the case of psoriasis or nerves in the case of multiple sclerosis), and they are then classified as a so-called organ-specific autoimmune disorder, or it is directed against the entire system, thus causing a non-organ-specific systemic autoimmune disorder.
  • a non-organ-specific systemic autoimmune disorder the immune system attacks various organs of the body (for example in the case of systemic lupus erythematosus with reactions against skin, joints, kidneys, etc.).
  • IRAK4 The kinase IRAK4 or signal transduction via IRAK4 plays a central role in the underlying pathology of numerous autoimmune disorders (Chaudhary et al., J Med Chem, 2015).
  • the central role of IRAK4 has already been demonstrated by direct comparison of wild type (WT) mice with genetically modified animals having a kinase-inactivated form of IRAK4 (IRAK4 KDKI) in an animal model of multiple sclerosis where IRAK4 KDKI animals had improved MS symptoms 9 Staschke et al., J Immunol, 2009).
  • IRAK4 has also been shown that the expression of IRAK4 correlates with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
  • IFN ⁇ interferon-alpha
  • 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.
  • peripheral arthritides such as psoriatic arthritis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), axial arthritis (in particular Bekhterev's disease), sarcoidosis, systemic lupus erythematosus, psoriasis, vitiligo, giant cell arteriitis, atopic dermatitis, allergic eczema/contact allergy, multiple sclerosis and chronic inflammatory bowel diseases (in particular Crohn's disease and ulcerative colitis) (Staschke, et al., J Immunol, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal
  • the inhibition of IRAK4 can be utilized for the prophylaxis and/or treatment of disorders which are mediated by the receptors mentioned.
  • TLRs and also components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, myasthenia gravis, vasculitis, for example Behçet's disease and giant cell arteritis, pancreatitis, systemic lupus erythematosus, dermatomyositis and polymyositis, diabetes mellitus (type 1 and type 2), diabetic nephropathy, osteoarthritis, Sjögren syndrome, Still's disease, multiple sclerosis and sepsis (Yang, Tuzun, et al., J Immunol, 2005; Zhou et al., Arthritis Rheum, 2005; Candia, Marquez et al., The Journal of Rheumatology, 2007; Li, Eur J Immunol, 2008; Scanzello, Plaas, et al.
  • Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa and acne vulgaris are likewise associated with the IRAK4-mediated TLR signalling pathway or the IL-1R family (Schmidt, Mittnacht, et al., J Dermatol Sci, 1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad, et al., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali, et al., Am J Clin Dermatol, 2010; Viguier, Guigue, et al., Annals of Internal Medicine, 2010; Carrier et al., J Invest Dermatol, 2011; Cevikbas, Steinhoff, J Invest Dermatol,
  • TLRs and also IL-1R family members are additionally also involved in the pathogenesis of other inflammatory disorders such as allergy, Behçet's disease, crystal arthropathies such as gout, systematic lupus erythematosus, adult-onset Still's disease and chronic inflammatory bowel disorders such as ulcerative colitis and Crohn's disease, and so inhibition of IRAK4 here is a suitable prophylactic and/or therapeutic approach (Liu-Bryan, Scott, et al., Arthritis & Rheumatism, 2005; Piggott, Eisenbarth, et al., J Clin Inves, 2005; Christensen, Shupe, et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., Immunity, 2006; Heimesaat, Fischer, et al.,
  • IRAK4-mediated TLR processes have been described in the pathogenesis of inflammatory eye disorders such as uveitis, keratitis and allergic conjunctivitis (Li et al., Curr Mol Med. 2009; Bascherini et al., Clin Rheumatol. 2015; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012).
  • pain examples include hyperalgesia, allodynia, post-operative pain, neuropathic pain, abdominal pain, inflammation-induced pain, lower back pain, and chronic pain
  • CAPS cystopyrin-associated periodic syndromes
  • FCAS familial cold autoinflammatory syndrome
  • MWS Muse-Wells syndrome
  • NOMID nonatal-onset multisystem inflammatory disease
  • CONCA chronic infantile, neurological, cutaneous, and articular
  • FMF familial mediterranean fever
  • HIDS hyper-IgD syndrome
  • TRAPS tumor necrosis factor receptor 1-associated periodic syndrom
  • juvenile idiopathic arthritis adult-onset Still's disease
  • Adamantiades-Behçet's disease rheumatoid arthritis, osteoarthritis, Schnitzler's syndrome
  • SAPHO acronym for synovitis, acne, pustulosis, hyperostosis and osteitis
  • PAPA acronym for pyogenic arthritis, Pyoderma gangraenosum and acne
  • PASS acronym for pyodermatitis
  • the ligand of IL-33R, IL-33 is involved particularly in the pathogenesis of atopic dermatitis and allergic eczema/dermatitis and Bekhterev's disease, and so the inhibition of IRAK4 for prophylaxis and/or treatment is a suitable therapeutic approach (Li et al., J Investig Med, 2013; Theoharides et al., J Pharmacol Exp Ther. 2015; Saluja et al., Clin Transl Allergy.
  • Components of the IL-1 receptor family are associated with different inflammatory disorders such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS) and CRMO (chronic recurrent multifocal osteomyelitis), and so prophylactic and/or therapeutic action is to be expected in the indications mentioned through the inhibition of IRAK4 (Kang et al., J Immunol, 2007; Imaoka et al., Eur Resp J, 2008; Couillin et al., J Immunol, 2009; Lloyd, Curr OpinImmunol, 2010; Pauwels, et al., Eur Respir J, 2011; Haenuki, et al., J Allergy Clin Immunol, 2012; Yin, et al., ClinExplmmunol, 2012; Alexander-Brett, et al., J Clin Invest, 2013; Bunting, et al
  • MS multiple sclerosis
  • immunosuppressants or immunomodulators such as NSAIDs, hydroxychloroquin, systemic steroids (glucocorticoids), mycophenolat mofetil (MMF), azathioprine, leflunomide, methotrexate, cyclosporine or cyclophosphamide, frequently in combination and as interval/maintenance therapy, or belimumab or rituximab, antibodies to be applied parenterally.
  • Psoriasis therapy depends on the degree of severity and is carried out using topical steroids and vitamin D3 analogues (or a combination of both) or topic dithranol or retinoid, frequently together with exfoliating compounds (such as salicylic acid or urea) to be applied externally, and phototherapy.
  • exfoliating compounds such as salicylic acid or urea
  • calcineurine inhibitors such as tacrolimus and pimecrolimus are employed, too.
  • Systemic therapies available are, inter alia, methotrexate, cyclosporine, fumaric esters, apremilast, retinoid TNF blockers and other active compounds.
  • Biologics such as TNF blockers (e.g.
  • interleukin-inhibiting monoclonal antibodies such as ustekinumab and secukinumab are also used in psoriasis treatments.
