WO2018060174A1 - Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs - Google Patents

Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
pain
methyl
diseases
benzimidazol
methoxy
Prior art date
Application number
PCT/EP2017/074320
Other languages
German (de)
French (fr)
Inventor
Sven Ring
Ulrich Bothe
Reinhard Nubbemeyer
Ulf Bömer
Judith GÜNTHER
Nicole Schmidt
Dorothee ANDRES
Holger Siebeneicher
Andreas Sutter
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2018060174A1 publication Critical patent/WO2018060174A1/en

Links

Classifications

    • 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).

Abstract

The invention relates to substituted benzimidazoles of formula (I), to the use thereof for treating and/or preventing diseases, and to the use thereof for producing drugs for treating and/or preventing diseases, in particular for treating and/or preventing endometriosis and endometriosis-associated pains and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria, and dyschezia, lymphomas, rheumatoid arthritis, spondyloarthritides (in particular psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver diseases, insulin resistance, kidney disorders, tumor diseases and psoriasis.

Description

SUBSTITUIERTE BENZI M IDAZOLE, PHARMAZEUTISCHE PRÄPARATE DIESE ENTHALTEND, SOWIE DEREN VERWENDUNG ZUR HERSTELLUNG VON ARZNEI M ITTELN  SUBSTITUTED BENZI M IDAZOLE, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR USE FOR THE MANUFACTURE OF ARZNEI MICLES
Die vorliegende Anmeldung betrifft neue substituierte Benzimidazole, Verfahren zu ihrer Herstellung, Zwischenstufen zur Verwendung bei der Herstellung der neuen Verbindungen, die Verwendung der neuen substituierten Benzimidazole zur Behandlung und/oder Prophylaxe von Krankheiten sowie ihre Verwendung zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe von Krankheiten, insbesondere von proliferativen Erkrankungen, von Autoimmunerkrankungen, von metabolischen und von inflammatorischen Erkrankungen wie z.B. Rheumatoider Arthritis, Spondyloarthritiden (insbesondere Spondylarthritis psoriatica und Morbus Bechterew), chronisch obstruktiver Lungenerkrankung (englisch chronic obstructive pulmonary disease, Abkürzung: COPD), Multipler Sklerose, Systemischem Lupus Erythematodes, Gicht, des metabolischen Syndroms, Fettleberhepatitis, Insulinresistenz, Nierenerkrankungen, Endometriose und entzündungsinduziertem oder chronischem Schmerz sowie von Lymphomen. 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.
Die vorliegende Erfindung betrifft neue substituierte Benzimidazole der allgemeinen Formel (I), die die Interleukin-1 Receptor- Associated Kinase 4 (IRAK4) hemmen. The present invention relates to novel substituted benzimidazoles of general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4).
Humanes IRAK4 (Interleukin-1 receptor-associated kinase 4) spielt eine Schlüsselrolle bei der Aktivierung des Immunsystems. Deshalb ist diese Kinase ein wichtiges therapeutisches Zielmolekül für die Entwicklung von entzündungshemmenden Substanzen. IRAK4 wird von einer Vielzahl von Zellen exprimiert und vermittelt die Signaltransduktion von Toll-like Rezeptoren (TLR), außer TLR3, sowie Rezeptoren der Interleukin (IL)-l ß Familie, bestehend aus dem IL-1R (Rezeptor), IL-18R, IL- 33R und IL-36R (Janeway und Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).  Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a key role in activating the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of anti-inflammatory substances. IRAK4 is expressed by a variety of cells and mediates the signal transduction of Toll-like receptors (TLR), except TLR3, as well as receptors of the interleukin (IL) -l ß family, consisting of the IL-1R (receptor), IL-18R, IL-33R and IL-36R (Janeway and Medzhitov, Annu., Rev. Immunol., 2002; Dinarello, Annu., Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).
Weder IRAK4 Knockout Mäuse noch humane Zellen von Patienten, denen IRAK4 fehlt, reagieren auf die Stimulation von TLRs (außer TLR3) und der IL- l ß Familie (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).  Neither IRAK4 knockout mice nor human cells from patients lacking IRAK4 respond to the stimulation of TLRs (except TLR3) and the IL-1β 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).
Die Bindung der TLR Liganden bzw. der Liganden der IL-lß Familie an den jeweiligen Rezeptor führt zur Rekrutierung und Bindung von MyD88 [Myeloid differentiation primary response gene (88)] an den Rezeptor. Infolgedessen tritt MyD88 mit IRAK4 in Interaktion und es kommt zur Bildung eines aktiven Komplexes, welcher mit den Kinasen IRAK1 oder IRAK2 interagiert und diese aktiviert (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009). Infolgedessen wird der NF (nuclear factor)-KB Signalweg und der MAPK (Mitogen-activated protein kinase) Signalweg aktiviert (Wang, Deng, et al., Nature, 2001). Die Aktivierung des NF-KB Signalweges als auch des MAPK Signalweges führt zu Prozessen, die mit verschiedenen Immunprozessen assoziiert sind. So kommt es beispielsweise zu einer erhöhten Expression von unterschiedlichen inflammatorischen Signalmolekülen und Enzymen, wie z.B. Zytokinen, Chemokinen und COX-2 (Cyclooxygenase-2), und zu einer erhöhten mRNA Stabilität von inflammationsassoziierten Genen wie beispielsweise 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). Des Weiteren können diese Prozesse mit der Proliferation und der Differenzierung von bestimmten Zelltypen, wie z.B. Monozyten, Makrophagen, Dendritischen Zellen, T-Zellen und B-Zellen einhergehen (Wan, Chi, et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007). Die zentrale Rolle von IRAK4 in der Pathologie von unterschiedlichen inflammatorischen Erkrankungen konnte bereits durch den direkten Vergleich von Wildtyp (WT) Mäusen mit genetisch veränderten Tieren mit einer Kinase-inaktiven Form des IRAK4 (IRAK4 KDKI) gezeigt werden. IRAK4 KDKI Tiere weisen ein verbessertes Krankheitsbild im Tiermodell für Multiple Sklerose, Atherosklerose, Herzinfarkt und Alzheimer auf (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012). Des Weiteren zeigte sich, dass die Deletion von IRAK4 im Tiermodell vor einer viral-induzierten Myokarditis infolge einer verbesserten anti-viralen Reaktion bei gleichzeitig verringerter systemischer Inflammation schützt (Valaperti, Nishii, et al., Circulation, 2013). Außerdem wurde gezeigt, dass die Expression von IRAK4 mit dem Ausmaß des Vogt-Koyanagi-Harada-Syndroms korreliert (Sun, Yang, et al., PLoS ONE, 2014). Zudem konnte die hohe Relevanz von IRAK4 für die Immunkomplex- vermittelte IFNa (Interferonalpha) Produktion durch plasmazytoide Dendritische Zellen, ein Schlüsselprozess bei der Pathogenese des Systemischen Lupus Erythematodes (SLE), gezeigt werden (Chiang et al., The Journal of Immunology, 2010). Des Weiteren ist der Signalweg mit Fettleibigkeit (Adipositas) assoziiert (Ahmad, R., P. Shihab, et al., Diabetology & Metabolie Syndrome, 2015) The binding of the TLR ligands or ligands of the IL-lß family to the respective receptor leads to the recruitment and binding of MyD88 [myeloid differentiation primary response gene (88)] to the receptor. As a result, 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). As a result, the NF (nuclear factor) -KB signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway are activated (Wang, Deng, et al., Nature, 2001). Activation of the NF-κB pathway as well as the MAPK signaling pathway leads to processes associated with various immune processes. Thus, for example, there is an increased expression of different 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). Furthermore, 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. O'Neill, British Journal of Haematology, 2007). The central role of IRAK4 in the pathology of various inflammatory diseases has already been demonstrated by the direct comparison of wild-type (WT) mice with genetically modified animals with a kinase-inactive form of IRAK4 (IRAK4 KDKI). 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). Furthermore, it 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). In addition, expression of IRAK4 has been shown to correlate with the extent of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014). In addition, the high relevance of IRAK4 for 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). , Furthermore, the signaling pathway is associated with obesity (Ahmad, R., P. Shihab, et al., Diabetology & Metabolism Syndrome, 2015).
