WO2018060174A1 - Benzimidazoles substitués, préparations pharmaceutiques les contenant et leur utilisation pour la production de médicaments - Google Patents

Benzimidazoles substitués, préparations pharmaceutiques les contenant et leur utilisation pour la production de médicaments Download PDF

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WO2018060174A1
WO2018060174A1 PCT/EP2017/074320 EP2017074320W WO2018060174A1 WO 2018060174 A1 WO2018060174 A1 WO 2018060174A1 EP 2017074320 W EP2017074320 W EP 2017074320W WO 2018060174 A1 WO2018060174 A1 WO 2018060174A1
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pain
methyl
diseases
benzimidazol
methoxy
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PCT/EP2017/074320
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German (de)
English (en)
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Sven Ring
Ulrich Bothe
Reinhard Nubbemeyer
Ulf Bömer
Judith GÜNTHER
Nicole Schmidt
Dorothee ANDRES
Holger Siebeneicher
Andreas Sutter
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to novel substituted benzimidazoles, processes for their preparation, intermediates for use in the preparation of the novel compounds, the use of the novel substituted benzimidazoles for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of proliferative diseases, of autoimmune diseases, of metabolic and of inflammatory diseases such as Rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis and ankylosing spondylitis), chronic obstructive pulmonary disease (abbreviation: COPD), multiple sclerosis, systemic lupus erythematosus, gout, metabolic syndrome, fatty hepatitis, insulin resistance, renal disease, endometriosis, and inflammation-induced or chronic pain as well as lymphoma.
  • proliferative diseases of autoimmune diseases, of metabolic and of inflammatory diseases such as Rhe
  • the present invention relates to novel substituted benzimidazoles of general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4).
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • TLR Toll-like receptors
  • IL interleukin
  • IRAK4 knockout mice nor human cells from patients lacking IRAK4 respond to the stimulation of TLRs (except TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002, Davidson, Currie, et al , The Journal of Immunology, 2006; Ku, Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
  • TLR ligands or ligands of the IL-lß family leads to the recruitment and binding of MyD88 [myeloid differentiation primary response gene (88)] to the receptor.
  • MyD88 interacts with IRAK4 to form an active complex which interacts with and activates the IRAK1 or IRAK2 kinases (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004, Precious et al. Biol. Chem., 2009).
  • NF nuclear factor
  • MAPK mitogen-activated protein kinase
  • inflammatory signal molecules and enzymes such as cytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammation-associated genes such as COX-2, IL-6 (interleukin-6) -, IL-8 ( Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004).
  • these processes may be associated with the proliferation and differentiation of certain cell types such as monocytes, macrophages, dendritic cells, T cells and B cells (Wan, Chi, et al., Nat Immunol, 2006, McGettrick and J.
  • IRAK4 KDKI animals have an improved disease pattern in the animal model of multiple sclerosis, atherosclerosis, myocardial infarction and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008, Maekawa, Mizue, et al., Circulation, 2009; Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012).
  • IRAK4 has been shown that deletion of IRAK4 in the animal model protects against viral-induced myocarditis as a result of an improved anti-viral response with concomitantly reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013).
  • expression of IRAK4 has been shown to correlate with the extent of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
  • IRAK4 immune-complex-mediated IFNa (interferonpha) production by plasmacytoid dendritic cells, a key process in the pathogenesis of systemic lupus erythematosus (SLE), has been demonstrated (Chiang et al., The Journal of Immunology, 2010).
  • the signaling pathway is associated with obesity (Ahmad, R., P. Shihab, et al., Diabetology & Metabolism Syndrome, 2015).
  • IRAK4 affects the differentiation of the so-called Th17 T cells, components of adaptive immunity.
  • Th17 T cells fewer IL-17 producing T cells (Th17 T cells) are generated compared to WT mice.
  • IRAK4 By the inhibition of IRAK4 is the prophylaxis and / or treatment of atherosclerosis, diabetes mellitus type 1, rheumatoid arthritis, spondyloarthritis (especially psoriatic psoriasis and ankylosing spondylitis), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, inflammatory bowel disease and viral diseases such HIV (human immunodeficiency virus), hepatitis virus possible (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal of Inflammation, Vol.
  • IRAK4 Due to the central role of IRAK4 in the MyD88-mediated signaling cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be used for the prophylaxis and / or treatment of disorders mediated by said receptors.
  • TLRs as well as components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis such as Behcet's disease, granulomatosis with polyangiitis and giant cell arteritis, pancreatitis, systemic lupus erythematosus, dermatomitis and polymyositis Including metabolic syndrome including, for example, insulin resistance, hypertension, dyslipoproteinemia and obesity, diabetes mellitus (type 1 and type 2), diabetic nephropathy, osteoarthritis, Sjogren's syndrome, and sepsis (Yang, Tuzun, et al., J Immunol Candia, Marquez et al., The Journal of Rheumatology, 2007; Scanzello, Plaas, et al Curr Opin Rheumatol, 2008; Deng, Ma-Krupa, et al.
  • Diabetes Complications 2014; Kaplan, Yazgan, et al., Scand J Gastroenterol, 2014; Talabot-Aye, et al., Cytokines, 2014; Zong, Dorph, et al., Ann Rheum Di, 2014; Ballak, Stienstra, et al., Cytokines, 2015; Timper, Seelig, et al., J. Diabetes Complications, 2015).
  • Skin disorders such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway and the IL-1R family, respectively (Schmidt, Mittnacht, et al.
  • Pulmonary diseases such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension are also associated with various TLR-mediated signaling pathways.
  • COPD obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • ILD interstitial lung disease
  • sarcoidosis and pulmonary hypertension
  • the pathogenesis of pulmonary diseases can be both infectiously mediated and non-infectious mediated processes (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004, Jeyaseelan, Chu, et al., Infection and Immunity , Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al ., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research
  • TLRs as well as IL-1R family members are also involved in the pathogenesis of other inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
  • inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
  • TLR- and IL-1R family-mediated gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, especially endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia
  • IRAK4 inhibitors Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima, et al., Journal of Obstetrics and Gynecology Research, 2013; Santulli, Borghes
  • IRAK4 inhibitors may also positively affect atherosclerosis (Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Sedimbi, Hagglof, et al. Cell Mol Life Sei, 2013).
  • IRAK4-mediated TLR processes in the pathogenesis of eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis are described (Kaarniranta and Salminen, J Mol Med (Berl), 2009, 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; Guo Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012, Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).