  • atopic dermatitis atopic dermatitis
  • eczema use is made of steroids, salicylic acid, urea, calcineurine inhibitors such as tacrolimus, antibiotics (e.g. mupirocin), antihistamines, cyclosporine and phototherapy.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • hydroxychloroquine and steroids e.g. prednisone
  • DARDS chemical disease-modifying drugs
  • Biologics such as TNF blockers (infliximab, adalimumab, golimumab and certolizumab pegol, and also etanercept), rituximab, abatacept or interleukin-inhibiting monoclonal antibodies such as ustekinumab, tocilizumab and secukinumab, or Jak/STAT inhibitors such as tofacitinib are used for treating arthritides.
  • TNF blockers infliximab, adalimumab, golimumab and certolizumab pegol, and also etanercept
  • rituximab abatacept
  • interleukin-inhibiting monoclonal antibodies such as ustekinumab, tocilizumab and secukinumab
  • Jak/STAT inhibitors such as tofacitinib are used for treating arthritides.
  • Patients with chronic inflammatory bowel disorders are treated, for example, with antibiotics such as ciprofloxacin and metronidazole, antidiuretics such as loperamide or laxatives (bisacodyl) and probiotic bacteria (Mutaflor, VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917).
  • antibiotics such as ciprofloxacin and metronidazole
  • antidiuretics such as loperamide or laxatives (bisacodyl) and probiotic bacteria
  • probiotic bacteria Meltobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fe
  • prednisolone prednisolone
  • sulfasalazine, azathioprine, mercaptopurine, methotrexate, cyclosporine, TNF-blockers (e.g. adalimumab, etanercept) and integrin antibodies (e.g. vedolizumab, natalizumab) are used for treatment.
  • all of the therapies described may cause serious side-effects, e.g. osteoporosis, negative effects on glucose levels (systemic steroids), in some cases lethal infections, reactivation of tuberculosis (TNF blockers), organ damage (pancreatitis, hepatitis, pneumonitis), infusion and injection reactions, auto-antibody formation (most parenteral biologics), increased risk of cancer (TNF blockers) and others. None of the therapies mentioned cures the disorders described, and new episodes and exacerbations are very frequent, in particular when the therapy is discontinued.
  • autoimmune disorders in particular of multiple sclerosis, systemic lupus erythematosus, psoriasis, peripheral arthritides (in particular psoriatic arthritis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), axial arthritis (in particular Bechterew disease), chronic inflammatory bowel disorders (in particular Crohn's disease, ulcerative colitis), atopic dermatitis and
  • a further embodiment of the invention consists in the use of the compounds of the general formula (I) for the treatment and/or prophylaxis of multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis and allergic eczema, arthritis (in particular psoratic arthritis, Bechterew disease, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), chronic inflammatory bowel disorders (in particular Crohn's disease, ulcerative colitis).
  • arthritis in particular psoratic arthritis, Bechterew disease, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis
  • chronic inflammatory bowel disorders in particular Crohn's disease, ulcerative colitis.
  • multiple sclerosis which is also referred to as encephalomyelitis disseminata (ED)
  • MS encephalomyelitis disseminata
  • ED encephalomyelitis disseminata
  • the course of MS may differ strongly.
  • the two most significant forms of progression of MS is the episodic and the chronically progressive (progredient) course.
  • an initially episodic remitting course (relapsing remitting, RR-MS for short) later changes to a chronically progredient course (secondary progressive, SP-MS for short).
  • secondary progressive, SP-MS for short Less often (in about 10% of MS cases) there is a chronically progressive course even at the beginning (primary progressive, PP-MS for short), without any episodes of the disorder being noticeable beforehand.
  • systemic lupus erythematosus is to be understood as meaning a chronic and life-threatening autoimmune disorder which may lead to multiple organ pathologies, skin manifestations (e.g. butterfly rash) and a kidney disorder (lupus nephritis).
  • SLE systemic lupus erythematosus
  • pDCs plasmacytoid dendritic cells
  • TLR endosomal nucleic acid-specific toll-like receptors
  • type I interferon such as IFN-alpha and TNF- ⁇
  • IFN-alpha and TNF- ⁇ type I interferon
  • TNF- ⁇ type I interferon
  • psoriasis is understood as meaning a chronic skin inflammation with episodic progression and increased flaking of the skin. Characteristic symptoms are silver-white roundish skin lesions which flake strongly and preferably occur at knees, elbows and scalp. The affected areas are frequently very itchy.
  • Th1 and Th17 cells T helper cells of type 1 or type 17.
  • proinflammatory cytokines such as IFN- ⁇ , TNF- ⁇ , IL-23 and IL-17 are produced (Deng et al., Clin Rev Allergy Immunol.
  • atopic dermatitis and allergic eczema is to be understood as meaning a chronic inflammatory skin disorder associated with itching.
  • allergic eczema is the result of a specific inappropriate overreaction of the immune system to an external allergen which, per se, would not be harmful to the organism, in contrast, in the case of neurodermatitis patients the protective function of the skin is reduced.
  • contact with physical, chemical or microbial stimuli may then result in inflammation.
  • Atopic dermatitis frequently starts in infancy and childhood and typically progresses with episodes which may alternate with phases with few symptoms, if any (Malajian and Guttman-Yassky, Cytokine, 2015).
  • Allergic reactions such as allergic eczema may trigger or maintain atopic dermatitis (Fischer et al., Der Hautmaschine, 2003).
  • IgE immunoglobulin E
  • Allergic eczema requires uncovering of the causes, i.e. the allergen, by an epicutane test, and subsequently allergen avoidance is of central importance.
  • An immune reaction of type Th2 is common to inflammatory skin disorders, i.e.
  • the autoreactive immune system in these patients is stimulated via TLR or receptors of the IL-1 family, resulting in the activation of Th2 cells.
  • proinflammatory cytokines such as IL-4, IL-5, IL-13, IL-18, IL-33, etc., are produced (Kaesler et al., J Allergy Clin Immunol.
  • arthritis psoriatic arthritis, rheumatoid arthritis, reactive arthritis, Bechterew disease, systemic juvenile idiopathic arthritis
  • axial arthritis characterized by an inflammation of the spinal joints (e.g. Bechterew disease) is distinguished from peripheral arthritis where the joints of the extremities such as toes, ankles, knee, fingers, hands or else elbows are mainly affected.
  • peripheral arthritis can be symmetrical, i.e. the same joints of both sides of the body are both affected (e.g. rheumatoid arthritis) or else asymmetrical, i.e. inflamed joints are distributed unevenly over both sides of the body (e.g.
  • psoriatic arthritis Here, the mobility of the inflamed joints is painfully restricted, and the skin above is reddened and hyperthermic.
  • the arthritic disorders are characterized by episodic progredient progression which may result in destruction of the joints and serious disability up to invalidity.
  • autoreactive B cells, Th1 cells and Th17 cells and also proinflammatory cytokines such as IFN- ⁇ , TNF, IL-6, IL-12, IL-23 and IL-17 play a central role in induction, but also progression, of the pathological processes of arthritis.
  • chronic inflammatory bowel disease with its main forms Crohn's disease and ulcerative colitis is to be understood as meaning an episodic inflammation of the gastrointestinal tract which can persist the entire life.