Neben der essentiellen Rolle von IRAK4 bei der angeborenen Immunität gibt es auch Hinweise, dass IRAK4 die Differenzierung der sogenannten Thl7 T-Zellen, Komponenten der adaptiven Immunität, beeinflusst. In Abwesenheit der IRAK4 Kinaseaktivität werden weniger IL- 17 produzierende T-Zellen (Thl7 T-Zellen) im Vergleich zu WT Mäusen generiert. Durch die Inhibition von IRAK4 ist die Prophylaxe und/oder Behandlung von Atherosklerose, Diabetes mellitus Typ 1, Rheumatoide Arthritis, Spondyloarthritiden (insbesondere Spondylarthritis psoriatica und Morbus Bechterew), Lupus erythematodes, Psoriasis, Vitiligo, Riesenzellarteriitis, chronisch entzündlicher Darmerkrankung und Viruserkrankungen, wie z.B. HIV (Humane Immundefizienz- Virus), Hepatitis Virus möglich (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal of Inflammation, 2014; Wang, et al., Experimental and Therapeutic Medicine, 2015; Ciccia, et al., Rheumatology, 2015). Durch die zentrale Rolle von IRAK4 in der MyD88-vermittelten Signalkaskade von TLRs (außer TLR3) und der IL-1 Rezeptorfamilie kann die Inhibition von IRAK4 zur Prophylaxe und/oder Behandlung von durch die genannten Rezeptoren vermittelte Erkrankungen genutzt werden. TLRs als auch Komponenten der IL- 1 Rezeptorfamilie sind in der Pathogenese der Rheumatoiden Arthritis, der Psoriasis Arthritis, Myasthenia gravis, der Vaskulitis wie beispielsweise Morbus Behcet, Granulomatose mit Polyangiitis und Riesenzellarteriitis, Pankreatitis, des Systemischen Lupus Erythematodes, der Dermamyositis und Polymyositis, des Metabolischen Syndroms inklusive z.B. Insulinresistenz, Hypertonie, Dyslipoproteinämie und Adipositas, der Diabetes mellitus (Typ 1 und Typ 2), der diabetischen Nephropathie, der Osteoarthritis, des Sjögren-Syndroms, und der Sepsis involviert (Yang, Tuzun, et al., J Immunol, 2005; Candia, Marquez et al., The Journal of Rheumatology, 2007; Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Deng, Ma-Krupa, et al., Circ Res, 2009; Roger, Froidevaux, et al, PNAS, 2009; Devaraj, Tobias, et al., Arterioscler Thromb Vase Biol, 2011; Kim, Cho, et al., Clin Rheumatol, 2010; Carrasco et al., Clinical and Experimental Rheumatology, 2011; Gambuzza, Licata, et al., Journal of Neuroimmunology, 2011; Fresno, Archives Of Physiology And Biochemistry, 2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012; Ouziel, Gustot, et al., Am J Patho, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012, Okiyama et al., Arthritis Rheum, 2012; Chen et al., Arthritis Research & Therapy, 2013; Holle, Windmoller, et al., Rheumatology (Oxford), 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sei, 2013; Caso, Costa, et al., Mediators of Inflammation, 2014; Cordiglieri, Maroida, et al., J Autoimmun, 2014; Jialal, Major, et al., J Diabetes Complications, 2014; Kaplan, Yazgan, et al., Scand J Gastroenterol, 2014; Talabot-Aye, et al., Cytokine, 2014; Zong, Dorph, et al., Ann Rheum Di, 2014; Ballak, Stienstra, et al., Cytokine, 2015; Timper, Seelig, et al., J Diabetes Complications, 2015). Hauterkrankungen wie Psoriasis, atopische Dermatitis, Kindler Syndrom, bullösen Pemphigoid, allergische Kontaktdermatitis, Alopecia areata, Acne inversa und Acne vulgaris sind mit dem IRAK4- vermittelten TLR-Signalweg bzw. der IL-1R Familie assoziiert (Schmidt, Mittnacht, et al., J Dermatol Sei, 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., Annais of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Dispenza, Wolpert, et al., J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab, et al., BMC Dermatology, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sei, 2013; Wollina, Koch, et al. Indian Dermatol Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014). Auch bei pulmonalen Erkrankungen wie Lungenfibrose, obstruktiver Lungenerkrankung (COPD), akutem Atemnot-Syndrom (ARDS), akuter Lungenschädigung (ALI), interstitieller Lungenerkrankung (ILD), Sarkoidose und pulmonaler Hypertonie zeigt sich eine Assoziation mit verschiedenen TLR- vermittelten Signalwegen. Bei der Pathogenese der pulmonalen Erkrankungen kann es sich sowohl um infektiös vermittelte als auch um nicht-infektiös vermittelte Prozesse handeln (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu, et al., Infection and Immunity, 2005; 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, 2013; Dubaniewicz, A., Human Immunology, 2013). TLRs als auch IL-1R Familienmitglieder sind auch in die Pathogenese anderer inflammatorischer Erkrankungen wie Allergie, Behcet-Krankheit, Gicht, Lupus erythematodes, Adult Morbus Still-Krankheit, Perikarditis und chronisch entzündliche Darmerkrankungen, wie Kolitis ulcerosa und Morbus Crohn, Transplantatabstoßung und Graft- versus- Host-Reaktion involviert, so dass die Inhibition von IRAK4 hier ein geeigneter prophylaktischer und/oder therapeutischer Ansatz ist (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., PLoS ONE, 2007; Heimesaat, Nogai, et al., Gut, 2010; Kobori, Yagi, et al., J Gastroenterol, 2010; Schmidt, Raghavan, et al., Nat Immunol, 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokine & Growth Factor Reviews, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen, et al., Contact Dermatitis, 2014; D'Elia, Brucato, et al., Clin Exp Rheumatol, 2015; Jain, Thongprayoon, et al., Am J Cardiol., 2015; Li, Zhang, et al., Oncol Rep., 2015). In addition to the essential role of IRAK4 in innate immunity, there is also evidence that IRAK4 affects the differentiation of the so-called Th17 T cells, components of adaptive immunity. In the absence of IRAK4 kinase activity, fewer IL-17 producing T cells (Th17 T cells) are generated compared to WT mice. 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. Wang, et al., Experimental and Therapeutic Medicine, 2015; Ciccia, et al., Rheumatology, 2015). 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., Circ Res, 2009; Roger, Froidevaux, et al al, PNAS, 2009; Devaraj, Tobias, et al., Arterioscler Thromb Vase Biol, 2011; Kim, Cho, et al., Clin Rheumatol, 2010; Carrasco et al., Clinical and Experimental Rheumatology, 2011; Gambuzza, Licata, et al., Journal of Neuroimmunology, 2011; Fresno, Archives of Physiology And Biochemistry, 2011; Volin and Koch, J Interferon Cytokine Res, 2011; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012; Ouziel, Gustot, et al., Am J Patho, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012, Okiyama et al., Arthritis Rheum, 2012; Chen et al., Arthritis Research & Therapy, 2013; Holle, Windmoller, et al., Rheumatology (Oxford), 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sei, 2013; Caso, Costa, et al., Mediators of Inflammation, 2014; Cordiglieri, Maroida, et al., J Autoimmune, 2014; Jialal, Major, et al., J. 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. J Dermatol Sei, 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., Annais of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology , 2012; Dispenza, Wolpert, et al., J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab, et al. , BMC Dermatology, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sei, 2013; Wollina, Koch, et al Dermatol Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014). 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. 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, 2013; Dubaniewicz, A., Human Immunology, 2013). 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. inhibition of IRAK4 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 Heimesaat, Fischer, et al., PLoS ONE, 2007; Heimesaat, Nogai, et al., Gut, 2010; Kobori, Yagi, et al., J Gastroenterol, 2010; Schmidt, Raghavan, et al., Nat Immunol, 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventha l and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokines & Growth Factor Reviews, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen, et al., Contact Dermatitis, 2014; D'Elia, Brucato, et al., Clin Exp Rheumatol, 2015; Jain, Thongprayoon, et al., Am J Cardiol., 2015; Li, Zhang, et al., Oncol Rep., 2015).
Durch TLR- und IL-1R Familie- vermittelte gynäkologische Erkrankungen wie Adenomyosis, Dysmenorrhoe, Dyspareunie und Endometriose, insbesondere Endometriose-assoziierte Schmerzen und andere Endometriose-assoziierte Symptome wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie, können durch den prophylaktischen und/oder therapeutischen Einsatz von IRAK4 Inhibitoren positiv beeinflusst werden (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 Gynaecology Research, 2013; Santulli, Borghese, et al., Human Reproduction, 2013). Der prophylaktische und/oder therapeutische Einsatz von IRAK4 Inhibitoren kann außerdem Atherosklerose positiv beeinflussen (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). By 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, may by prophylactic and / or therapeutic use of 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, Borghese, et al., Human Reproduction, 2013). The prophylactic and / or therapeutic Use of 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).
Neben den bereits aufgeführten Erkrankungen werden IRAK4-vermittelte TLR-Prozesse in der Pathogenese von Augenerkrankungen wie retinale Ischämie, Keratitis, allergisch bedingte Konjunktivitis, Keratoconjunctivitis sicca, Makuladegeneration und Uveitis beschrieben (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, Gao, et al., Immunol Cell Biol, 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014). In addition to the diseases already listed, 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).
Die Inhibition von IRAK4 ist außerdem ein geeigneter therapeutischer Ansatz für fibrotische Erkrankungen, wie beispielsweise Leberfibrose, Myokarditis, primär biliäre Zirrhose, zystische Fibrose (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). 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).