  • Inhibition of IRAK4 is also a suitable therapeutic approach for fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Biochim Biophys Acta., 2015).
  • fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Bio
  • IRAK4 has in TLR and IL-1R family-mediated diseases can be chronic liver diseases such as fatty liver hepatitis and especially non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic fatty liver disease (NASH) steatohepatitis), alcoholic hepatitis (ASH - alcoholic steatohepatitis) can be preventively and / or therapeutically treated with IRAK4 inhibitors (Nozaki, Saibara, et al., Alcohol Clin Exp Res, 2004, Csak, T., A. Velayudham, et al.
  • NASH non-alcoholic fatty liver disease
  • IRAK4 inhibitors are also useful in the treatment of renal dysfunction and kidney disease, such as chronic kidney disease (CKD), chronic renal failure, glomerular disease, diabetic nephropathy, lupus nephritis, IgA nephritis (Berger's disease), nephrosclerosis.
  • CKD chronic kidney disease
  • chronic renal failure glomerular disease
  • diabetic nephropathy lupus nephritis
  • IgA nephritis (Berger's disease)
  • nephrosclerosis nephrosclerosis
  • the inhibition of IRAK4 also includes the treatment / and / or prevention of cardiovascular and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension, hypertension (Oyama, Blais, et al., Circulation Timmers, Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med Sei Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sei (Lond), Christina and Frangogiannis, European Journal of Clinical Investigation, 2013, Thompson and Webb, Clin Sei (London), 2013; Hernanz, Martinez-Revelles, et al., British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015 Bomfim, Echem, et al., Life Sciences, 2015) as well as Alzheimer's, stroke, stroke, craniocerebral
  • TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 Due to the involvement of TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 in itching and pain, including acute, chronic, inflammatory and neuropathic pain, a therapeutic effect in the above indications due to the inhibition of IRAK4 is assumed.
  • pain examples include hyperalgesia, allodynia, premenstrual pain, endometriosis-associated pain, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain
  • CRPS complex regional pain syndrome
  • trigeminal neuralgia prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain
  • Wilf Livshits, et al., Brain, Behavior, and Immunity, 2008
  • Kim Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al., Annais of the New York Academy of Sciences, 2012; Guerrero, Cunha
  • lymphomas such as ABC-DLBCL (activated B cell diffuse large B-cell lymphoma), mantle cell lymphoma and Waldenström's disease, as well as chronic lymphocytic leukemia, melanoma, pancreatic tumors and hepatocellular carcinoma are characterized by mutations in MyD88 or changes in MyD88 activity , which can be treated by an IRAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Ochi, Nguyen, et al., J Exp Med, 2012; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; (Liang, Chen, et al., Clinical Cancer Research, 2013).
  • ABC-DLBCL activated B cell diffuse large B-cell lymphoma
  • MyD88 plays an important role in Ras-dependent tumors, so that IRAK4 inhibitors are also suitable for their treatment (Kfoury, A., KL Corf, et al., Journal of the National Cancer Institute, 2013 It is also of therapeutic benefit in breast cancer, ovaria carcinoma, colorectal carcinoma, head and neck carcinoma, lung cancer, prostate cancer due to the inhibition of IRAK4, as the indicated indications are associated with the signaling pathway (Szczepanski, Czystowska, et al., Cancer Res, 2009; Zhang, He, et al., Mol Biol Rep, 2009; Wang, Qian, et al., Br J Cancer Kim, 2010; Jo, et al., World J Surg Oncol, 2012; Zhao, Zhang, et al .; Front Immunol, 2014; Chen, Zhao, et al., Int J Clin Exp Pathol, 2015).
  • Inflammatory diseases such as CAPS (cryopyrin-associated periodic syndromes), including FCAS (familial cold urticaria), MWS (Mückle-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 (Tumor Necrosis Factor Receptor 1-Associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Behcet's Disease, Rheumatoid Arthritis, Osteoarthritis, Keratoconjunctivitis sicca, PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne), Schnitzler syndrome and Sjögren syndrome are treated by blocking the IL-1 signaling pathway, so here too an IRAK4 inhibitor is suitable for the treatment of these diseases (Narayana
  • the ligand of IL-33R, IL-33 is particularly involved in the pathogenesis of acute renal failure, so inhibition of IRAK4 for prophylaxis and / or treatment is a suitable therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011).
  • Components of the IL-1 receptor family are with myocardial infarction, different pulmonary Diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), so that a prophylactic and / or therapeutic effect in the indicated indications is to be expected from the inhibition of IRAK4 (Kang, Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al., The Journal of Immunology, 2009; Abbate, Kontos, et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke, et al., European Respiratory Journal, 2011; Haenuki, Matsushita, et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li,
  • IRAK4 inhibitors are known from the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).
  • WO2015091426 describes indazoles, such as example WO2015091426-64, which are substituted at position 2 with a carboxamide side chain and inhibit IRAK-4. However, benzimidazoles are not described. In WO2003030902 and in Bioorg. Med. Chem. Lett. 16 (2006) 2842-2845 2-amino-imidazole derivatives have been described as IRAK4 inhibitors. Imidazole derivatives which have a substituent at the 2-position which are linked to the imidazole via a carbon atom are not described.
  • WO 13042137 describes benzimidazoles (compare Genetic Structure WO 13042137) as IRAK4 inhibitors substituted at position 2 with morpholine, the morpholine being linked via the ring nitrogen to the benzimidazole. Furthermore, the benzimidazoles are not substituted at position 1 (compare the generic structure WO 13042137: X is selected from O, S, NH). The substituent R 1 of WO 13042137 is selected from hydrogen, cyano, halogen, hydroxy,
  • WO 13042137-48 (6'amino-N- (2-morpholino-LH- benzo [d] imidazol-6-yl) - [2,3'-bipyridine] -6-carboxamide) is explicitly disclosed as the sole benzimidazole derivative.
  • WO2006030031 describes inter alia benzimidazoles as positive allosteric modulators of mGluR2, which may be substituted at position 1 with Ci-Cö-alkyl. However, substitution with methyl is not explicitly disclosed. Also, no benzimidazoles are explicitly disclosed.
  • WO2004072069 describes benzimidazole carboxamides as vanilloid receptor (VRI) antagonists for pain treatment, which may be substituted at the carboxamide group with substituted heteroaryl. Possible heteroaryls are pyridyl, preferably 3-pyridyl, isothiazolyl, thiazolyl, oxazolyl or pyrazolyl.