  • Crohn's disease and ulcerative colitis share many pathological characteristics and clinical symptoms (such as bloody diarrhoea with abdominal cramps followed by weight loss) they also differ in many aspects. Whereas in the case of Crohn's disease inflammation may occur in the entire gastrointestinal tract from the oral cavity to the anus, in the case of ulcerative colitis patients it is limited to the colon. Also, in the case of Crohn's disease, the spread of the intestinal inflammation is more uneven, i.e.
  • ulcerative colitis ulcerative colitis patients in particular have an increased risk of bowel cancer (Geremia et al., Autoimmunity Rev, 2014). Both diseases occur more frequently between the ages of 20 and 40, however, children and adolescents may also be affected.
  • the chronic-inflammatory bowel disorders cannot be cured; however, frequency and intensity of the episodes of the disease can be reduced by treatment with medicaments, for example by sulfasalazine, steroids or biologics (such as anti-TNF antibodies) and lifestyle modification.
  • 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.
  • Compounds of the formula (I) are understood to mean the compounds as such as well as 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 compounds of the general formula (I).
  • the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds of the general formula (I).
  • Physiologically acceptable salts of the compounds of the general formula (I) 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, tarta
  • Physiologically acceptable salts of the compounds of the general formula (I) 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
  • Solvates in the context of the invention are described as those forms of the compounds of the general formula (I) 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 compounds of the general formula (I) 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 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 all the tautomeric forms.
  • the compounds of the general formula (I) can also be present in the form of all suitable isotopic variants of the compounds of the general formula (I).
  • An isotopic variant of an inventive compound is understood here as meaning a compound in which at least one atom within the inventive 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 inventive 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.
  • Particular isotopic variants of an inventive 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 compounds of the general formula (I) may therefore in some cases also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds of the general formula (I) 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.
  • compounds of the general formula (I) additionally also encompasses prodrugs of the compounds of the general formula (I).
  • prodrugs in this context refers to compounds which may themselves be biologically active or inactive but are converted (for example metabolically or hydrolytically) to compounds of the general formula (I) during their residence time in the body.
  • Alkyl in the context of the invention represents a straight-chain or branched alkyl radical 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 radical 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 radical 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 radical 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.
  • radicals in the compounds of the general formula (I) When radicals in the compounds of the general formula (I) are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals 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 radical substituted by 1, 2 or 3 fluorine atoms. Particular preference is given to 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl. Very particular preference is given to a 4,4,4-trifluorobutyl radical.
  • R 1 is a C 2 -C 6 -alkyl radical 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 radical 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 radical.
  • R 1 is a C 2 -C 6 -alkyl radical substituted by a C 1 -C 6 -alkyl-SO 2 group.
  • a methyl-SO 2 -substituted C 2 -C 4 -alkyl radical 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 radical 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 radical substituted by an oxetane group.
  • 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 radical or a C 1 -C 3 -alkyl radical substituted by one hydroxyl group or a C 1 -C 3 -alkyl radical substituted by one hydroxyl group and three fluorine atoms.
  • R 4 particular preference is given to the following radicals: 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 radicals. Particular preference is given here to a trifluoromethyl radical.
  • 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 radical is unsubstituted or monosubstituted by hydroxyl or by cyclopropyl or substituted by three fluorine atoms.
  • R is a cyclopropyl radical.
  • 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 radical or a tri-fluorine-substituted C 1 -C 4 -alkyl radical. 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.
  • the present invention especially provides the use of following compounds for treatment and/or prophylaxis of autoimmune disorders which are mediated by IRAK4:
  • the invention further provides for the use of the abovementioned compounds 1) to 22) for treatment and/or prophylaxis of multiple sclerosis, systemic lupus erythematosus, psoriasis, arthritis (psoriatic arthritis, Bekhterev's disease, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), chronic-inflammatory bowel disorders (Crohn's disease, ulcerative colitis), atopic dermatitis and allergic eczema.
  • multiple sclerosis systemic lupus erythematosus
  • psoriasis arthritis
  • arthritis psoriatic arthritis, Bekhterev's disease, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis
  • chronic-inflammatory bowel disorders Crohn's disease, ulcerative colitis
  • atopic dermatitis and allergic eczema atopic dermatitis and allergic eczema
  • the invention further provides for the use of compounds of the general formula (III)
  • a further embodiment of the invention is the use of compounds of the general formula (III), in which R 1 , R 4 and R 5 are as defined above, for treatment and/or prophylaxis of multiple sclerosis, systemic lupus erythematosus, psoriasis, arthritis (psoriatic arthritis, Bekhterev's disease, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis), chronic-inflammatory bowel disorders (Crohn's disease, ulcerative colitis), atopic dermatitis and allergic eczema.
  • R 1 , R 4 and R 5 are as defined above
  • the compounds of the general formula (III) are inhibitors of interleukin-1 receptor associated kinase-4 (IRAK4).
  • the compounds of the general formula (I) act as inhibitors of IRAK4 kinase and have an unforeseeable useful pharmacological activity spectrum.
  • the present invention also provides the use of the compounds of the general formula (I) for treatment and/or prophylaxis of diseases in man and animals.
  • autoimmune disorders such as inflammatory nervous disorders (MS), inflammatory joint disorders (various forms of arthritis), inflammatory skin disorders (psoriasis, atopic dermatitis and allergic eczema), inflammatory bowel disorders (IBD) and multi-organ disorders (SLE) with the inventive IRAK4 inhibitors is particularly preferred.
  • MS inflammatory nervous disorders
  • joint disorders variable forms of arthritis
  • inflammatory skin disorders psoriasis, atopic dermatitis and allergic eczema
  • IBD inflammatory bowel disorders
  • SLE multi-organ disorders
  • the compounds of the general formula (I) are suitable for prophylaxis and/or treatment of various disorders and disease-related states, especially disorders mediated by TLR (except for TLR3) and/or the IL-1 receptor family and/or disorders whose pathology is mediated directly by IRAK4.
  • IRAK4-associated disorders include multiple sclerosis, arthritis (psoriatic arthritis, rheumatoid arthritis, Bekhterev's disease, reactive arthritis, systemic juvenile idiopathic arthritis), gout, Vogt-Koyanagi-Harada syndrome, systematic lupus erythematosus, chronic-inflammatory bowel disorders (Crohn's disease, ulcerative colitis), psoriasis, atopic dermatitis and allergic eczema.
  • the compounds of the general formula (I) can also be used for prophylaxis and/or treatment of disorders mediated by MyD88 and TLR (except for TLR3).
  • inventive compounds of the general formula (I) are suitable for prophylaxis and/or treatment of the TLR-mediated disorders such as rheumatoid arthritis, psoriatic arthritis, reactive arthritis, systemic juvenile idiopathic arthritis, Bekhterev's disease, psoriasis, atopic dermatitis, systemic lupus erythematosus, Behçet's disease, gout.