Durch die Schlüsselstellung, die IRAK4 in TLR- und IL-1R Familie- vermittelten Erkrankungen hat, können chronische Lebererkrankungen wie beispielsweise Fettleberhepatitis und insbesondere nichtalkoholischen Fettlebererkrankungen (NAFLD - non-alcoholic fatty liver disease) und/oder nichtalkoholischer Fettleberhepatitis (NASH - non-alcoholic steatohepatitis), alkoholtoxische Hepatitis (ASH - alkoholische Steatohepatitis) präventiv und/oder therapeutisch mit IRAK4 Inhibitoren behandelt werden (Nozaki, Saibara, et al., Alcohol Clin Exp Res, 2004; Csak, T., A. Velayudham, et al., Am J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama, et al., Gastroenterology, 2010; Kamari, Shaish, et al., J Hepatol, 2011; Ye, Li, et al., Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013; Ceccarelli, S., V. Nobili, et al., World J Gastroenterol, 2014; Miura, Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic, et al., World J Gastroenterol, 2014). Des Weiteren sind IRAK4 Inhibitoren auch zur Behandlung von Nierenfunktionsstörungen und Nierenerkrankungen geeignet, wie beispielsweise chronische Nierenkrankheit (chronic kidney disease, CKD), chronisches Nierenversagen, glomeruläre Krankheiten, diabetische Nephropathie, Lupus- Nephritis, IgA-Nephritis (Morbus Berger), Nephrosklerose. Die genannten Erkrankungen sind mit dem TLR Signalweg als auch mit Komponenten der IL-1 Rezeptorfamilie assoziiert (Suzuki, Suzuki, et al., Journal of the American Society of Nephrology, 2008; Hahn, Cho, et al., Pediatric Nephrology, 2009; Conti, Spinelli, et al., Clinical Reviews in Allergy & Immunology, 2010 ;Bao, Na, et al., Journal of Clinical Immunology, 2011; Devaraj, Tobias, et al., Arterioscler Thromb Vase Biol, 2011; Rosa Ramirez, and Ravi Krishna Dasu, Curr Diabetes Rev, 2012; Urbonaviciute, Starke, et al. Arthritis & Rheumatism, 2013; Batal, et al., Transplantation, 2014; Jialal, Major, et al., J Diabetes Complications, 2014; Lin, and Tang, Nephrology Dialysis Transplantation, 2014; Zawada, Rogacev, et al., Epigenetic, 2014; Elsherbiny and Al-Gayyar, Cytokine, 2016; Yang, et al., Mol Med Rep, 2016). Aufgrund der zentralen Rolle von IRAK4 in TLR-vermittelten Prozessen ist durch die Inhibition von IRAK4 auch die Behandlung /und/oder Prävention von kardiovaskulären und neurologischen Erkrankungen wie z.B. myokardialem Reperfusionsschaden, Myokardinfarkt, Hypertonie, Bluthochdruck (Oyama, Blais, et al., Circulation, 2004; 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), 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sei (Lond), 2013; Hernanz, Martinez- Revelles, et al., British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015; Bomfim, Echem, et al., Life Sciences, 2015) sowie Alzheimer, Schlaganfall, Hirnschlag, Schädel- Hirn-Trauma, Amyotrophe Lateralsklerose (ALS) und Parkinson möglich (Brough, Tyrrell, et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, et al., The Journal of Immunology, 2011; Lim, Kou, et al., The American Journal of Pathology, 2011; Beraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Noelker, Morel, et al., Sei. Rep., 2013; Wang, Wang, et al., Stroke, 2013; Xiang, Chao, et al., Rev Neurosci, 2015; Lee, Lee, et al., J Neuroinflammation, 2015). The key position that 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. J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama, et al., Gastroenterology, 2010; Kamari, Shaish, et al., J Hepatol, 2011; Ye, Li, et al., Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013; Ceccarelli, S., V. Nobili, et al., World J Gastroenterol, 2014; Miura, Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic, et al., World J Gastroenterol, 2014). Furthermore, 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. These diseases are associated with the TLR signaling pathway as well as components of the IL-1 receptor family (Suzuki, Suzuki, et al., Journal of the American Society of Nephrology, 2008; Hahn, Cho, et al., Pediatric Nephrology, 2009; Conti, Spinelli, et al., Clinical Reviews in Allergy & Immunology, 2010; Bao, Na, et al., Journal of Clinical Immunology, 2011; Devaraj, Tobias, et al., Arterioscler Thromb Vase Biol, 2011; Rosa Ramirez, and Ravi Krishna Dasu, Curr Diabetes Rev, 2012; Urbonaviciute, Starke, et al., Arthritis & Rheumatism, 2013; Batal, et al., Transplantation, 2014; Jialal, Major, et al., J Diabetes Complications; 2014; Lin, and Tang, Nephrology Dialysis Transplantation, 2014; Zawada, Rogacev, et al., Epigenetic, 2014; Elsherbiny and Al-Gayyar, Cytokines, 2016; Yang, et al., Mol Med Rep, 2016). Due to the central role of IRAK4 in TLR-mediated processes, 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 trauma, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Brough, Tyrrell, et al., Trends in Pharmacological Sciences, 2011 Carty and Bowi e, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng, et al., The Journal of Immunology, 2011; Lim, Kou, et al., The American Journal of Pathology, 2011; Beraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Noelker, Morel, et al., Sei. Rep., 2013; Wang, Wang, et al., Stroke, 2013; Xiang, Chao, et al., Rev Neurosci, 2015; Lee, Lee, et al., J Neuroinflammation, 2015).
Aufgrund der Involvierung von TLR-vermittelten Signalen und IL-1 Rezeptorfamilie- vermittelten Signalen über IRAK4 bei Juckreiz und Schmerz inklusive akutem, chronischem, entzündlichem und neuropathischem Schmerz ist von einer therapeutischen Wirkung in den genannten Indikationen durch die Inhibierung von IRAK4 auszugehen. Für Schmerz seien beispielhaft Hyperalgesie, Allodynie, prämenstrueller Schmerz, Endometriose-assoziierter Schmerz, postoperativer Schmerz, interstitielle Zystitis, CRPS (komplexes regionales Schmerzsyndrom), Trigeminusneuralgie, Prostatitis, Schmerz verursacht durch Rückenmarksverletzungen, entzündungsinduzierter Schmerz, Kreuzschmerzen, Krebsschmerzen, Chemotherapie- assoziierter Schmerz, HIV behandlungs-induzierte Neuropathie, Verbrennungs-induzierter Schmerz und chronischer Schmerz zu nennen (Wolf, 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, et al., European Journal of Pharmacology, 2012; Kwok, Hutchinson, et al., PLoS ONE, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; Han, Zhao, et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; Liu, Zhang, et al., Cell Research, 2014; Park, Stokes, et al., Cancer Chemother Pharmacol, 2014; Van der Watt, Wilkinson, et al., BMC Infect Dis, 2014; Won, K. A., M. J. Kim, et al., J Pain, 2014; Min, Ahmad, et al., Photochem Photobiol., 2015; Schrepf, Bradley, et al., Brain Behav Immun, 2015; Wong, L., J. D. Done, et al., Prostate, 2015). 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. Examples of pain 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 (Wolf, 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, et al., European Journal of Pharmacology, 2012; Kwok, Hutchinson, et al., PLoS ONE; 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; Zhao, et al., Neuroscience, 2013; Liu and Ji, Pfluger's Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; Liu, Zhang, et al., Cell Research, 2014; Park, Stokes, et al., Cancer Chemother Pharmacol, 2014; Van der Watt, Wilkinson, et al., BMC Infect Dis, 2014; Won, KA, MJ Kim, et al., J Pain, 2014; Min, Ahmad, et al., Photochem Photobiol., 2015; Schrepf, Bradley, et al., Brain Behav Immun, 2015; Wong, L., JD Done, et al., Prostate, 2015).
Dies gilt auch für einige onkologische Erkrankungen. Bestimmte Lymphome, wie beispielsweise ABC-DLBCL (Aktivierte B Zellen-Diffuses großzelliges B-Zell-Lymphom), Mantelzelllymphon und Morbus Waldenström als auch chronisch lymphatische Leukämie, Melanoma, Pankreastumor und Leberzellkarzinom sind durch Mutationen in MyD88 oder Veränderungen in der MyD88-Aktivität charakterisiert, die durch einen IRAK4 Inhibitor behandelt werden können (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). Des Weiteren spielt MyD88 eine wichtige Rolle in Ras-abhängigen Tumoren, so dass IRAK4 Inhibitoren auch zu deren Behandlung geeignet sind (Kfoury, A., K. L. Corf, et al., Journal of the National Cancer Institute, 2013). Es ist außerdem von einer therapeutischen Wirkung bei Brustkrebs, Ovarialkarzinom, Kolorektales Karzinom, Kopf-Hals-Karzinom, Lungenkrebs, Prostatakrebs durch die Inhibierung von IRAK4 auszugehen, da die genannten Indikationen mit dem Signalweg assoziiert sind (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).  This also applies to some oncological diseases. Certain 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). Furthermore, 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).