  • WO2004072069-11 N- (1H-benzimidazol-6-yl) -6- (4-fluorophenyl) -2-methyl-nicotinamide
  • WO2004072069-12 6- (4-fluorophenyl) - 2-methyl-N- (1-methyl-1H-benzimidazol-6-yl) nicotinamide
  • WO200157020 describes benzimidazoles as inhibitors of factor Xa.
  • the benzimidazoles may be substituted at position 2 with:
  • Ci-Cs-alkyl which is not substituted
  • R 10 can be H or methyl
  • WO 2010042785 describes the use of benzimidazoles for negative chemotaxis.
  • the benzimidazoles described may be substituted at position 5 with alkoxy.
  • WO 2013186229 describes TNF-alpha modulating benzimidazoles.
  • 1-methyl substituted benzimidazoles are not disclosed.
  • WO2007076092 describes benzimidazoles as Raf kinase modulator, which are substituted at position 5 but not with alkoxy.
  • no benzimidazole derivatives are described as IRAK4 inhibitors which simultaneously have an alkoxy radical at position 5, an acylamino radical at position 6 and a 1-methyl radical.
  • the object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (IRAK4).
  • IRAK4 Interleukin-1 Receptor Associated Kinase-4
  • the present invention relates to compounds of the general formula (I)
  • R 5 is hydrogen, C 1 -C 3 -alkyl
  • R 6 is C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl; for cyclopropylmethyl or Ci-Cö-alkyl, which may be substituted one to three times with fluorine, is; R 3 is Cs-Cö-cycloalkyl or Ci-Cö-alkyl, which may be substituted one to five times with fluorine, is; R 4 is hydrogen or fluorine;
  • the new IRAK4 inhibitors are particularly useful in the treatment and prevention of proliferative, metabolic and inflammatory diseases characterized by an overreacting immune system. Especially mentioned here are inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, neurological diseases, pain disorders and cancers.
  • the new IRAK4 inhibitors are suitable for treatment and prevention
  • autoimmune and inflammatory diseases in particular rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, spondyloarthritis and gout,
  • liver diseases such as fatty liver as well
  • kidney diseases especially chronic renal disease, nephropathies as well
  • gynecological diseases especially endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), subsequently as Embodiments mentioned compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But also included are salts which are not suitable for pharmaceutical applications themselves, but can be used for example for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C , 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 1231, 1241, 1291 and 1311.
  • isotopic variants of a compound of the invention such as those in which one or more radioactive Isotopes may be useful, for example, to study the mechanism of action or drug distribution in the body; because of the comparatively easy production and detectability, compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the instructions given for the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs may be present either as a single polymorph or as a mixture of several polymorphs in all mixing ratios.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, 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.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical with the number of carbon atoms given in each case. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a symbol * on a bond means the point of attachment in the molecule.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly.
  • R 5 is hydrogen, C 1 -C 3 -alkyl
  • R 6 is C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl.
  • R 1 is or a group selected from:
  • R 5 is hydrogen, C 1 -C 3 -alkyl
  • R 6 is C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl.
  • R 5 is hydrogen or methyl.
  • R 6 is methyl or ethyl.
  • R 6 is methyl.
  • R 2 is C 1 -C 4 -alkyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl.
  • R 2 is methyl, ethyl or where-propyl.
  • R 2 is methyl or ethyl.
  • R 3 is cyclopropyl or Ci-C t-alkyl, which may be mono- to trisubstituted by fluorine.
  • R 3 is methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl or trifluoromethyl.
  • R 3 is 1,1-difluoroethyl or trifluoromethyl.
  • R 4 is hydrogen.
  • R 5 is hydrogen or methyl
  • R 6 is methyl or ethyl
  • R 2 is C 1 -C 4 alkyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl
  • R 3 is cyclopropyl or C 1 -C 4 -alkyl which may be substituted one to three times by fluorine;
  • R 4 is hydrogen
  • Another object of the present invention are also compounds of the general formula (I), in which
  • R 5 is hydrogen or methyl
  • R 6 is methyl
  • R 2 is methyl, ethyl or where-propyl
  • R 3 is methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl or trifluoromethyl; and R 4 is hydrogen;
  • Another object of the present invention are compounds in which
  • R 1 stands for or for a group selected from:
  • R 5 is hydrogen or methyl
  • R 6 is methyl
  • the present invention particularly relates to the following compounds:
  • the compounds of the invention act as inhibitors of IRAK4 kinase, and show a surprising, valuable spectrum of pharmacological activity.
  • the substances weakly or not at all inhibit the kinases Flt3 (Fms-like tyrosine kinase 3) and Trk (tropomyosin-related kinase) -A, both kinases whose inhibition can be associated with possible side effects (see section “Kinase assays", see more) Section “Inhibition of IKAK4 Kinase Activity and Selectivity to TrkA and Flt3").
  • the compounds according to the invention show no indication of mutagenic potential (compare the section "in vitro micronucleus test") Therefore, in addition to the above-mentioned another object of the present invention, the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases Humans and animals.
  • gynecological diseases inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, Autoimmune diseases, pain disorders, metabolic diseases, gout, liver diseases, metabolic syndrome, insulin resistance, kidney diseases and cancers with the IRAK4 inhibitors according to the invention are particularly preferred.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular of TLR (except TLR3) and / or IL-1 receptor amily-mediated diseases or diseases whose pathology is mediated directly by IRAK4 , IRAK4-associated diseases include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondyloarthritis and arthritis.
  • the compounds of the invention may also be used for the prophylaxis and / or treatment of MyD88 and TLR (except TLR3) -mediated diseases.
  • These include multiple sclerosis, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis and ankylosing spondylitis), metabolic syndrome including insulin resistance, diabetes mellitus, osteoarthritis, Sjögren's syndrome, giant cell arteritis, sepsis, poly- and dermatomyositis, skin conditions such as psoriasis, atopic dermatitis, alopecia areata , Acne inversa and Acne vulgaris, pulmonary diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension.
  • COPD chronic obstructive
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of TLR-mediated diseases Behcet's disease, gout, endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschez. Furthermore, the compounds according to the invention are suitable for the prophylaxis and / or treatment of graft rejection, lupus erythematosus, Adult Still's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
  • the use of the compounds according to the invention is also suitable for the treatment and / or prevention of the following diseases: eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis; Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
  • eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis
  • Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
  • the mechanism of action of the compounds of the invention also enables the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated liver diseases, in particular NAFLD, NASH, ASH, liver fibrosis and cirrhosis. Furthermore, the compounds according to the invention are suitable for the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated kidney diseases, in particular chronic kidney disease and nephropathies.