  • inventive compounds of the general formula (I) are suitable for prophylaxis and/or treatment in the case of multiple sclerosis, adult-onset Still's disease, allergic eczema and chronic inflammatory bowel disorders, such as ulcerative colitis and Crohn's disease.
  • the prophylaxis and/or treatment of pruritus and pain, especially of acute, chronic, inflammatory and neuropathic pain, is also provided by the compounds of the general formula (I).
  • the compounds of the general formula (I) are suitable for the treatment and/or prevention of disorders mediated via the IL-1 receptor family.
  • disorders include CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular) syndrome, FMF (familial mediterranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumour necrosis factor receptor 1-associated periodic syndrome), juvenile idiopathic arthritis, adult-onset Still's disease, gout, Adamantiades-Behçet's disease, rheumatoid arthritis, psoriasis, arthritis, Bekhterev's disease, reactive arthritis, systematic juvenile idiopathic arthritis, osteoarthritis, keratoconjunctivitis sicca and Sjögren syndrome, multiple C
  • Pulmonary disorders such as asthma, COPD, idiopathic interstitial pneumonia and ARDS, chronic-inflammatory bowel disorders such as Crohn's disease and ulcerative colitis are associated with dysregulation of the IL-1 receptor family and are suitable for therapeutic and/or prophylactic use of the compounds of the general formula (I).
  • the compounds of the general formula (I) can also be used for treatment and/or prevention of IL-1 receptor family-mediated neurological disorders such as multiple sclerosis and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis.
  • the compounds of the general formula (I) are suitable for the treatment and/or prophylaxis of pain disorders, especially of acute, chronic, inflammatory and neuropathic pain.
  • This preferably includes hyperalgesia, allodynia, pain from arthritis (such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, Bekhterev's disease and reactive arthritis, systemic juvenile idiopathic arthritis), post-operative pain, pain caused by spinal cord injuries, inflammation-induced pain, lower back pain and chronic pain.
  • the present invention further also provides a method for treatment and/or prevention of disorders, especially the disorders mentioned above, using an effective amount of at least one of the compounds of the general formula (I).
  • 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.
  • prevention is to be understood as meaning a maintenance therapy after remission of the disorder for preventing a recidivism (relapse). This means that a new acute inflammatory episode can be prevented or at least delayed.
  • Remission of a disorder is to be understood as meaning temporary or permanent ceasing of disease symptoms of a physical or psychic nature but without achieving permanent recovery.
  • Recidivism or “relapse” is to be understood as meaning the reoccurrence of a disease or its symptoms after a treatment which was temporarily successful, or after spontaneous remission.
  • the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
  • the compounds of the general formula (I) 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 compounds of the general formula (I) and one or more further active ingredients, especially for treatment and/or prevention of the abovementioned disorders.
  • active ingredients suitable for combinations include:
  • active ingredients such as antibacterial (e.g. penicillins, vancomycin, ciprofloxacin, mupirocin), antiviral (e.g. aciclovir, oseltamivir) and antimycotic (e.g. naftifin, nystatin) substances, gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporine, Methotrexat®, TNF blockers (e.g. Humira®, etanercept, infliximab, golimumab and certolizumab pegol), IL-1 inhibitors (e.g.
  • anakinra, canakinumab, rilonacept phosphodiesterase inhibitors (e.g. apremilast), Jak/STAT in general (e.g. tofacitinib, baricitinib, GLPG0634), leflunomide, fingolimod, teriflunomide, dimethyl fumarates (e.g. tecfidera), IL-6 antagonists (Actemra, sarilumab), IL-2 inhibitors (e.g. Stelara), glatiramer acetate (e.g.
  • Copaxone Glatopa
  • Tysabri cyclophosphamide
  • rituximab belimumab
  • calcineurin inhibitors e.g. tacrolimus
  • rapamycin mycophenolate mofetil
  • interferons e.g. betaferon
  • corticosteroids/glucocorticoids e.g. prednisone, prednisolone, dexamethasone, methylprednisolone, hydrocortisone, betamethasone
  • cyclophosphamide azathioprine and sulfasalazine
  • paracetamol antihistamines
  • azelastine in Allergodil® hydroxyzine in Atarax®, clemastine in Tavegil®
  • non-steroidal anti-inflammatory substances NSAIDS
  • aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine
  • inventive IRAK4 inhibitors can also be combined with the following active ingredients:
  • 6-mercaptopurine ACE inhibitors (e.g. benazepril), acetylcholinesterase inhibitors (e.g. donepezil), angiotensin receptor blockers (e.g. losartan, valsartan), anion exchangers (e.g. colestyramin, colestipol, colesevelam), antibiotics such as, for example, ciprofloxacin and metronidazol, anti-CD3 antibodies, anticholinergics (e.g. glycopyrronium), antidiabetics such as, for example, metformin, antidiarrheal drugs such as, for example, loperamide or laxatives (bisacodyl), anticonvulsive drugs (e.g.
  • gabapentin anti-T-lymphocyte globulin/antilymphocyte globulin, apremilast, azathioprine, basiliximab, belimumab, beta-2 sympathomimetics (e.g. salbutamol), beta-blockers (e.g. metoprolol), beta-interferon (IFN-beta) (e.g. IFN beta-1b, IFN beta-1a Avonex® and Betaferon®), biologics for B cell and T cell therapy (e.g. rituximab, abatacept), calcineurine inhibitors (e.g. tacrolimus), calcium channel blockers (e.g.
  • nifedipine chloroquin
  • cortisone cyclophosphamide
  • cyclosporin daclizumab
  • dithranol diuretics
  • DPP-4 dipeptidyl peptidase 4 inhibitors
  • statins e.g. simvastatin, fluvastatin
  • fibrates e.g.
  • fingolimod fumarates (dimethyl fumarates), glatiramer acetate, glinides (e.g. nateglinide), glucocorticoids, urea, hydroxychloroquine, IgE antibodies, immunoglobulines, immunosuppressive drugs such as mitoxantrone, azathioprine and cyclophosphamide, incretin mimetics (hormone glucose-dependent insulinotropic peptide (GIP)- and glucagon-like peptide 1 (GLP-1)-analogues/agonists) (e.g.
  • GIP glucose-dependent insulinotropic peptide
  • GLP-1 glucagon-like peptide 1
  • exenatide liraglutide, lixisenatide
  • insulin sensitizers e.g. pioglitazone
  • insulin therapy e.g. NPH insulin, insulin lispro
  • interferons e.g. NPH insulin, insulin lispro
  • integrin antibodies e.g. vedolizumab, natalizumab
  • Jak/STAT inhibitors e.g. tofacitinib, baricitinib, GLPG0634
  • cortisol-containing preparations e.g. montelukast
  • leflunomide e.g.