Inflammatorische Erkrankungen wie CAPS (Cryopyrin-assoziierte periodische Syndrome), inklusive FCAS (familiäre Kälteurtikaria), MWS (Mückle- Wells-Syndrom), NOMID- (neonatal-onset multisystem inflammatory disease) und CONCA- (chronic infantile, neurological, cutaneous, and articular) Syndrom; FMF (familiäres Mittelmeerfieber), HIDS (Hyper-IgD-Syndrom), TRAPS (Tumornekrosefaktor-Rezeptor 1-assoziiertes periodisches Syndrom), juvenile idiopathische Arthritis, Adult Morbus Still-Krankheit, Morbus Adamantiades-Behcet, rheumatoide Arthritis, Osteoarthritis, Keratoconjunctivitis sicca, PAPA-Syndrom (Pyogene Arthritis, Pyoderma gangraenosum und Akne), Schnitzler Syndrom und Sjögren Syndrom werden durch die Blockierung des IL-1 Signalweges behandelt, so dass auch hier ein IRAK4 Inhibitor zur Behandlung der genannten Krankheiten geeignet ist (Narayanan, Corrales, et al., Cornea, 2008; Brenner, Ruzicka, et al., British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of Immunology, 2011; Gul, Tugal-Tutkun, et al., Ann Rheum Dis, 2012; Pettersson, Annais of MedicinePetterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordström, Knight, et al., The Journal of Rheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013; de Koning, Clin Transl Allergy, 2014). Der Ligand des IL-33R, IL-33, ist insbesondere in der Pathogenese von akutem Nierenversagen involviert, so dass die Inhibition von IRAK4 zur Prophylaxe und/oder Behandlung ein geeigneter Therapieansatz ist (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011). Komponenten der IL-1 Rezeptorfamilie sind mit Myokardinfarkt, unterschiedlichen pulmonalen Erkrankungen wie Asthma, COPD, idiopathischer interstitieller Pneumonie, allergische Rhinitis, Lungenfibrose und akutem Atemnot-Syndrom (ARDS) assoziiert, so dass eine prophylaktische und/oder therapeutische Wirkung in den genannten Indikationen durch die Inhibierung von IRAK4 zu erwarten ist (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, et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013; Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013; Martinez-Gonzälez, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Immunology, 2014; Lugrin, Parapanov, et al., The Journal of Immunology, 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 (Narayanan, Corrales, et al , Cornea, 2008; Brenner, Ruzicka, et al., British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of Immunology, 2011; Gul, Tugal-Tutkun, et al. Ann Rheum Dis, 2012; Pettersson, Annais of Medicine Petterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordstrom, Knight, et al., The Journal of Rheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013; de Koning, Clin Transl Allergy, 2014). 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, et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013; Alexander Brett, et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al ., BioMed Research International, 2013; Byers, Alexander-B Rett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013; Martinez-Gonzalez, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Immunology, 2014; Lugrin, Parapanov, et al., The Journal of Immunology, 2015).
Aus dem Stand der Technik sind eine Vielzahl von IRAK4 Inhibitoren bekannt (siehe beispielsweise Annual Reports in Medicinal Chemistry (2014), 49, 117 - 133). A large number of IRAK4 inhibitors are known from the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).
WO2015091426 beschreibt Indazole wie Beispiel WO2015091426-64, die an der Position 2 mit einer Carboxamidseitenkette substituiert sind und IRAK-4 inhibieren. Benzimidazole werden jedoch nicht beschrieben. In WO2003030902 und in Bioorg. Med. Chem. Lett. 16 (2006) 2842-2845 sind 2-Amino- Imidazolderivate als IRAK4 Inhibitoren beschrieben worden. Imidazolderivate, die an der 2-Position einen Substituenten aufweisen, der über ein Kohlenstoffatom mit dem Imidazol verknüpft vorliegen, werden nicht beschrieben. WO 13042137 beschreibt Benzimidazole (vergleiche die Genetische Struktur WO 13042137) als IRAK4-Inhibitoren, die an Position 2 mit Morpholin substituiert sind, wobei das Morpholin über den Ringstickstoff mit dem Benzimidazol verknüpft ist. Des Weiteren sind die Benzimidazole an Position 1 nicht substituiert (vergleiche die Generische Struktur WO 13042137: X ist ausgewählt aus O, S, NH). Der Substituent R1 aus WO 13042137 ist ausgewählt aus Wasserstoff, Cyano, Halogen, Hydroxy, 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,
-NO2, -NR3R4, optional substituiertes Alkyl, Heterocycloalkyl oder Heteroaryl. R1 hat jedoch nicht die Bedeutung Alkoxy oder substituiertes Alkoxy. WO 13042137-48 (6'amino-N-(2-morpholino-lH- benzo[d]imidazol-6-yl)-[2,3'-bipyridine]-6-carboxamide) wird als einziges Benzimidazol-Derivat explizit offenbart. -NO 2 , -NR 3 R 4 , optionally substituted alkyl, heterocycloalkyl or heteroaryl. However, R 1 does not have the meaning alkoxy or substituted alkoxy. 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.
Figure imgf000010_0001
Figure imgf000010_0001
Generische Struktur WO 13042137 Generic structure WO 13042137
WO2006030031 beschreibt unter anderem Benzimidazole als positive allosterische Modulatoren des mGluR2, die an Position 1 mit Ci-Cö-Alkyl substituiert sein können. Eine Substitution mit Methyl ist jedoch nicht explizit offenbart. Ebenfalls sind keine Benzimidazole explizit offenbart. WO2004072069 beschreibt Benzimidazolcarboxamide als Vanilloid Rezeptor (VRl) Antagonisten für die Schmerzbehandlung, welche an der Carboxamidgruppe mit substituiertem Heteroaryl substituiert sein können. Als mögliche Heteroaryle sind Pyridyl, bevorzugt 3-Pyridyl, Isothiazolyl, Thiazolyl, Oxazolyl oder Pyrazolyl genannt. Des Weiteren können sie an Position 1 mit Ci-Ci2-Alkyl und an Position 5 mit Alkoxy substituiert sein. Es werden jedoch keine Alkoxyderivate an Position 5 explizit beschrieben. Explizit werden nur zwei Benzimidazole offenbart: WO2004072069-11 (N-(1H- Benzimidazol-6-yl)-6-(4-fluorophenyl)-2-methyl-nicotinamide) und WO2004072069-12 (6-(4- Fluorophenyl)-2-methyl-N-( 1 -methyl- 1 H-benzimidazol-6-yl)-nicotinamide). 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. Furthermore, they can be substituted with alkoxy at position 1 with Ci-Ci 2 alkyl and in position. 5 However, no alkoxy derivatives at position 5 are explicitly described. Explicitly only two benzimidazoles are disclosed: WO2004072069-11 (N- (1H-benzimidazol-6-yl) -6- (4-fluorophenyl) -2-methyl-nicotinamide) and WO2004072069-12 (6- (4-fluorophenyl) - 2-methyl-N- (1-methyl-1H-benzimidazol-6-yl) nicotinamide).
WO200157020 beschreibt Benzimidazole als Inhibitoren des Factor Xa. Die Benzimidazole können an Position 2 substituiert sein mit: WO200157020 describes benzimidazoles as inhibitors of factor Xa. The benzimidazoles may be substituted at position 2 with:
• Ci-Cs-Alkyl, welches jedoch nicht substituiert ist,  Ci-Cs-alkyl, which is not substituted,
• G-Cs-OR10, wobei R10 H sein kann, G-Cs-OR 10 , where R 10 can be H,
•
Figure imgf000010_0002
wobei R10 H oder Methyl sein kann •
Figure imgf000010_0002
where R 10 can be H or methyl
Es werden keine Alkylsubstituenten an Position 2 beschrieben, die mit einer Sulfongruppe substituiert sind.  No alkyl substituents at position 2 substituted with a sulfone group are described.
WO 2010042785 beschreibt die Verwendung von Benzimidazolen für negative Chemotaxis. Die beschriebenen Benzimidazole können an Position 5 mit Alkoxy substituiert sein. In WO 2013186229 werden TNF-alpha modulierende Benzimidazole beschrieben. 1-Methyl substituierte Benzimidazole werden jedoch nicht offenbart. 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. However, 1-methyl substituted benzimidazoles are not disclosed.
WO2007076092 beschreibt Benzimidazole als Raf-Kinase Modulator, welche an Position 5 jedoch nicht mit Alkoxy substituiert sind. Es werden also im Stand der Technik keine Benzimidazolderivate als IRAK4-Inhibitoren beschrieben, die gleichzeitig einen Alkoxyrest an Position 5, einen Acylaminorest an Position 6 und einen 1- Methylrest aufweisen. WO2007076092 describes benzimidazoles as Raf kinase modulator, which are substituted at position 5 but not with alkoxy. Thus, in the prior art, 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.
Die Aufgabe der vorliegenden Erfindung besteht darin, neue Verbindungen zur Verfügung zu stellen, die als Inhibitoren der Interleukin-1 Receptor Associated Kinase-4 (IRAK4) wirken. The object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (IRAK4).
Gegenstand der vorliegenden Erfindung sind Verbindungen der allgemeinen Formel (I) The present invention relates to compounds of the general formula (I)
Figure imgf000011_0001
Figure imgf000011_0001
(I)  (I)
in der: R1 für -C(=0)0(Ci-C3-Alkyl), R6S(=0)2-, R6S(=0)- oder für eine Gruppe steht, ausgewählt aus: in which: R 1 is -C (= O) O (C 1 -C 3 -alkyl), R 6 is S (= O) 2 -, R 6 is S (= O) - or represents a group selected from:
Figure imgf000011_0002
Figure imgf000011_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff, Ci-C3-Alkyl steht und R 5 is hydrogen, C 1 -C 3 -alkyl and
R6 für Ci-C t-Alkyl, Cyclopropyl, Cylopropylmethyl oder 2,2,2-Trifluorethyl steht; für Cyclopropylmethyl oder Ci-Cö-Alkyl, welches ein- bis dreifach mit Fluor substituiert kann, steht; R3 für Cs-Cö-Cycloalkyl oder Ci-Cö-Alkyl, welches ein- bis fünffach mit Fluor substituiert sein kann, steht; R4 für Wasserstoff oder Fluor steht; 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;
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze. Die neuen IRAK4 Inhibitoren sind insbesondere zur Behandlung und zur Prävention von proliferativen, metabolischen und entzündlichen Erkrankungen geeignet, die durch ein überreagierendes Immunsystem charakterisiert sind. Besonders genannt seien hier entzündliche Hauterkrankungen, Herz-Kreislauf-Erkrankungen, Lungenerkrankungen, Augenerkrankungen, neurologische Erkrankungen, Schmerzerkrankungen und Krebserkrankungen. as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. 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.