  • the prophylaxis and / or treatment of itching and pain, in particular of acute, chronic, inflammatory and neuropathic pain by the compounds of the invention is given.
  • the compounds of the invention are suitable for the prophylaxis and / or treatment of oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors.
  • oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors.
  • the compounds of the invention are useful for the treatment and / or prevention of diseases mediated via the IL-1 receptor family.
  • diseases include CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold urticaria), MWS (Mückle-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 (Tumor Necrosis Factor Receptor 1-Associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Behcet's Disease, Rheumatoid Arthritis, Psoriatic Arthritis , Ankylosing spondylitis, osteoarthritis, keratoconjunctivitis sicca and sjögren syndrome, multiple sclerosis, lupus erythematos
  • Pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia and ARDS, gynecological diseases such as endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyscheza, chronic inflammatory bowel diseases such as Crohn's disease and colitis ulcerosa are associated with Dysregulation of the IL-1 receptor family associated and suitable for the therapeutic and / or prophylactic use of the compounds of the invention.
  • the compounds of the invention may also be used for the treatment and / or prevention of IL 1 receptor family-mediated neurological disorders such as stroke, Alzheimer's, stroke, traumatic brain injury and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis ,
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pain disorders, in particular of acute, chronic, inflammatory and neuropathic pain.
  • pain disorders in particular of acute, chronic, inflammatory and neuropathic pain.
  • hyperalgesia allodynia
  • pain in arthritis such as osteoarthritis, rheumatoid arthritis and spondylarthritis
  • premenstrual pain endometriosis-associated pain
  • post-operative pain pain in interstitial cystitis
  • CRPS complex regional pain syndrome
  • trigeminal neuralgia pain in prostatitis, pain caused by spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain and chronic pain.
  • the present invention also provides a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds according to the invention.
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, depressing, restraining or curing a disease, a disease, a disease, an injury, or a health disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • therapy is hereby understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • active substances such as antibacterial (eg penicillins, vancomycin, ciprofloxacin), antiviral (eg acyclovir, oseltamivir) and antifungal (eg naftifine, nystatin) substances and gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporin, methotrexate®, TNF antagonists (eg Humira® Etanercept, infliximab), IL-1 inhibitors (eg anakinra, canakinumab, rilonacept), phosphodiesterase inhibitors (eg apremilast), Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin , Mycophenolate mofetil, interferon
  • immunotherapy eg aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab, Lenalidomide, lenograstim, mifamurtide, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermine, teceleukin, tocilizumab), antiproliferative substances such as but not limited to amsacrine, arglabine, arsenic trioxide,
  • the following active ingredients rituximab, cyclophosphamide, doxorubicin, doxorubicin in combination with estrone, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 1311-chTNT, abiraterone, aclarubicin, alitretinoin, bisantrene, Calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, crisantaspase, darbepoetinefa, decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitoxanol, epoetine alfa, filgrastim, fotemustine, gallium nitrate, gemcitabine, glutoxime, histamine dihydroch
  • non-drug therapy such as chemotherapy (eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin), radiotherapy (eg I-125 seeds, palladium-103 seed, radium-223 chloride) or phototherapy (eg temoporfin, talaporfin), which are accompanied by a drug treatment with the IRAK4 inhibitors according to the invention or which are supplemented after the non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy by a drug treatment with the IRAK4 inhibitors according to the invention.
  • chemotherapy eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin
  • radiotherapy eg I-125 seeds, palladium-103 seed, radium-223 chloride
  • phototherapy eg temoporfin, talaporfin
  • IRAK4 inhibitors according to the invention can, in addition to those already mentioned, also be combined with the following active substances:
  • Active ingredients for Alzheimer's therapy such as acetylcholinesterase inhibitors (eg donepezil, rivastigmine, galantamine, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists (eg memantine); L-DOPA / carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O) Methyltransferase) inhibitors (eg entacapone), dopamine agonists (eg ropinrol, pramipexole, bromocriptine), MAO-B (monoamine oxidase B) inhibitors (eg selegiline), anticholinergics (eg trihexyphenidyl) and NMDA antagonists (eg amantadine) for treatment of Parkinson's; Beta interferon (IFN-beta) (eg IFN beta-lb, IFN beta-la Avonex® and Betaferon®), glatiram
  • rheumatoid diseases such as rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis methotrexate leflunomide, Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), TNF antagonists (eg Humira®, etanercept, infliximab), IL -1 inhibitors (eg anakinra, canakinumab, rilonacept), and biologists for B-cell and T-cell therapy (eg rituximab, abatacept).
  • Jak / STAT inhibitors eg tofacitinib, baricitinib, GLPG0634
  • TNF antagonists eg Humira®, etanercept, infliximab
  • IL -1 inhibitors eg anakinra, canakinumab, rilonacept
  • Neurotrophic substances such as acetylcholinesterase inhibitors (eg donepezil), MAO (monoamine oxidase) inhibitors (eg selegiline), interferons and anticonvulsants (eg gabapentin); Active substances for the treatment of cardiovascular diseases such as beta-blockers (eg metoprolol), ACE inhibitors (eg benazepril), angiotensin receptor blockers (eg losartan, valsartan), diuretics (eg hydrochlorothiazide), calcium channel blockers (eg nifedipine), statins (eg simvastatin , Fluvastatin); Anti-diabetics such as metformin, glinides (eg nateglinide), DPP-4 (dipeptidyl-peptidase-4) inhibitors (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT
  • Lipid lowering agents such as fibrates (eg bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (eg nicotinic acid / laropiprant), ezetimibe, statins (eg simvastatin, fluvastatin), anion exchangers (eg colestyramine, colestipol, colesevelam).
  • Agents such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL # 3®, Lactobacillus GG, Lactobacillus plantarum, L.
  • Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • calcineurin inhibitors eg, tacrolimus and ciclosporin
  • cell division inhibitors eg, azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus
  • rapamycin basiliximab, daclizumab
  • anti-CD3 antibodies anti-T lymphocyte globulin / anti-lymphocyte globulin on organ transplantation
  • Vitamin D3 analogs such as calcipotriol, tacalcitol or calcitriol
  • Salicylic acid urea
  • ciclosporin methotrexate
  • efalizumab in dermatological diseases.