  • glibenclamide tolbutamide
  • teriflunomide tocilizumab
  • topic steroids ustekinumab
  • vedolizumab vitamin D3 analogues
  • vitamin D3 analogues such as, for example, calcipotriol, tacalcitol or calcitriol
  • cell division inhibitors e.g. azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus
  • ⁇ -glucosidase inhibitors e.g. acarbose, miglitol, voglibiose
  • medicaments comprising at least one of the compounds of the general formula (I) and one or more further active ingredients, especially EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors), P2X4 inhibitors (P2X purinoceptor 4), MKNK1/2 inhibitors (MAP kinase-interacting serine/threonine-protein kinase 1/2) 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
  • P2X4 inhibitors P2X purinoceptor 4
  • MKNK1/2 inhibitors MAP kinase
  • the compounds of the general formula (I) can act systemically and/or locally.
  • they can be administered in a suitable manner, for example by the oral, parenteral, subcutaneous, intraarticular, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal or conjunctival route, via the ear or as an implant or stent.
  • the compounds of the general formula (I) 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 compounds of the general formula (I) rapidly and/or in a modified manner and which contain the compounds of the general formula (I) 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 inventive 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, 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 inventive compound
  • tablets or films/oblates which disintegrate rapidly in the oral cavity
  • films/lyophilizates for example hard or soft gelatin capsules
  • Parenteral administration can be accomplished with avoidance of a resorption step (for example by an intravenous, intraarterial, intraarticular, 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, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.
  • the compounds of the general formula (I) 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
  • the present invention further provides medicaments which comprise at least one inventive compound, typically together with one or more inert, nontoxic, pharmaceutically suitable excipients, and the use thereof for the aforementioned purposes.
  • 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, WO200411328) 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 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. It is possible to utilize various 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).
  • 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.
  • inventive 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.
  • 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 inventive 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).
  • the compounds of the general formula (I) 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 compounds of the general formula (I) 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 compounds of the general formula (I) 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 extractive stirring with diethyl ether 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 compounds 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 is 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.
  • IC 50 values of the example compounds with respect to the secretion of TNF- ⁇ in THP-1 cells Example IC 50 [ ⁇ M] 1 1.0 2 15.1 3 0.7 4 5.6 5 5.4 6 0.9 7 16.4 8 1.0 9 6.5 10 1.0 11 0.2 12 0.3 13 0.1 14 0.2 15 0.2 16 0.2 17 0.5 18 0.3 19 0.1 20 0.2 21 1.8
  • 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 charged 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 sown in 96-well plates at a cell density of 2.5 ⁇ 10 5 cells/well.
  • the compounds of the general formula (I) 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 preincubated 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), psoriasis, atopic dermatitis, systemic lupus erythematosus or else multiple sclerosis (Lubberts, Nat. Rev. Rheumatol., 2015; Marinoni et al., Auto. Immun.
  • the DCs After the DCs had been harvested, they were resuspended in complete medium and sown in a cell density of 2 ⁇ 107 cells/well in a 96-well plate (Costar, Cat. No. 3599).
  • the compounds of the general formula (I) 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. It was ensured here that the DMSO concentration present was always 0.1% DMSO for each of the 9 concentrations used. There was a 30-minute preincubation of the DCs with the compounds of the general formula (I).
  • the DCs were then stimulated to produce IL-23 by means of 10 ng/ml of LPS (Sigma, Escherichia coli serotype 0127:B8, Cat. No. L3129) (TLR4 ligand) and 2.5 ⁇ g/ml of TLR7/8 ligand R848 (Invivogen, Cat. No. tlrl-r848-5), both of which bring about the activation of the IRAK4-mediated signalling pathway, in an incubator (37° C., 95% rH, 5% CO 2 ) for 24 hours. After this incubation time of 24 hours, the supernatants were removed and analysed with the aid of a commercially available hIL-23 ELISA (eBiosciences, Cat. No. 88-7237-88), which was conducted according to the manufacturer's instructions.
  • the results of the inhibition of IL-23 in human DCs are shown by way of example for Example Compound 12 in FIG. 1 .
  • the inhibitory action of the compounds of the general formula (I) on induced production of the proinflammatory cytokine IL-17 which is considered to be a key cytokine in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, Bechterew disease (ankylosing spondylitis), reactive arthritis, psoriasis, atopic dermatitis, systemic lupus erythematosus, chronic-inflammatory bowel diseases and also multiple sclerosis, was investigated in human Th17 cells.
  • human PBMCs were obtained from anticoagulated human whole blood as follows: 20 ml of human blood were added to leucosep tubes which had been initially charged with 15 ml of Ficoll-Paque (Biochrom, Cat. No. L6115) beforehand. The blood was centrifuged at 800 g for 15 min at room temperature, and plasma including platelets was then removed and discarded. The PBMCs were transferred into centrifuge tubes and made up with PBS (phosphate-buffered saline) (Gibco, Cat. No. 14190). The cell suspension was centrifuged at 250 g for 10 min at room temperature, 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)).
  • RPMI 1640 without L-glutamine
  • FCS 50 U/ml penicillin, 50 ⁇ g/ml streptomycin
  • P11-010 50 ⁇ g/ml streptomycin
  • 1% L-glutamine Sigma, Cat. No. G7513
  • CD4+ T-cells were isolated by magnetic cell separation (CD4+ T cell isolation kit, Miltenyi Biotech, Cat. No. 130-096-533) on a column (LS column, Miltenyi Biotech, Cat. No. 130-042-401) from the PBMCs.
  • the CD4+ T cells obtained in this manner were sown in 96-well plates (flat bottom, Costar, Cat. No. 3599) at a cell density of 5 ⁇ 10 4 CD4+ T cells/well.
  • This assay was carried out using complete medium.
  • the compounds of the general formula (I) were subjected to serial dilution in a constant volume of 100% DMSO and employed in the assay at 9 different concentrations in the range from 10 ⁇ M to 1 nM such that the final DMSO concentration was 0.1% DMSO.
  • the cells were preincubated with the respective concentration of the compounds of the general formula (I) in an incubator for 30 minutes.
  • a Th17 differentiation cocktail consisting of anti-CD3/anti-CD28 beads (2500 beads per 50 000 cells; T cell activation kit, Miltenyi Biotech, Cat. No. 130-091-441), recombinant human (rh) IL-23 (20 ng/ml; eBioscience, Cat. No. 14-8239-63), rhIL-1beta (20 ng/ml; eBioscience, Cat. No. 34-8018), rhIL-6 (20 ng/ml; eBioscience, Cat. No. 34-8069) and rhIL-2 (100 IU/ml; eBioscience, Cat. No.
  • the pDCs thus obtained 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 plated out in a cell density of 5 ⁇ 10 4 cells/well in a 96-well microtitre plate (Costar, Cat. No. 3599).
  • the compounds of the general formula (I) 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 used.
  • the pDCs were stimulated either with a TLR7/8 ligand (imiquimod, R837, Invivogen, Cat. No. tlrl-imq) or with a TLR9 ligand (CPG-A, ODN2216, Invivogen, Cat. No. tlrl-2216-1) and this led to activation of the IRAK-4-mediated signalling pathways.
  • Example Compound 12 After incubation for 24 hours, the cell culture supernatants were removed and analysed by means of 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. 3 .