Des Weiteren sind die neuen IRAK4 Inhibitoren geeignet zur Behandlung und Prävention Furthermore, the new IRAK4 inhibitors are suitable for treatment and prevention
• von Autoimmun und inflammatorischen Erkrankungen, insbesondere Rheumatoide Arthritis, Multiple Sklerose, Systemischer Lupus Erythematodes, Spondyloarthritiden und Gicht,  Of autoimmune and inflammatory diseases, in particular rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, spondyloarthritis and gout,
· von Stoffwechselerkrankungen, insbesondere Lebererkrankungen wie Fettleber sowie · Of metabolic diseases, especially liver diseases such as fatty liver as well
• sowie Nierenerkrankungen, insbesondere chronische Nierenkrankheit, Nephropathien sowie• as well as kidney diseases, especially chronic renal disease, nephropathies as well
• von gynäkologischen Erkrankungen, insbesondere von Endometriose sowie von Endometriose-assoziierten Schmerzen und anderen Endometriose-assoziierten Symptomen wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie. • gynecological diseases, especially endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia.
Wenn bei den im Folgenden beschriebenen Synthese-Intermediaten und Ausführungsbeispielen der Erfindung eine Verbindung in der Form eines Salzes der korrespondierenden Base bzw. Säure aufgeführt ist, so ist die exakte stöchiometrische Zusammensetzung eines solchen Salzes, wie es nach dem jeweiligen Herstell- und/oder Reinigungsverfahren erhalten wurde, in der Regel nicht bekannt. Sofern nicht genauer spezifiziert, sind daher Namens- und Strukturformel -Zusätze wie beispielsweise "Hydrochlorid", "Trifluoracetat", "Natrium-Salz" bzw. "x HCl", "x CF3COOH", "x Na+" bei solchen Salzen nicht stöchiometrisch zu verstehen, sondern haben allein deskriptiven Charakter bezüglich der enthaltenen salzbildenden Komponenten. When a compound in the form of a salt of the corresponding base or acid is listed in the synthesis intermediates and embodiments of the invention described below, the exact stoichiometric composition of such a salt, as according to the respective preparation and / or purification process was received, usually unknown. Unless specified otherwise, name and structural formula additions such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF 3 COOH", "x Na + " are thus included in such salts not to understand stoichiometrically, but solely descriptive of the contained salt-forming components.
Sinngemäß gleiches gilt für den Fall, dass Synthese-Intermediate oder Ausführungsbeispiele oder Salze hiervon nach den beschriebenen Herstell- und/oder Reinigungsverfahren in Form von Solvaten, wie beispielsweise Hydraten, erhalten wurden, deren stöchiometrische Zusammensetzung (sofern definierter Art) nicht bekannt ist.  The same applies mutatis mutandis to the case that synthesis intermediates or embodiments or salts thereof according to the described preparation and / or purification processes in the form of solvates, such as hydrates, were obtained whose stoichiometric composition (if defined type) is not known.
Erfindungsgemäße Verbindungen sind die Verbindungen der Formel (I) und deren Salze, Solvate und Solvate der Salze, die von Formel (I) umfassten Verbindungen der nachfolgend genannten Formeln und deren Salze, Solvate und Solvate der Salze sowie die von Formel (I) umfassten, nachfolgend als Ausführungsbeispiele genannten Verbindungen und deren Salze, Solvate und Solvate der Salze, soweit es sich bei den von Formel (I) umfassten, nachfolgend genannten Verbindungen nicht bereits um Salze, Solvate und Solvate der Salze handelt. 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.
Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen bevorzugt. Umfasst sind aber auch Salze, die für pharmazeutische Anwendungen selbst nicht geeignet sind, aber beispielsweise für die Isolierung oder Reinigung der erfindungsgemäßen Verbindungen verwendet werden können.  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.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen Säureadditionssalze von Mineralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfonsäure, Toluolsulfonsäure, Benzolsulfonsäure, Naphthalindisulfonsäure, Essigsäure, Trifluoressigsäure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure und Benzoesäure.  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.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kaliumsalze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C- Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Methylmorpholin, Arginin, Lysin, Ethylendiamin und N-Methylpiperidin.  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.
Als Solvate werden im Rahmen der Erfindung solche Formen der erfindungsgemäßen Verbindungen bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungsmittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt.  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.
Die erfindungsgemäßen Verbindungen können in Abhängigkeit von ihrer Struktur in unterschiedlichen stereoisomeren Formen existieren, d.h. in Gestalt von Konfigurationsisomeren oder gegebenenfalls auch als Konformationsisomere (Enantiomere und/oder Diastereomere, einschließlich solcher bei Atropisomeren). Die vorliegende Erfindung umfasst deshalb die Enantiomere und Diastereomere und ihre jeweiligen Mischungen. Aus solchen Mischungen von Enantiomeren und/ oder Diastereomeren lassen sich die stereoisomer einheitlichen Bestandteile in bekannter Weise isolieren; vorzugsweise werden hierfür chromatographische Verfahren verwendet, insbesondere die HPLC -Chromatographie an achiraler bzw. chiraler Phase. 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.
Sofern die erfindungsgemäßen Verbindungen in tautomeren Formen vorkommen können, umfasst die vorliegende Erfindung sämtliche tautomere Formen. Die vorliegende Erfindung umfasst auch alle geeigneten isotopischen Varianten der erfindungsgemäßen Verbindungen. Unter einer isotopischen Variante einer erfindungsgemäßen Verbindung wird hierbei eine Verbindung verstanden, in welcher mindestens ein Atom innerhalb der erfindungsgemäßen Verbindung gegen ein anderes Atom der gleichen Ordnungszahl, jedoch mit einer anderen Atommasse als der gewöhnlich oder überwiegend in der Natur vorkommenden Atommasse ausgetauscht ist. Beispiele für Isotope, die in eine erfindungsgemäße Verbindung inkorporiert werden können, sind solche von Wasserstoff, Kohlenstoff, Stickstoff, Sauerstoff, Phosphor, Schwefel, Fluor, Chlor, Brom und Iod, wie 2H (Deuterium), 3H (Tritium), 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 1231, 1241, 1291 und 1311. Bestimmte isotopische Varianten einer erfindungsgemäßen Verbindung, wie insbesondere solche, bei denen ein oder mehrere radioaktive Isotope inkorporiert sind, können von Nutzen sein beispielsweise für die Untersuchung des Wirkmechanismus oder der Wirkstoffverteilung im Körper; aufgrund der vergleichsweise leichten Herstell- und Detektierbarkeit sind hierfür insbesondere mit 3H- oder 14C-Isotopen markierte Verbindungen geeignet. Darüber hinaus kann der Einbau von Isotopen, wie beispielsweise von Deuterium, zu bestimmten therapeutischen Vorteilen als Folge einer größeren metabolischen Stabilität der Verbindung führen, wie beispielsweise eine Verlängerung der Halbwertszeit im Körper oder eine Reduktion der erforderlichen Wirkdosis; solche Modifikationen der erfindungsgemäßen Verbindungen können daher gegebenenfalls auch eine bevorzugte Ausführungsform der vorliegenden Erfindung darstellen. Isotopische Varianten der erfindungsgemäßen Verbindungen können nach den dem Fachmann bekannten Verfahren hergestellt werden, so beispielsweise nach den weiter unten beschriebenen Methoden und den für die Ausführungsbeispiele angegebenen Vorschriften, indem entsprechende isotopische Modifikationen der jeweiligen Reagenzien und/oder Ausgangsverbindungen eingesetzt werden. Ein weiterer Gegenstand der vorliegenden Erfindung sind alle möglichen kristallinen und polymorphen Formen der erfindungsgemäßen Verbindungen, wobei die Polymorphe entweder als einzelne Polymorphe oder als Gemisch mehrerer Polymorphe in allen Mischungsverhältnissen vorliegen können. If the compounds according to the invention can occur in tautomeric forms, 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. Examples of 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. Certain 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. Moreover, the incorporation of 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; Such 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.
Außerdem umfasst die vorliegende Erfindung auch Prodrugs der erfindungsgemäßen Verbindungen. Der Begriff "Prodrugs" bezeichnet hierbei Verbindungen, welche selbst biologisch aktiv oder inaktiv sein können, jedoch während ihrer Verweilzeit im Körper zu erfindungsgemäßen Verbindungen umgesetzt werden (beispielsweise metabolisch oder hydrolytisch). In addition, the present invention also includes prodrugs of the compounds of the invention. The term "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).