  • Glucocorticoids eg, prednisone
  • immunosuppressants such as azathioprines, cyclophosphamide, mycophenolate mofetil; Hydroxychloroquine, ACE inhibitors (eg captopril, benazepril, enalapril, fosinopril), angiotensin receptor blockers (eg losartan, valsartan), beta-blockers (eg metoprolol), calcium channel blockers (eg nifedipine), and immunosuppressants such as cyclosporine for the treatment of Kidney diseases, nephropathies and glomerular diseases.
  • ACE inhibitors eg captopril, benazepril, enalapril, fosinopril
  • angiotensin receptor blockers eg losartan, valsartan
  • beta-blockers eg metoprolol
  • calcium channel blockers eg nifedip
  • drugs which contain at least one of the compounds according to the invention and one or more further active compounds, in particular EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKRIC3 inhibitors (Aldo-keto reductase family 1 member C3 inhibitors), for the treatment and / or prevention of the aforementioned diseases.
  • EP4 inhibitors prostaglandin E2 receptor 4 inhibitors
  • P2X3 inhibitors P2X purinoceptor 3
  • PTGES inhibitors prostaglandin E synthase inhibitors
  • AKRIC3 inhibitors Aldo-keto reductase family 1 member C3 inhibitors
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, via the ear or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, rapidly disintegrating in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • parenteral application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg 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 body weight.
  • carboxylic acids V3 can be prepared from carboxylic esters (intermediate V2) by saponification (compare, for example, the reaction of ethyl 6- (hydroxymethyl) pyridine-2-carboxylate with aqueous sodium hydroxide solution in methanol, WO2004113281) or, in the case of an ieri-butyl ester - by reaction with an acid such as hydrogen chloride or trifluoroacetic acid (see for example Dalton Transactions, 2014, 43, 19, 7176 - 7190) are produced.
  • the carboxylic acids V3 can also be used in the form of their alkali metal salts.
  • the preparation of the intermediates V2 may optionally take place from the intermediates VI, which as substituent X 1 carry a chlorine, bromine or iodine, by reaction in a carbon monoxide atmosphere optionally under excess pressure in the presence of a phosphine ligands such as l, 3-bis (diphenylphoshino ) propane, a palladium compound such as palladium (II) acetate and a base such as triethylamine with the addition of ethanol or methanol in a solvent such as dimethyl sulfoxide (for manufacturing methods cf. for example WO2012112743, WO 2005082866, Chemical Communications (Cambridge , England), 2003, 15, 1948 - 1949, WO200661715).
  • a phosphine ligands such as l, 3-bis (diphenylphoshino ) propane
  • a palladium compound such as palladium (II) acetate
  • a base such as trieth
  • the intermediates VI are either commercially available or can be prepared in literature ways. Exemplary methods of preparation are described in WO 2012061926, European Journal of Organic Chemistry, 2002, 2, 327-330, Synthesis, 2004, 10, 1619-124, Journal of the American Chemical Society, 2013, 135, 32, 12122-12134, Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039-4043, US2007185058, WO2009117421.
  • X is chlorine, bromine or iodine.
  • R d is methyl, ethyl, benzyl or ieri-butyl.
  • R 3 , R 4 have the definitions described in the general formula (I).
  • Intermediates 1 can be prepared by alkylating the phenol group of 2-amino-4-chloro-5-nitrophenol (CAS-RN6358-07-2) by the methods known to the person skilled in the art (cf., for example, Science of Synthesis, Georg Thieme Verlag).
  • the alkylation can be carried out with alkyl halides or alkyl sulfonates. Preference is given to the use of the alkylation reaction with alkyl bromides / alkyl iodides and potassium carbonate in DMF.
  • Intermediates 2 are obtained from intermediates 1 by introducing a "Boc" (tert-butoxycarbonyl group) amino-protecting group
  • the tert-butoxycarbonyl group can be prepared by the methods known to the person skilled in the art (see also PGM Wuts, TW Greene, Greene's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541), preferably by treatment with di-tert-butyl dicarbonate, 4-dimethylaminopyridine and triethylamine in dichloromethane
  • the intermediates 3 are obtained from the intermediates 2 by reaction with methylamine (see also WO2008 / 5457).
  • the reaction is carried out in ethanol with methylamine (for example in a sealed vessel under pressure at a bath temperature of 70 ° C).
  • the intermediates 4 are obtained by reduction of the nitro group from the intermediates 3.
  • the reduction can be carried out by the methods known to the person skilled in the art (compare, for example, Science of Synthesis, Georg Thieme Verlag).
  • the nitro group can be reacted with palladium on carbon under a hydrogen atmosphere, by the use of palladium on carbon and ammonium formate in methanol, by the use of iron and ammonium chloride in water and ethanol or methanol (Journal of the Chemical Society, 1955, 2412-2419 ) are reduced.
  • the intermediates 5 are obtained in two stages starting from the intermediates 4.
  • an acylation with 5-methoxy-4,4-dimethyl-5-oxopentanoic acid (CAS-RN 2840-71-3).
  • various coupling reagents known in the literature can be used (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. Rev., 2009, 38, 606).
  • 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride may be used in combination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475, Bioorg.Med.Chem. Lett., 2008, 18, 2093), (1H-benzotriazole).
  • acetic acid is used.
  • the acid can be used as a solvent or, if appropriate, the reaction can also be carried out in a solvent such as dichloromethane.
  • the cleavage can be effected by treatment with trifluoroacetic acid in dichloromethane.
  • a subset (I) -1 of the compounds (I) according to the invention is obtained by acylation of the intermediates 6 with suitable carboxylic acids.
  • Suitable carboxylic acids Various coupling reagents known in the literature can be used for this purpose (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. Rev., 2009, 38, 606).
  • 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride may be used in combination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475, Bioorg. Med. Chem.
  • Propanphosphonklareanhydrid (as a solution in ethyl acetate or DMF, CAS-RN 68957-94-8) or di-lH-imidazol-l-ylmethanon (CDI) can be used as coupling reagents, in each case to the reaction mixture, a base such as triethylamine or N-ethyl N-isopropylpropan-2-amine is added.
  • the coupling reagent HATU in combination with the base triethylamine is preferred.
  • Suitable solvents are, for example, THF or DMF.
  • the solvent is DMF.
  • the object is achieved compounds (I) -2 (the compounds (I) -2 represent a subset of the compounds of the invention (I)) (see also PGM Wuts, TW Greene, Greene's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541).