  • the 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 compounds of the general formula (I) on TLR4-mediated disorders, since an LPS-mediated inflammation model was used.
  • female NMRI mice about 6 weeks old; Charles River Laboratories, Germany
  • the healthy control group was treated with the vehicle (ethanol-peanut oil 10:90 v/v) in which the substance had been dissolved (substance vehicle) and also with the vehicle in which the LPS had been dissolved.
  • the positive control group was also administered intraperitoneally (i.p.) with 0.2 mg in each case of LPS/kg body weight (Sigma, Cat. No. L4391) (lipopolysaccharides from E. coli 0111:B4).
  • the positive control group was treated with the substance vehicle described above.
  • the substance was administered orally 1 hour before induction of inflammation by administration of LPS.
  • a final blood sample was taken from the animals after 1.5 hours.
  • the concentration of the cytokines TNF- ⁇ and IL-6 in the plasma was determined using the mouse TNF- ⁇ and mouse IL-6 Ready-SET-Go ELISA Kits (eBioscience, mTNF ⁇ Cat. No. 88-7324-88, mIL-6 Cat. No. 88-7064-88) in accordance with the manufacturer's instructions.
  • IRAK4 inhibitors are effective in the TLR-mediated inflammation model.
  • Application of LPS leads to a rapid induction of proinflammatory cytokines such as TNF- ⁇ and IL-6 in the plasma, which is inhibited in a dose-dependent manner by treatment with the compounds of the general formula (I). This is shown by way of example for Compound 12 and 11 in FIG. 4 .
  • clinically relevant comparative substances were also tested in the animal model for comparison of inhibitory effectiveness, such as, for example the TNF antagonists adalimumab (Humira®) or etanercept, both of which were in each case administered subcutaneously 1 h prior to induction of the inflammation with LPS at dosages of 1.5 mg/kg, 5 mg/kg and 10 mg/kg.
  • TNF antagonists adalimumab Humira®
  • etanercept both of which were in each case administered subcutaneously 1 h prior to induction of the inflammation with LPS at dosages of 1.5 mg/kg, 5 mg/kg and 10 mg/kg.
  • the treatment only with the vehicle (Cremophor-ethanol-water 40:10:50 v/v/v) of the test substance either in a preventative manner (from day 0) or in a therapeutic manner (from day 9).
  • the treatment with different dosages of the test substance likewise started either in a preventative manner or in a therapeutic manner by oral application.
  • the starting condition of the animals was determined beforehand in terms of the disease activity scores (rating of the severity of arthritis based on a points system).
  • the volume of the paws was measured, too, via plethysometer (IITC Life Science Inc., USA) as a measure for joint swelling.
  • the experiment was terminated and a magnetic resonance imaging scan was carried out in the MRT (magnetic resonance tomograph; MAGNETOM Avanto syngo MR B17, Siemens, Germany) under inhalative anaesthesia (isoflurane) using the MRT sequence STIR (short-tau inversion recovery for fat signal suppression and for the detection of oedema) as imaging method for analysing the degree of severity of the arthritis.
  • MRT magnetic resonance tomograph
  • MAGNETOM Avanto syngo MR B17 Siemens, Germany
  • inhalative anaesthesia isoflurane
  • STIR short-tau inversion recovery for fat signal suppression and for the detection of oedema
  • the synovial fluid was obtained from the arthritic joints by intraarticular rinsing of the knee joint with 150 ⁇ l of sterile saline and examined for the cytokine concentrations present using a commercial multiplex ELISA instrument from Meso Scale Discovery (MSD) (proinflammatory panel 1; Cat. No. K15059D-1). Knee joint biopsies were then used for analysing cytokine concentrations (by multiplex-ELISA from MSD) or CRP levels (rat C-reactive protein, Cat. No.
  • MSD Meso Scale Discovery
  • knee joint biopsies were pulverized in a cooled bead mill at ⁇ 196° C.
  • NE neutrophile elastase
  • a fluorescent-labelled substrate [MeOSuc-AAPV-AMC (N-methoxysuccinyl-Ala-Ala-Pro-Val-7-amino-4-methylcoumarin), Cat. No. 1-1270, Bachem, Germany] with high specificity for NE (Castillo et al., 1979; Wiesner et al., 2005) was used.
  • Recombinant murine NE Cat. No. 4517-SE-010, R&D Systems, Germany; dissolved in homogenate buffer, see above was used as standard curve, and the homogenate buffer as blank value.
  • the amount of neutrophil elastase was calculated using the NE standard curve by means of the software SoftmaxPro 6.4.
  • Statistical analysis was effected using single-factor variance analysis (ANOVA) and comparison with the control group by means of multiple comparative analysis (Dunnett's test).
  • this rat arthritis model represents joint inflammation in cases of human arthritides such as psoriatic arthritis, rheumatoid arthritis, reactive arthritis and Bechterew disease (Bendele, J Musculoskel Neuron Interact 2001; McCann et al., Arthritis Res Ther, 2010).
  • human arthritides such as psoriatic arthritis, rheumatoid arthritis, reactive arthritis and Bechterew disease (Bendele, J Musculoskel Neuron Interact 2001; McCann et al., Arthritis Res Ther, 2010).
  • DMARD disease-modifying antirheumatic drug
  • the clinically relevant comparative substance i.e. the TNF antagonist etanercept (10 mg/kg or 25 mg/kg from day 0), which was administered subcutaneously every third day, was also tested in the animal model for comparison of the inhibitory effectiveness.
  • the paw volume was measured via plethysometer (IITC Life Science Inc., USA) as a measure of the joint swelling.
  • the starting condition was determined beforehand in each case one day before the start of the experiment (day ⁇ 1) and the disease activity score and the paw volume were subsequently scored three times per week from day 8 onwards.
  • day 21 the experiment was terminated and knee joint biopsies were examined for histopathological analyses of inflammation symptoms in the synovia and in the intra- and periarticular tissue.
  • Statistical analysis was effected using single-factor variance analysis (ANOVA) and comparison with the control group by means of multiple comparative analysis (Dunnett's test).
  • the i.v. administration of a collagen antibody cocktail including the subsequent i.p. administration of LPS in mice leads to acute arthritis with distinct joint inflammation in mice (Holmdahl et al., APMIS 1989; McCann et al., Arthritis Res Ther, 2010) and thus represents a further animal model for the arthritic indications psoriatic arthritis, rheumatoid arthritis, reactive arthritis and Bechterew disease.
  • preventative, but also therapeutic, treatment with the Example Compound 12 it was possible to markedly inhibit this collagen antibody-induced arthritis, and the histopathological data of the hind paw joints indicate disease-modifying action. This is illustrated by FIG. 6 .
  • the treatment groups received different daily doses of the Example Compound 12 as preventative therapy, i.e. from day 0, by oral administration.
  • Parameters such as incidence rate and symptoms of an EAE were checked daily.