Im Rahmen der vorliegenden Erfindung haben die Substituenten, soweit nicht anders spezifiziert, die folgenden Bedeutungen: Alkyl steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkylrest mit der jeweils angegebenen Anzahl an Kohlenstoffatomen. Beispielhaft seien 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 und 2-Ethylbutyl genannt. In the context of the present invention, the substituents, unless otherwise specified, have the following meanings: In the context of the invention, 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 steht im Rahmen der Erfindung für einen monocychschen, gesättigten Alkylrest mit der jeweils angegebenen Anzahl an Kohlenstoffatomen. Beispielhaft seien Cyclopropyl, Cyclobutyl, Cyclopentyl und Cyclohexyl genannt. 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.
Ein Symbol * an einer Bindung bedeutet die Verknüpfungsstelle im Molekül. A symbol * on a bond means the point of attachment in the molecule.
Wenn Reste in den erfindungsgemäßen Verbindungen substituiert sind, können die Reste, soweit nicht anders spezifiziert, ein- oder mehrfach substituiert sein. Im Rahmen der vorliegenden Erfindung gilt, dass für alle Reste, die mehrfach auftreten, deren Bedeutung unabhängig voneinander ist. If 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.
Eine weitere Ausführungsform von R1 ist -C(=0)OCH3,
Figure imgf000015_0001
oder eine Gruppe, ausgewählt aus: Another embodiment of R 1 is -C (= O) OCH 3,
Figure imgf000015_0001
or a group selected from:
Figure imgf000015_0002
Figure imgf000015_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff, Ci-C3-Alkyl steht und R 5 is hydrogen, C 1 -C 3 -alkyl and
R6 für Ci-C t-Alkyl, Cyclopropyl, Cylopropylmethyl oder 2,2,2-Trifluorethyl steht. R 6 is C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl.
Eine ebenfalls weitere Ausführungsform von R1 ist oder eine Gruppe, ausgewählt aus: Another embodiment of R 1 is or a group selected from:
Figure imgf000016_0001
Figure imgf000016_0001
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff, Ci-C3-Alkyl steht und R 5 is hydrogen, C 1 -C 3 -alkyl and
R6 für Ci-C t-Alkyl, Cyclopropyl, Cylopropylmethyl oder 2,2,2-Trifluorethyl steht. R 6 is C 1 -C 4 -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl.
Eine weitere Ausführungsform für R5 ist Wasserstoff oder Methyl. Another embodiment of R 5 is hydrogen or methyl.
Eine weitere Ausführungsform für R6 ist Methyl oder Ethyl. Another embodiment of R 6 is methyl or ethyl.
Eine ebenfalls weitere Ausführungsform für R6 ist Methyl. Another embodiment of R 6 is methyl.
Eine weitere Ausführungsform von R2 ist Ci-C t-Alkyl, 2,2,2-Trifluorethyl oder 2,2-Difluorethyl. Eine ebenfalls weitere Ausführungsform von R2 ist Methyl, Ethyl oder wo-Propyl. Another embodiment of R 2 is C 1 -C 4 -alkyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl. Another embodiment of R 2 is methyl, ethyl or where-propyl.
Eine ebenfalls weitere Ausführungsform von R2 ist Methyl oder Ethyl. Another embodiment of R 2 is methyl or ethyl.
Eine weitere Ausführungsform von R3 ist Cyclopropyl oder Ci-C t-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann. Another embodiment of R 3 is cyclopropyl or Ci-C t-alkyl, which may be mono- to trisubstituted by fluorine.
Eine ebenfalls weitere Ausführungsform von R3 ist Methyl, Ethyl, 2,2,2-Trifluorethyl, 1,1- Difluorethyl oder Trifluormethyl. Another embodiment of R 3 is methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl or trifluoromethyl.
Eine ebenfalls weitere Ausführungsform von R3 ist 1,1-Difluorethyl oder Trifluormethyl. Eine weitere Ausführungsform von R4 ist Wasserstoff. Another embodiment of R 3 is 1,1-difluoroethyl or trifluoromethyl. Another embodiment of R 4 is hydrogen.
Ein weiterer Gegenstand der vorliegenden Erfindung sind Verbindungen der Formel (I), in der R1 für -C(=0)0(Ci-C3 Alkyl), R6S(=0)2-, oder für eine Gruppe steht, ausgewählt aus: Another object of the present invention are compounds of formula (I), in which R 1 is -C (= 0) 0 (Ci-C 3 alkyl), R 6 S (= 0) 2 -, or represents a group, selected from:
Figure imgf000016_0002
Figure imgf000016_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff oder Methyl steht und R 5 is hydrogen or methyl and
R6 für Methyl oder Ethyl steht; R2 für Ci-C4-Alkyl, 2,2,2-Trifluorethyl oder 2,2-Difluorethyl steht; R 6 is methyl or ethyl; R 2 is C 1 -C 4 alkyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl;
R3 für Cyclopropyl oder Ci-C4-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann, steht; und R 3 is cyclopropyl or C 1 -C 4 -alkyl which may be substituted one to three times by fluorine; and
R4 für Wasserstoff steht. R 4 is hydrogen.
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze. as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
Ein weiterer Gegenstand der vorliegenden Erfindung sind außerdem Verbindungen der allgemeinen Formel (I), in der Another object of the present invention are also compounds of the general formula (I), in which
R1 für -C(=0)OMe, R6S(=0)2- oder für eine Gruppe steht, ausgewählt aus: R 1 is -C (= O) OMe, R 6 is S (= O) 2 - or is a group selected from:
Figure imgf000017_0001
Figure imgf000017_0001
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff oder Methyl steht und R 5 is hydrogen or methyl and
R6 für Methyl steht; R 6 is methyl;
R2 für Methyl, Ethyl oder wo-Propyl steht; R 2 is methyl, ethyl or where-propyl;
R3 für Methyl, Ethyl, 2,2,2-Trifluorethyl, 1,1-Difluorethyl oder Trifluormethyl steht; und R4 für Wasserstoff steht; R 3 is methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl or trifluoromethyl; and R 4 is hydrogen;
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze. as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
Ein weiterer Gegenstand der vorliegenden Erfindung sind Verbindungen, in denen Another object of the present invention are compounds in which
R1 für oder für eine Gruppe steht, ausgewählt aus: R 1 stands for or for a group selected from:
Figure imgf000017_0002
Figure imgf000017_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff oder Methyl steht und R 5 is hydrogen or methyl and
R6 für Methyl steht; R 6 is methyl;
für Methyl oder Ethyl steht;  is methyl or ethyl;
1,1-Difluorethyl oder Trifluormethyl steht; und  1,1-difluoroethyl or trifluoromethyl; and
für Wasserstoff steht; sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze. Gegenstand der vorliegenden Erfindung sind insbesondere die folgenden Verbindungen: is hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. The present invention particularly relates to the following compounds:
Figure imgf000018_0001
Figure imgf000018_0001
Die erfindungsgemäßen Verbindungen wirken als Inhibitoren der IRAK4 Kinase, und zeigen ein überraschendes, wertvolles pharmakologisches Wirkspektrum. Insbesondere inhibieren die Substanzen schwach oder gar nicht die Kinasen Flt3 (Fms-like tyrosine kinase 3) und Trk (tropomyosin-related kinase)-A, beides Kinasen, deren Inhibition mit möglichen Nebenwirkungen assoziert werden können (vergleiche Abschnitt„Kinaseassays", genauer siehe Abschnitt„Inhibition der IKAK4 Kinaseaktivtät und Selektivität gegenüber TrkA und Flt3"). Darüber hinaus zeigen die erfindungsgemäßen Verbindungen keinen Hinweis auf mutagenes Potential (vergleiche hierzu den Abschnitt„in vitro Mikrokerntest"). Daher ist neben den weiter oben genannten ein weiterer Gegenstand der vorliegenden Erfindung die Verwendung der erfindungsgemäßen Verbindungen zur Behandlung und/oder Prophylaxe von Krankheiten bei Menschen und Tieren. The compounds of the invention act as inhibitors of IRAK4 kinase, and show a surprising, valuable spectrum of pharmacological activity. In particular, 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"). Moreover, 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.
Die Behandlung und/oder Prophylaxe von gynäkologischen Erkrankungen, entzündlichen Hauterkrankungen, Herz-Kreislauf-Erkrankungen, Lungenerkrankungen, Augenerkrankungen, Autoimmunerkrankungen, Schmerzerkrankungen, Stoffwechselerkrankungen, Gicht, Lebererkrankungen, des metabolischen Syndroms, der Insulinresistenz, Nierenerkrankungen und von Krebserkrankungen mit den erfindungsgemäßen IRAK4 Inhibitoren ist besonders bevorzugt. The treatment and / or prophylaxis of 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.
Die erfindungsgemäßen Verbindungen sind geeignet für die Prophylaxe und/oder Behandlung von verschiedenen Erkrankungen und krankheitsbedingten Zuständen, insbesondere von TLR- (außer TLR3) und/oder IL- 1 -Rezeptorf amilie-vermittelten Erkrankungen bzw. Erkrankungen, dessen Pathologie direkt durch IRAK4 vermittelt ist. Als IRAK4-assoziierte Erkrankungen sind Multiple Sklerose, Atherosklerose, Herzinfarkt, Alzheimer, viral-induzierte Myokarditis, Gicht, Vogt- Koyanagi-Harada-Syndrom, Lupus erythematodes, Psoriasis, Spondyloarthritiden und Arthritis zu benennen. 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.