  • the hydrolysis of the methyl ester may be carried out by suitable bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a solvent such as methanol, ethanol, tetrahydrofuran or dioxane with the addition of water.
  • suitable bases such as sodium hydroxide, potassium hydroxide or lithium hydroxide in a solvent such as methanol, ethanol, tetrahydrofuran or dioxane with the addition of water.
  • Preferred is the use of lithium hydroxide in a solution of water and THF at 60 ° C.
  • a subset (I) -3 of the compounds (I) according to the invention is prepared starting from the intermediates 8 by acylation with the appropriate carboxylic acids (compare the analogous preparation of (I) -1 from the intermediates 6 as in Synthetic Scheme 2).
  • the compounds (I) -4 can be prepared by Grignard reaction with, for example, methylmagnesium bromide (I) -4 corresponds to a subset of the compounds (I)) according to the invention.
  • the reaction may be carried out in a suitable solvent such as tetrahydrofuran or 2-methyltetrahydrofuran or in a mixture of tetrahydrofuran and 2-methyltetrahydrofuran.
  • a further subset (I) -5 of the compounds (I) according to the invention is obtained according to synthesis scheme 4.
  • Intermediate 4 is reacted analogously to synthesis scheme 2 with a suitable carboxylic acid in the context of an amide synthesis.
  • suitable carboxylic acids are commercially available or can be prepared by literature methods (see, for example, Bioorganic and Medicinal Chemistry, 2011, vol. 19, 17, 5093-5102).
  • Preferred for amide synthesis is the use of HATU in the presence of triethylamine in DMF.
  • the intermediates 9 are obtained by treatment with acetic acid.
  • Intermediate 10 are obtained by the reaction with trifluoroacetic acid in dichloromethane.
  • the compounds (I) -5 are then obtained by reaction with carboxylic acids.
  • the methods described in Synthetic Scheme 2 come into consideration. Preference is given to the use of HATU and triethylamine in DMF.
  • the substituents R 2, R 3, R 4 and R 6 are as in the general formula (I) indicated the subset (I) -4 of the invention compounds (I) is obtained according to an alternative synthetic scheme.
  • the intermediates 11 are obtained from intermediates 4 analogously to synthesis scheme 2 (preparation of intermediates 5 from intermediates 4), the carboxylic acid 4-hydroxy-4-methylpentanoic acid used being prepared by basic hydrolysis of 5,5-dimefhyldihydrofuran-2 (3 //) - on (CAS RN 3123-97-5, see, for example, J. Org. Chem., 2001, vol. 66, 23, 7832-7840).
  • the intermediates 12 are prepared from the intermediates 11 analogously to synthesis scheme 2.
  • the subset (I) -4 of the compounds (I) according to the invention is prepared starting from the intermediates 12 by acylation with the appropriate carboxylic acids (compare the analogous preparation of (I) -1 from the intermediates 6 as in Synthetic Scheme 2).
  • Another object of the invention are compounds of general formula (II),
  • R 2 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
  • R 6 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
  • the compounds of general formula (II) are suitable for the preparation of a subset of the compounds of general formula (I).
  • the invention further provides a process for preparing a subset (I) -5 of the compounds of the general formula (I) according to the invention from compounds of the formula (II)
  • R 2 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
  • R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 6 -alkyl which may be substituted one to five times by fluorine;
  • R 4 is hydrogen or fluorine
  • R 6 is OC t -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl;
  • UPLC-MS Method C Instrument Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.05% formic acid, eluent B: acetonitrile + 0.05% formic acid; Gradient: 0- 1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 mL / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm.
  • UPLC-MS Method D Instrument Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.2% ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 mL / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm; ELSD.
  • the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG C-terminus in amide form
  • the concentration of Iraq4 was adjusted to the respective activity of the enzyme and adjusted so that the assay was in the linear range worked. Typical concentrations were on the order of about 0.2 nM.
  • the reaction was stopped by addition of 5 ⁇ M of a solution of TR-FRET detection reagents [0.1 ⁇ L streptavidin-XL665 (Cisbio Bioassays, France, catalog No. 610SAXLG) and 1.5 nM anti-phosho-serine antibodies [Merck Millipore, "STK Antibody", Catalog No. 35-002] and 0.6 nM LANCE EU-W1024-labeled anti-mouse IgG antibody (Perkin-Elmer, Product No.
  • AD0077 alternatively, a terbium cryptate labeled 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 for 1 h at 22 ° C to allow the formation of a complex of the biotinylated phosphorylated substrate and the detection reagents. Subsequently, the amount of the phosphorylated substrate was evaluated by measuring the resonance energy transfer from europium chelate-labeled anti-mouse IgG antibody to streptavidin-XL665. For this purpose, in a TR-FRET meter, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer), which measured fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm.
  • a TR-FRET meter e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer), which measured fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm.
  • the ratio of 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 microtiter plates at 11 different concentrations ranging from 20 ⁇ to 0.073 nM (20 ⁇ , 5.7 ⁇ , 1.6 ⁇ , 0.47 ⁇ , 0.13 ⁇ , 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM).
  • Serial dilutions were made prior to assay (2 mM to 7.3 nM in 100% DMSO) by serial dilutions.
  • the IC 50 values were calculated with a 4-parameter fit.
  • the example compounds show inhibition of IRAK4 kinase activity (see Table 1).
  • Table 1 IC 50 values of the example compounds in the IRAK4, Flt3 and TrkA kinase assay
  • IRAK4 amino acid 1-460 of IRAK4 accession number NP_057207.2 (Uniport No Q9NWZ3) was used, which was developed by Carna Biosciences, Japan (product number: 09 -445-20N) was purchased.
  • the biotinylated IRAK4 protein was immobilized using the streptavidin-biotin interaction on an SA Biacore chip (GE Healthcare, product number 29104992).
  • the biotinylated IRAK4 protein in lx HBS-EP + (prepared from 10x HBS-EP + buffer (GE Healthcare, product number BR100669)) was diluted to 5 ⁇ g / ml and then captured on the streptavidin surface of the SA-Biacore chip in the same buffer. This resulted in a signal of about 1000 response units.
  • the reference cell consisted of unsatisfied streptavidin.
  • test substances were diluted to 10 mM in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, Germany) and then further diluted in running buffer (lx HBS-EP + pH 7.4 [prepared from HBS-EP + buffer 10x (GE Healthcare): 0.1 M HEPES, 1.5 M NaCl, 30mM EDTA and 0.5% v / v detergent P20], 1% v / v DMSO).