  • the EAE symptoms were scored using a point system which represents the degree of severity of the disorder (EAE disease activity score):
  • Example Compound 12 The statistical analysis was carried out using the monofactorial variance analysis ANOVA and the comparison with the control group by multiple comparative analysis (Dunnett test).
  • the example compound was comparable or even superior to the efficacy of a steroid (prednisolone; 1 mg/kg daily p.o. from day 0) or teriflunomide (Aubagio®; 10 mg/kg daily p.o. from day 0) which were also tested in the experiment as clinical comparative substances. This is illustrated in FIG. 7 .
  • the compounds of the general formula (I) were examined for their anti-inflammatory effects in an animal model of psoriasis.
  • topical administration of imiquimod (IMQ) a TLR7/8 ligand and potent immune activator, leads to a psoriasis-like phenotype on the skin.
  • IMQ imiquimod
  • a TLR7/8 ligand and potent immune activator leads to a psoriasis-like phenotype on the skin.
  • imiquimod equivalent to 70 mg of 5% Aldara® cream, Meda AB
  • a healthy control group which was also tested, received paraffin oil instead.
  • the IMQ disease control like the healthy control group, were treated preventatively, i.e. from day 0, orally (p.o.) daily with the vehicle (Solutol HS15-water (40/60 v/v)) of the test compound.
  • the daily p.o. treatment with different dosages of the test compound was also initiated on day 0.
  • the manifestation of the psoriasis was assessed visually every day by means of a point system using the clinical scores described below:
  • the IMQ-mediated skin inflammation in the mouse represents an animal model for the indication psoriasis or for the skin phenotype in psoriatic arthritis (van der Fits et al., J Immunol 2009). By treatment with the Example Compound 12, it was possible to inhibit induced psoriasis.
  • the example compound was comparable or even superior to the efficacy of a steroid (Betamethasone, Celestene®; 2.5 mg/kg daily p.o.) or of a TNF antagonist (etanercept; 5 mg/kg every other day i.p.), which were also tested in the experiment, as clinical comparative substances. This is illustrated by FIG. 8 .
  • the model of the DNFB (2,4-dinitro-1-fluorobenzene)-induced allergic contact dermatitis (contact allergy) in the mouse represents an inflammatory skin disorder with the background of an immune reaction of the delayed type (delayed-type hypersensitivity; DTH) mainly mediated by T-helper lymphocytes of type 1 (Th1 cells).
  • DTH delayed-type hypersensitivity
  • Th1 cells T-helper lymphocytes of type 1
  • control groups were only treated, 1 h prior to triggering the skin inflammation, with the vehicle (ethanol:peanut oil, 10:90 v/v) of the test substance, p.o., the treatment groups received the appropriate dosage of the test substance, likewise orally.
  • the ear thickness was determined individually for each ear using a digital caliper, and the weight of the ears of each mouse was determined.
  • NE 1-1270, Bachem, Germany
  • recombinant murine NE Cat. No. 4517-Se-010, R&D Systems, Germany; dissolved in homogenate buffer
  • the homogenate buffer was used as blank value.
  • 25 ⁇ l of ear homogenate were used and pipetted into a black 96-well microtitter plate (flat bottom, NUNC, Germany) and then mixed with 25 ⁇ l of a 1 mM MeOSuc-AAPV-AMC substrate solution in cold TrisBSA buffer.
  • Example Compound 11 By treatment with the Example Compound 11 and the Example Compound 12, it was possible to inhibit the ThH1-mediated skin inflammation triggered by DNFB. This is shown in FIG. 9 .
  • the model of the TMA (trimellitic anhydride)-induced allergic contact dermatitis (contact allergy) in the mouse represents an inflammatory skin disorder with the background of an immune reaction of the delayed type (delayed-type hypersensitivity; DTH) mainly mediated by eosinophils and T-helper lymphocytes of type 2 (THh2 cells).
  • DTH delayed-type hypersensitivity
  • THh2 cells T-helper lymphocytes of type 2
  • control groups were only treated, 1 h prior to triggering the skin inflammation, with the vehicle (ethanol:peanut oil 10:90 v/v) of the test substance, p.o., the treatment groups received the appropriate dosage of the test substance, likewise orally.
  • the ear thickness was determined individually for each ear using a digital caliper, and the weight of the ears of each mouse was determined.
  • the control groups healthy control and colitis disease control
  • Treatment with the various dosages of the test substance is carried out preventatively, i.e. from day 0, by oral administration with the first DSS dose.
  • occult bloody stool is detected using a haemoccult test (Cat. No. 3060; Beckman Coulter, Germany).
  • a video endoscopy (Karl Storz Endoskope, Germany) is carried out under inhalative anaesthesia with isoflurane to assess the severity of the colitis, where the extent of intestinal damage is assessed using a point system (score) of 0 to 4 points, as follows:
  • example compound 12 was comparable to the efficacy of approved biologics (anti-IL-12p40 at 10 mg/kg Q3D [every third day] i.p. from day 0 or anti-TNF Humira® [Adalimumab] at 10 mg/kg Q3D s.c. from day 0), which were included in the experiment as clinically relevant reference substances. This is illustrated in FIG. 12 .
  • the compounds are assessed in an SLE (systemic lupus erythematosus)-model for their in vivo efficacy.
  • SLE systemic lupus erythematosus
  • Pristane a mineral oil (2,6,10,14-tetramethylpentadecane) leads, after injection into mice, to systemic lupus erythematosus with characteristic organ involvement (e.g. nephritis, mild erosive arthritis), typical auto-antibody production, for example anti-double strand (ds) DNA antibodies (Leiss et al., Lupus 2013) and dependency on type 1 interferon (e.g.
  • Both a healthy control group and a disease control group are also tested in the experiment. Both control groups are treated only with the vehicle (ethanol:peanut oil 10:90 v/v) of the test substance, p.o. Treatment with various dosages of the test substance is carried out preventatively, i.e. from day 0, by oral administration about 1 h after the pristane injection. Additionally, on day 0, the baseline of the animals with respect to the protein status in urine (proteinuria measured using Coomassie brilliant blue G 250 with BSA [bovine serum albumine] as reference), the auto-antibody concentration (e.g. anti-dsDNA) and the creatinine values in the serum and the paw volume (using a plethysometer) are determined.
  • vehicle ethanol:peanut oil 10:90 v/v
  • Treatment with various dosages of the test substance is carried out preventatively, i.e. from day 0, by oral administration about 1 h after the pristane injection. Additionally, on day 0, the baseline of the animals with respect to
  • Example compound 12 was slightly superior to the immunosuppressant cyclophosphamide (50 mg/kg once per week p.o. from day 0), which was included in the experiment as clinical reference substance. This is illustrated in FIG. 11 by the assessment of renal pathology.
  • these compounds are assessed in a relapsing-remitting animal model of MS for their in vivo efficacy for thereputic treatment of an acute MS episode or for preventing new episodes.
  • the relapsing-remitting PLP 139-151 (proteolipid-protein)-induced EAE model is a standard animal model for testing pharmacological substances for potential use in MS patients.