Die erfindungsgemäßen Verbindungen können ferner für die Prophylaxe und/oder Behandlung von MyD88- und TLR (außer TLR3)- vermittelte Erkrankungen eingesetzt werden. Dies umfasst Multiple Sklerose, Rheumatoide Arthritis, Spondyloarthritiden (insbesondere Spondylarthritis psoriatica und Morbus Bechterew), Metabolisches Syndrom inklusive Insulinresistenz, Diabetes mellitus, Osteoarthritis, Sjögren-Syndrom, Riesenzellarteriitis, Sepsis, Poly- und Dermatomyositis, Hauterkrankungen wie Psoriasis, atopische Dermatitis, Alopecia areata, Acne inversa und Acne vulgaris, pulmonale Erkrankungen wie Lungenfibrose, chronisch obstruktive Lungenerkrankung (COPD), akutes Atemnot-Syndrom (ARDS), akute Lungenschädigung (ALI), interstitielle Lungenerkrankung (ILD), Sarkoidose und pulmonale Hypertonie.  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.
Aufgrund des Wirkmechanismus der erfindungsgemäßen Verbindungen sind sie zur Prophylaxe und/oder Behandlung der TLR-vermittelten Erkrankungen Behcet-Krankheit, Gicht, Endometriose sowie von Endometriose- assoziierten Schmerzen und anderen Endometriose-assoziierten Symptomen wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie geeignet. Des Weiteren sind die erfindungsgemäßen Verbindungen zur Prophylaxe und/oder Behandlung bei Transplantatab stoßung, von Lupus erythematodes, Adult Morbus Still-Krankheit und chronisch entzündlichen Darmerkrankungen wie Kolitis ulcerosa und Morbus Crohn geeignet. Due to the mechanism of action of the compounds according to the invention, they 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.
Neben den bereits aufgeführten Erkrankungen ist die Verwendung der erfindungsgemäßen Verbindungen auch zur Behandlung und/oder Prävention folgender Erkrankungen geeignet: Augenerkrankungen wie Keratitis, allergisch bedingte Konjunktivitis, Keratoconjunctivitis sicca, Makuladegeneration und Uveitis; kardiovaskuläre Erkrankungen wie Atherosklerose, myokardialer Reperfusionsschaden, Myokardinfarkt, Hypertonie und neurologische Erkrankungen wie Alzheimer, Schlaganfall und Parkinson.  In addition to the diseases already mentioned, 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.
Der Wirkmechanismus der erfindungsgemäßen Verbindungen ermöglicht ferner die Prophylaxe und/oder Behandlung von TLR- und IL-1 Rezeptorfamilie vermittelten Lebererkrankungen, insbesondere NAFLD, NASH, ASH, Leberfibrose und Leberzirrhose. Weiterhin sind die erfindungsgemäßen Verbindungen zur Prophylaxe und/ oder Behandlung von TLR- und IL-1 Rezeptorfamilie vermittelten Nierenerkrankungen, insbesondere chronische Nierenkrankheit und Nephropathien geeignet. 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.
Weiterhin ist die Prophylaxe und/oder Behandlung von Juckreiz und Schmerz, insbesondere von akutem, chronischem, entzündlichem und neuropathischem Schmerz durch die erfindungsgemäßen Verbindungen gegeben. Furthermore, 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.
Aufgrund des Wirkmechanismus der erfindungsgemäßen Verbindungen sind sie zur Prophylaxe und/oder Behandlung von onkologischen Erkrankungen wie Lymphome, chronisch lymphatische Leukämie, Melanoma und Leberzellkarzinom, Brustkrebs, Prostatakrebs und Ras-abhängige Tumore geeignet.  Due to the mechanism of action of the compounds of the invention they 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.
Außerdem sind die erfindungsgemäßen Verbindungen geeignet zur Behandlung und/oder Prävention von Erkrankungen, die über die IL-1 Rezeptorfamilie vermittelt sind. Diese Erkrankungen umfassen CAPS (Cryopyrin-assoziierte periodische Syndrome) inklusive FCAS (familiäre Kälteurtikaria), MWS (Mückle- Wells-Syndrom), NOMID- (neonatal-onset multisystem inflammatory disease) und CONCA- (chronic infantile, neurological, cutaneous, and articular) Syndrom, FMF (familiäres Mittelmeerfieber), HIDS (Hyper-IgD-Syndrom), TRAPS (Tumornekrosefaktor- Rezeptor 1- assoziiertes periodisches Syndrom), juvenile idiopathische Arthritis, Adult Morbus Still-Krankheit, Morbus Adamantiades-Behcet, Rheumatoide Arthritis, Psoriasis Arthritis, Morbus Bechterew, Osteoarthritis, Keratoconjunctivitis sicca und Sjögren Syndrome, Multiple Sklerose, Lupus erythematodes, Alopecia areata, Diabetes mellitus Typ 1, Diabetes mellitus Typ 2 und die Folgen eines Myokardinfarktes. Pulmonale Erkrankungen wie Asthma, COPD, idiopathische interstitielle Pneumonie und ARDS, gynäkologische Erkrankungen wie Endometriose sowie Endometriose- assoziierte Schmerzen und andere Endometriose-assoziierte Symptome wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie, chronisch-entzündliche Darmerkrankungen wie Morbus Crohn und Kolitis ulcerosa sind mit einer Dysregulation der IL-1 Rezeptorfamilie assoziiert und für den therapeutischen und/oder prophylaktischen Einsatz der erfindungsgemäßen Verbindungen geeignet. Die erfindungsgemäßen Verbindungen können ferner für Behandlung und/oder Prävention von IL 1 Rezeptorfamilie-vermittelten neurologischen Erkrankungen wie Hirnschlag, Alzheimer, Schlaganfall, Schädel-Hirn-Trauma und dermatologische Erkrankungen wie Psoriasis, atopische Dermatitis, Acne inversa, Alopecia areata und allergische Kontaktdermatitis eingesetzt werden.  In addition, the compounds of the invention are useful for the treatment and / or prevention of diseases mediated via the IL-1 receptor family. These 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 erythematosus, alopecia areata, diabetes mellitus type 1, diabetes mellitus type 2 and the consequences of myocardial infarction. 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 ,
Weiterhin sind die erfindungsgemäßen Verbindungen geeignet für die Behandlung und/oder Prophylaxe von Schmerzerkrankungen, insbesondere von akutem, chronischem, entzündlichem und neuropathischem Schmerz. Hierfür seien vorzugsweise Hyperalgesie, Allodynie, Schmerz bei Arthritis (wie Osteoarthritis, rheumatoider Arthritis und Spondylarthritis), prämenstrueller Schmerz, Endometriose-assoziierter Schmerz, postoperativer Schmerz, Schmerz bei interstitieller Zystitis, CRPS (komplexes regionales Schmerzsyndrom), Trigeminusneuralgie, Schmerz bei Prostatitis, Schmerzen verursacht durch Rückenmarksverletzungen, entzündungsinduzierter Schmerz, Kreuzschmerzen, Krebsschmerzen, Chemotherapie-assoziierter Schmerz, HIV behandlungsinduzierte Neuropathie, Verbrennungs-induzierter Schmerz und chronischer Schmerz genannt. Furthermore, 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. These are preferably 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.
Im Weiteren ist Gegenstand der vorliegenden Erfindung auch ein Verfahren zur Behandlung und/oder Prävention von Erkrankungen, insbesondere der zuvor genannten Erkrankungen, unter Verwendung einer wirksamen Menge von mindestens einer der erfindungsgemäßen Verbindungen. Furthermore, 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.
Im Sinne der vorliegenden Erfindung umfasst der Begriff "Behandlung" oder "behandeln" ein Hemmen, Verzögern, Aufhalten, Lindern, Abschwächen, Einschränken, Verringern, Unter-drücken, Zurückdrängen oder Heilen einer Krankheit, eines Leidens, einer Erkrankung, einer Verletzung oder einer gesundheitlichen Störung, der Entfaltung, des Verlaufs oder des Fortschreitens solcher Zustände und/oder der Symptome solcher Zustände. Der Begriff "Therapie" wird hierbei als Synonym mit dem Begriff "Behandlung" verstanden. For the purposes of the present invention, the term "treatment" or "treating" 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. The term "therapy" is hereby understood to be synonymous with the term "treatment".
Die Begriffe "Prävention", "Prophylaxe" oder "Vorbeugung" werden im Rahmen der vorliegenden Erfindung synonym verwendet und bezeichnen das Vermeiden oder Vermindern des Risikos, eine Krankheit, ein Leiden, eine Erkrankung, eine Verletzung oder eine gesundheitliche Störung, eine Entfaltung oder ein Fortschreiten solcher Zustände und/oder die Symptome solcher Zustände zu bekommen, zu erfahren, zu erleiden oder zu haben. The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote 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.