  • running buffer lx HBS-EP + pH 7.4
  • 0.1 M HEPES 1.5 M NaCl
  • 30mM EDTA 0.5% v / v detergent P20
  • 1% v / v DMSO 1% v / v DMSO
  • test substances are injected for 80s and then taken up for 1000s dissociation.
  • the resulting grids are referenced twice against a blank and the reference surface and fitted with the Biacore T200 Evaluation Software with the formula stored in the software according to a 1: 1 binding model.
  • the example compounds show a long residence time on IRAK4 (see Table 2).
  • Table 2 Binding kinetics of the example compounds
  • Trk tropomyosin-related kinase
  • NGF nerve growth factor
  • TrkA is associated with nociceptive and neuropathic pain in adults, including chronic pain and cancer pain (Hirose, Kuroda, et al., Pain Practice, 2016).
  • Trk-A is important for the development of sympathetic nerves.
  • Patients with a loss-of-function mutation in TrkA develop hereditary sensory and autonomic neuropathy type IV (CIPA, congenital insensitivity to pain and anhidrosis), which is associated with a significant disturbance in the sense of pain and temperature (Indo, Clinical Genetics, 2012).
  • CIPA hereditary sensory and autonomic neuropathy type IV
  • TrkA appears to play a role in the maturation of cholinergic neurons, in the development of thymus, early ovarian development, and in the development of certain immune cells (Tessarollo, L., Cytokine & Growth Factor Reviews, 1998, Garcia-Suarez, Germana , et al., Journal of Neuroimmunology, 2000; Coppola, Barrick, et al., Development, 2004; Dissen, Garcia-Rudaz, et al., Seminars in Reproductive Medicine, 2009). Due to the mentioned potential functions, the selectivity for TrkA was determined.
  • HTRF Homogeneous Time Resolved Fluorescence
  • a kinase a recombinant fusion protein of N-terminal His6-tagged GST and a C-terminal fragment of human TrkA (amino acids 443-796 of TrkA Accession Number NP_002520.2) expressed in baculovirus-infected insect cells (Sf9) and purified by Affinity chromatography, purchased from ProQinase GmbH, Freiburg (Product No .: 0311-0000-2).
  • biotinylated poly-Glu, Tyr (4: 1) copolymer from CisBio Bioassays (# 61GT0BLA) was used.
  • the concentration of TrkA was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range (typical final TrkA concentrations in the 5 ⁇ L assay volume were on the order of about 20 pg / ⁇ ).
  • the reaction was stopped by adding 5 ⁇ l of a solution of HTRF detection reagents (30 nM streptavidin XL665 (Cisbio Bioassays, France) and 1.4 nM PT66 Eu chelate, a europium chelate-labeled anti-phospho tyrosine antibody from Perkin Elmer (PT66-Tb cryptate from Cisbio Bioassays can also be used instead of PT66-Eu chelate) in aqueous EDTA solution (100 mM EDTA, 0.2% (w / v) bovine serum albumin (BSA) in 50 mM HEPES / HC1 pH 7.0) The resulting mixture was incubated for 1 h at 22 ° C.
  • HTRF detection reagents 30 nM streptavidin XL665 (Cisbio Bioassays, France) and 1.4 nM PT66 Eu chelate, a europium chelate-labeled
  • the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer from the PT66.
  • Eu chelate to streptavidin-XL665 For this purpose, the fluorescence emissions at 620 nm and 665 nm were measured in an HTRF measuring device, eg a pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer) measured after excitation at 350 nm. The ratio of emissions at 665 nm and at 622 nm was taken as a measure of the amount of phosphorylated substrate.
  • test substances were incubated on the same microtiter plates at 11 different concentrations ranging from 20 ⁇ to 0.072 nM (20 ⁇ , 5.7 ⁇ , 1.6 ⁇ , 0.47 ⁇ , 0.13 ⁇ , 38 nM, 11 nM, 3 , 1 nM, 0.89 nM, 0.25 nM and 0.072 nM), the serial dilutions were prepared prior to the assay at the level of 100X concentrated solution [ie 2 mM to 7.2 nM in 100% DMSO] by serial dilutions , the exact concentrations may vary depending on the particular pipettors used) were tested in duplicate for each concentration and IC50 values were calculated with a 4-parameter fit.
  • the example compounds show a high selectivity towards TrkA (see Table 1).
  • Flt3 (Fms-like tyrosine kinase 3) is mainly expressed by hematopoietic precursor cells and is involved in the development of hematopoietic stem cells, in particular of dendritic cells
  • DCs Acute myeloid leukemia is associated with gain-of-function mutations in Flt3.
  • mice that do not express Flt3 exhibit increased sensitivity to cytomegalovirus and Toxoplasma gondii infections (Eidenschenk, Crozat, et al., PNAS,
  • the Flt3 signaling pathway is essential for the mobilization of DCs and for the T cell response to Plasmodium infections (Guermonprez, Helft, et al., Nature Medicine, 2013).
  • the function of Flt3 is for the
  • a recombinant fusion protein of N-terminal GST and a C-terminal fragment of human Flt3 (amino acid 564-end of Flt3 GenBank NM_004119) expressed in baculovirus-infected insect cells (Sf21) and purified by affinity chromatography was used, that of Merck Millipore (catalog # 14-500) was purchased.
  • the biotinylated peptide biotin-Ahx-GGEEEEYFELVKKKK C-terminus in amide form
  • was used e.g. can be bought at the company Biosynthan GmbH (Berlin-Buch, Germany).
  • concentration of Flt3 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear regime (typical Flt3 end concentrations in the 5 ⁇ L assay volume were on the order of about 0.2 nM).
  • the reaction was stopped by adding 5 ⁇ of a solution of HTRF detection reagents (0.2 ⁇ streptavidin XL665 (Cisbio Bioassays, France) and 3 nM PT66 Eu chelate, a europium chelate-labeled anti-phospho tyrosine antibody from Perkin Elmer [PT66-Tb cryptate from Cisbio Bioassays can also be used instead of the PT66-Eu chelate) in aqueous EDTA solution (50 mM EDTA, 0.1% (w / v) bovine serum albumin (BSA) in 50 mM HEPES pH 7.5 ).