  • an emulsion containing PLP 139-151 /CFA (Hooke KitTM PLP 139-151 /CFA Emulsion; Cat. No. EK-0120; Hooke Laboratories, Lawrence Mass., USA) is injected (0.05 ml/injection site) subcutaneously into female SJL mice (8-10 weeks old, Jackson Laboratories Bar Harbor, USA).
  • both control groups are treated with the vehicle (ethanol:peanut oil 10:90 v/v) of the test substance p.o.
  • the daily p.o. treatment with different dosages of the test substance or its vehicle is carried out therapeutically during the first episode or after the episode.
  • the therapeutic treatment after onset of EAE (first episode; treatment start day 12) serves to determine the possibility of treating an acute MS episode, whereas the therapeutic treatment with the example compound after the first episode (treatment start day 19) is intended to find out to what extent the test substance can prevent a new episode.
  • first EAE symptoms appear about day 11.
  • 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 6-day Th17 cell differentiation measured by the production of IL-17 after stimulation of ( ⁇ human CD4+ T cells with anti-CD3/anti-CD28/rhIL-23/rhIL-6/rhl-1beta/rhIL-2 (TH17 cell differentiation cocktail), shown in an exemplary manner for Example Compound 12 for 2 donors (A, B). Data are shown as mean values with standard deviations.
  • FIG. 3 Inhibition of INF- ⁇ in (A) imiquimod (R837, TLR7/8 ligand)- or (B) CpG-A-(TLR9 ligand)-stimulated human plasmacytoid DCs for Example Compound 12. Data are shown as mean values with standard deviations.
  • FIG. 4 (A) Treatment of an LPS-induced inflammation with Example Compound 12 leads to a reduced amount of secreted TNF ⁇ and IL-6 in the plasma of the mice. (B) Inhibition of TNF ⁇ by Example Compound 11 and 12 is in this case comparable to clinically relevant TNF-antagonists [adalimumab (Humira®), etanercept]. Data are shown as mean values with standard deviations. Single-factor ANOVA variance analysis with subsequent multiple comparative analysis with the LPS control group by means of Dunnett's test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001.
  • FIG. 5 Anti-inflammatory effects of Example Compound 11 in an animal model of arthritis (adjuvant-induced rat model).
  • D the imaging process by MRI (magnetic resonance imaging).
  • E in addition, marked inhibition of hyperalgesia, measured via the grip strength of the mice, was observed during the course of the experiments.
  • Figure E “%” means grip strength; “days” means days after induction of arthritis.
  • FIG. 6 Anti-inflammatory effects of Example Compound 12 in an animal model of arthritis (collagen antibody-induced mouse model, CAIA). Significant and dose-dependent inhibition of arthritic joint inflammation after prophylactic (day 0) (A) and therapeutic treatment (>day 9) (B) measured using the Disease Activity Scores. (C) histopathological analysis of the arthritic joints by haematoxylin/eosin staining confirmed the anti-inflammatory activity after therapeutic treatment. Inhibition of arthritis by Example Compound 12. The data corresponds to the mean values+standard deviations.
  • FIG. 7 Anti-inflammatory action of the Example Compound 12 in an animal model of multiple sclerosis (MOG 33-35 -induced EAE mouse model) in comparison to teriflunomide and prednisolone.
  • EAE disease activity score A
  • B incidence rate of the disorder
  • C histopathological damage of the spinal marrow
  • neuroaxial degeneration degeneration, neuroaxonal, white matter
  • lymphocyte infiltration into the white matter (infiltrate, lymphohitiocytic, white matter) or into the grey matter (cortex; infiltrate, lymphohitiocytic, grey matter) after treatment with Compound 12.
  • Figure D means histopathological score with respect to lymphohistiocytic infiltrates in the white matter.
  • Figure E means histopathological score with respect to lymphohistiocytic infiltrates in the grey matter.
  • FIG. 8 The anti-inflammatory action of Example Compound 12 in an animal model of the psoriasis (IMQ-induced mouse model).
  • IMQ-induced mouse model Significant inhibition of the clinical score (A) which comprises the clinical symptoms erythema, flaking and thickness of the skin on the back and of the histopathological assessment of the ears (B) or of the skin of the back (C), which assesses the pathological parameters parakeratosis, inflammation and exocytosis.
  • the data correspond to the mean values+standard deviations.
  • the statistical significances between IMQ 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).
  • Etanerc. etanercept
  • Betameth betamethasone
  • po per oral
  • ip intraperitoneal injection
  • bid twice daily
  • q2d e
  • FIG. 9 Anti-inflammatory effects of Example Compound 12 in an animal model of TH1-mediated skin inflammation (DNFB-induced skin inflammation model in the mouse). Significant and dose-dependent inhibition of the skin inflammation as evidenced by the ear weight (in mg), which correlates with oedema formation during the inflammation. The statistical significances between DNFB-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). Abbreviations: “mg” on the y-axis means ear weight; ctrl—healthy control; irritant—irritation control.
  • FIG. 10 Anti-inflammatory effects of Example Compound 12 in an animal model of TH2-mediated skin inflammation (TMA-induced skin inflammation model in the mouse). Inhibition of skin inflammation shown as an increase of ear thickness (delta [delta] ear thickness in mm) in comparison to baselines. An increased ear thickness is seen as a measure for the inflammation and represents oedema formation in the ear tissue during the inflammation reaction.
  • mm on the y-axis means the change (delta) in ear weight
  • ctrl healthy control.
  • FIG. 11 The anti-inflammatory effect of example compound 12 in the animal model of systemic lupus erythematosus (pristane-induced mouse model). Significant inhibition of kidney damage shown by histopathological assessments of kidneys. The data correspond to the mean values+standard deviations. The statistical significances between SLE control and the treatment groups were calculated by means of single-factor variance analysis ANOVA with subsequent multiple comparative analysis (Dunnet's test) (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001).
  • Score means renal histopathology score
  • IRAK4i means IRAK4 inhibitor, example compound 11 here
  • CPA cyclophosphamide
  • ctrl. healthy control
  • 2 ⁇ tilt daily.
  • FIG. 12 Anti-inflammatory effect of example compound 12 in IBD (Inflammatory Bowel Disease) animal model (DSS-induced colitis in mice). Significant inhibition of bowel inflammation including ulceration, determined by endoscopy on day 16. The endoscopic assessment was made by means of a scoring system with regard to the severity and extent of colon inflammation. The data correspond to the mean values+standard deviations. The statistical significances between DSS control and the treatment groups were calculated by means of single-factor variance analysis ANOVA with subsequent multiple comparative analysis (Dunnet's test) (*p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; ****p ⁇ 0.0001).
  • Score means endoscopy score
  • ⁇ IL-12p40-anti-mouse IL-12p40 monoclonal antibody IL-12p40-anti-mouse IL-12p40 monoclonal antibody
  • IRAK4i means IRAK4 inhibitor, example compound 11 here
  • BID tiltice daily
  • Q3D very third day.

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