  • HTRF detection reagents 0.2 ⁇ streptavidin XL665 (Cisbio Bioassays, France) and 3 nM PT66 Eu chelate, a europium chelate-labeled anti-phospho tyrosine antibody from Perkin Elmer [PT66-Tb cryptate from
  • the resulting mixture was incubated for 1 h at 22 ° C to allow the formation of a complex of the biotinylated phosphorylated substrate and the detection reagents. Subsequently, the amount of the phosphorylated substrate was evaluated by measuring the resonance energy transfer from the PT66 Eu chelate to the streptavidin XL665. For this purpose, in an HTRF meter, e.g. a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a
  • test substances were incubated on the same microtiter plate at 11 different concentrations ranging from 20 ⁇ to 0.072 nM (20 ⁇ , 5.7 ⁇ , 1.6 ⁇ , 0.47 ⁇ , 0.13 ⁇ , 38 nM, 11 ⁇ , 3.1 ⁇ , 0.89 ⁇ , 0.25 nM and 0.072 nM), the serial dilutions were prepared before the assay at the level of 100X concentrated solution [ie 2 mM to 7.2 nM in 100% DMSO] by serial Dilutions, the exact concentrations may vary depending on the particular pipettors used) were tested in duplicate for each concentration and IC50 values were calculated with a 4-parameter fit.
  • the example compounds show a high selectivity towards Flt3 (see Table 1).
  • TNF-a tumor necrosis factor-alpha
  • THP-1 cells human monocytic acute leukemia cell line
  • TNF- ⁇ is a cytokine involved in inflammatory processes.
  • the TNF- ⁇ release is triggered in this assay by incubation with bacterial lipopolysaccharide (LPS).
  • LPS bacterial lipopolysaccharide
  • THP-1 cells are supplemented in continuous suspension cell culture [RPMI 1460 medium without L-glutamax (GE Healthcare, Cat No: El 5-039) supplemented with fetal calf serum (FCS) 10% (Invitrogen, Cat # 10082- 147), 1% L-glutamine (Sigma, cat # G7513), 1% penicillin / streptomycin (PAA, cat # PI 1-010) and 50 ⁇ l 2-mercaptoethanol (Gibco, Cat 31350-010)] and should not exceed a cell concentration of 10x10 6 cells / ml.
  • the assay was carried out in cell culture medium (RPMI 1460 medium supplemented with L-glutamine, penicillin, streptomycin and 2-mercaptoethanol).
  • the THP-1 cells were seeded in 96-well plates with a cell density of 2.5 ⁇ 10 5 cells / well.
  • the compounds of the invention were serially diluted in a constant volume of 100% DMSO and used in the assay at 8 different concentrations ranging from 10 ⁇ to 3 nM so that the final DMSO concentration was 0.4% DMSO.
  • the cells were preincubated for 30 min before the actual stimulation.
  • stimulation was carried out with 1 ⁇ g / ml LPS (Sigma, Escherichia coli 0127: B8, Cat. No. L4516) for 6 hours.
  • the effect 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.
  • Table 3 IC 50 values of the exemplary compounds for TNF- ⁇ release in THP-1 cells that did not affect cell viability.
  • the assay was conducted in the absence and presence of an extrinsic metabolizing system (S9 Mix, Maron DM, Arnes BN, Revised methods for the salmonella mutagenicity test, Mutation Research, Vol. 113 / 3-4, pp. 173-215, 1983, Ong TM et al ..
  • extrinsic metabolizing system S9 Mix, Maron DM, Arnes BN, Revised methods for the salmonella mutagenicity test, Mutation Research, Vol. 113 / 3-4, pp. 173-215, 1983, Ong TM et al ..
  • Differential effects of cytochrome P450 inducers on promutagen activation capabilities and enzymatic activities of S-9 from rat liver, Journal of Environmental Pathology and Toxicology, 1980 Aug; 4 (l): 55-65).
  • V79 Chinese hamster cells were used.
  • Example Compound 7 showed no evidence of mutagenicity in in vitro MNT, with the substance tested to solubility limit (precipitation).
  • Example Compound 10 showed no evidence of mutagenicity in the in vitro MNT, with the substance being tested to the solubility limit (precipitation).
  • mice Female Balb / c mice (about 8 weeks, Charles River Laboratories, Germany) are injected with IL-1 ⁇ .p. applied and investigated the effect of the compounds of the invention on the IL-l ß -mediated cytokine secretion.
  • the group size is 5 animals each.
  • the control group is treated with the vehicles used to dissolve the substance and IL-1 ⁇ .
  • Each of the substance treatment groups and the positive control group is administered with 90 ⁇ g IL-1 ⁇ kg body weight (R & D, Cat. No. 401-ML / CF) i.p.
  • the substance or its vehicle in the positive control group is administered 6 hours before IL-1 ß administration.
  • TNF- ⁇ in the plasma after the final blood withdrawal is carried out 2 hours after administration of the IL-1 ß by means of the Mouse Prolnflammatory 7-Plex Tissue Culture Kit (MSD, cat.No K15012B) according to the manufacturer.
  • MSD Mouse Prolnflammatory 7-Plex Tissue Culture Kit
  • the treatment with different dosages of the test substance is preventive, i. from day 0, carried out by oral administration.
  • the disease status of the animals by means of disease activity score to the end day 20.
  • Statistical analysis is performed using the one-factorial analysis of variance (ANOVA) and comparison to the control group by multiple comparison analysis (Dunnett test).

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Abstract

La présente invention concerne des benzimidazoles substitués de formule (I), leur utilisation pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie de l'endométriose, ainsi que des douleurs associées à l'endométriose et d'autres symptômes associés à l'endométriose tels que la dysménorrhée, la dyspareunie, la dysurie et la dyschésie, de lymphomes, de la polyarthrite rhumatoïde, des spondylarthrites (en particulier de la spondylarthrite psoriasique et de la spondylarthrite ankylosante), du lupus érythémateux, de la sclérose en plaques, de la dégénérescence maculaire, de la BPCO, de la goutte, des stéatoses hépatiques, de l'insulino-résistance, des néphropathies, des maladies tumorales et du psoriasis.
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WO2021158498A1 (fr) * 2020-02-03 2021-08-12 Bristol-Myers Squibb Company Composés hétéroaryle tricycliques utiles en tant qu'inhibiteurs d'irak 4
WO2022156788A1 (fr) * 2021-01-22 2022-07-28 武汉人福创新药物研发中心有限公司 Composé de benzimidazole et son utilisation
WO2022267673A1 (fr) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 Indazole substitué par sulfoximide inhibiteur de la kinase irak4, son procédé de préparation et son utilisation

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