Die Behandlung oder die Prävention einer Krankheit, eines Leidens, einer Erkrankung, einer Verletzung oder einer gesundheitlichen Störung können teilweise oder vollständig erfolgen. The treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
Die erfindungsgemäßen Verbindungen können allein oder bei Bedarf in Kombination mit anderen Wirkstoffen eingesetzt werden. Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, enthaltend mindestens eine der erfindungsgemäßen Verbindungen und einen oder mehrere weitere Wirkstoffe, insbesondere zur Behandlung und/oder Prävention der zuvor genannten Erkrankungen. Als geeignete Kombinationswirkstoffe seien beispielhaft und vorzugsweise genannt: 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. As suitable combination active ingredients may be mentioned by way of example and preferably:
Allgemein sind Wirkstoffe wie antibakterielle (z.B. Penicilline, Vancomycin, Ciprofloxacin), antivirale (z.B. Aciclovir, Oseltamivir) und antimykotische (z.B. Naftifin, Nystatin) Substanzen und Gammaglobuline, immunomodulatorische und immunosuppressive Verbindungen wie Cyclosporin, Methotrexat®, TNF- Antagonisten (z.B. Humira®,, Etanercept, Infliximab), IL-1 Inhibitoren (z.B. Anakinra, Canakinumab, Rilonacept), Phosphodiesterasehemmer (z.B Apremilast), Jak/STAT Inhibitoren (z.B. Tofacitinib, Baricitinib, GLPG0634), Leflunomid, Cyclophosphamid, Rituximab, Belimumab, Tacrolimus, Rapamycin, Mycophenolate mofetil, Interferone, Corticosteroide (z.B. Prednisone, Prednisolone, Methylprednisolone, Hydrocortisone, Betamethason), Cyclophosphamide, Azathioprine und Sulfasalazine; Paracetamol, non-steroidale anti-inflammatorische Substanzen (NSAIDS) (z.B. Aspirin, Ibuprofen, Naproxen, Etodolac, Celecoxib, Colchicine) zu nennen. Für die Tumortherapie seien zu nennen: Immunotherapie (z.B. Aldesleukin, Alemtuzumab, Basiliximab, Catumaxomab, Celmoleukin, Denileukin-Diftitox, Eculizumab, Edrecolomab, Gemtuzumab, Ibritumomab-Tiuxetan, Imiquimod, Interferon-alpha, Interferon-beta, Interferon- gamma, Ipilimumab, Lenalidomid, Lenograstim, Mifamurtid, Ofatumumab, Oprelvekin, Picibanil, Plerixafor, Polysaccharid-K, Sargramostim, Sipuleucel-T, Tasonermin, Teceleukin, Tocilizumab), antiproliferative Substanzen wie beispielsweise aber nicht ausschließlich Amsacrin, Arglabin, Arsentrioxid, Asparaginase, Bleomycin, Busulfan, Dactinomycin, Docetaxel, Epirubicin, Peplomycin, Trastuzumab, Rituximab, Obinutuzumab, Ofatumumab, Tositumomab, Aromatase Inhibitoren (z.B. Exemestan, Fadrozol, Formestan, Letrozol, Anastrozol, Vorozol), Antiestrogene (z.B. Chlormadinon, Fulvestrant, Mepitiostan, Tamoxifen, Raloxifen, Toremifen), Estrogene (z.B. Estradiol, Polyestradiolphosphat), Gestagene (z.B. Medroxyprogesteron, Megestrol), Topoisomerase I Inhibitoren (z.B. Irinotecan, Topotecan), Topoisomerasen II Inhibitoren (z.B. Amrubicin, Daunorubicin, Elliptiniumacetat, Etoposid, Idarubicin, Mitoxantron, Teniposid), Mikrotubuli-aktive Substanzen (z.B. Cabazitaxel, Eribulin, Paclitaxel, Vinblastin, Vincristin, Vindesin, Vinorelbin), Telomeraseinhibitoren (z.B. Imetelstat), alkylierende Substanzen und Histon-Deacetylasen Inhibitoren (z.B. Bendamustin, Carmustin, Chlormethin, Dacarbazin, Estramustin, Ifosfamid, Lomustin, Mitobronitol, Mitolactol, Nimustin Prednimustin, Procarbazin, Ranimustin, Streptozotocin, Temozolomid, Thiotepa, Treosulfan, Trofosfamid, Vorinostat, Romidepsin, Panobinostat); Substanzen, die Prozesse der Zelldifferenzierung beeinflussen wie Abarelix, Aminoglutethimid, Bexaroten, MMP Inhibitoren (Peptidmimetika, Nicht-Peptidmimetika und Tetracycline wie z.B. Marimastat, BAY 12-9566, BMS-275291, Clodronate, Prinomastat, Doxycycline), mTOR Inhibitoren (z.B. Sirolimus, Everolimus, Temsirolimus, Zotarolimus), Antimetabolite (z.B. Clofarabin, Doxifluridin, Methotrexat, 5-Fluoruracil, Cladribin, Cy tarabin, Fludarabin, Mercaptopurin, Methotrexat, Pemetrexed, Raltitrexed, Tegafur, Tioguanin), Platin Verbindungen (z.B. Carboplatin, Cisplatin, Cisplatinum, Eptaplatin, Lobaplatin, Miriplatin, Nedaplatin, Oxaliplatin); Antiangiogene Verbindungen (z.B. Bevacizumab), antiandrogene Verbindungen (z.B. Bevacizumab, Enzalutamid, Flutamid, Nilutamid, Bicalutamid, Cyproteron, Cyproteronacetat), Proteasomeinhibitoren (z.B. Bortezomib, Carfilzomib, Oprozomib, ONYX0914), Gonadoliberin- Agonisten und -Antagonisten (z.B. Abarelix, Buserelin, Deslorelin, Ganirelix, Goserelin, Histrelin, Triptorelin, Degarelix, Leuprorelin), Methionine Aminopeptidase Inhibitoren (z.B. Bengamid-Derivate, TNP-470, PPI-2458), Heparanaseinhibitoren (z.B. SSTOOOl, PI-88); Inhibitoren gegen genetisch verändertes Ras-Protein (z.B. Farnesyl-Transferase Inhibitoren wie Lonafarnib, Tipifarnib), HSP90 Inhibitoren (z.B. Geldamycin-Derivate wie 17-Allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17- DMAG, Retaspimycin Hydrochloride, IPI-493, AUY922, BIIB028, STA-9090, KW-2478), Kinesin Spindieprotein Inhibitoren (z.B. SB715992, SB743921, Pentamidine/Chlorpromazine), MEK (mitogen-activated protein kinase kinase) Inhibitoren (z.B. Trametinib, BAY 86-9766 (Refametinib), AZD6244), Kinase-Inhibitoren (z.B.: Sorafenib, Regorafenib, Lapatinib, Sutent, Dasatinib, Cetuximab, BMS-908662, GSK2118436, AMG 706, Erlotinib, Gefitinib, Imatinib, Nilotinib, Pazopanib, Roniciclib, Sunitinib, Vandetanib, Vemurafenib), Hedgehog Signalinhibitoren (z.B. Cyclopamin, Vismodegib), BTK (Bruton's Tyrosine Kinase) Inhibitor (z.B. ibrutinib), JAK/pan-JAK (Janus Kinase) Inhibitor (z.B. SB-1578, Baricitinib, Tofacitinib, Pacritinib, Momelotinib, Ruxolitinib, VX-509, AZD-1480, TG-101348), PI3K Inhibitor (z.B. BAY 1082439, BAY 80-6946 (Copanlisib), ATU-027, SF-1126, DS-7423, GSK-2126458, Buparlisib, PF-4691502, BYL-719, XL-147, XL-765, Idelalisib), SYK (Spleen Tyrosine Kinase) Inhibitor (z.B. Fostamatinib, Excellair, PRT-062607), p53- Gentherapie, Bisphosphonate (z.B. Etridonat, Clodronat, Tiludronat, Pamidronat, Alendronsäure, Ibandronat, Risedronat, Zoledronat). Zur Kombination sind außerdem beispielhaft, aber nicht ausschließlich folgende Wirkstoffe zu nennen: Rituximab, Cyclophosphamide, Doxorubicin, Doxorubicin in Kombination mit Estron, Vincristine, Chlorambucil, Fludarabin, Dexamethasone, Cladribin, Prednisone, 1311-chTNT, Abirateron, Aclarubicin, Alitretinoin, Bisantren, Calciumfolinat, Calciumlevofolinat, Capecitabin, Carmofur, Clodronsäure, Romiplostim, Crisantaspase, Darbepoetin- alfa, Decitabin, Denosumab, Dibrospidiumchlorid, Eltrombopag, Endostatin, Epitiostanol, Epoetin- alfa, Filgrastim, Fotemustin, Galliumnitrat, Gemcitabin, Glutoxim, Histamindihydrochlorid, Hydroxycarbamid, Improsulfan, Ixabepilon, Lanreotid, Lentinan, Levamisol, Lisurid, Lonidamin, Masoprocol, Methyltestosteron, Methoxsalen, Methylaminolevulinat, Miltefosin, Mitoguazon, Mitomycin, Mitotan, Nelarabin, Nimotuzumab, Nitracrin, Omeprazol, Palifermin, Panitumumab, Pegaspargase, PEG-epoetin-beta (Methoxy-PEG-epoetin-beta), Pegfilgrastim, Peg-interferon-alfa-2b, Pentazocin, Pentostatin, Perfosfamid, Pirarubicin, Plicamycin, Poliglusam, Porfimer-Natrium, Pralatrexat, Quinagolid, Razoxan, Sizofiran, Sobuzoxan, Natriumglycididazol, Tamibaroten, die Kombination von Tegafur und Gimeracil und Oteracil, Testosteron, Tetrofosmin, Thalidomid, Thymalfasin, Trabectedin, Tretinoin, Trilostan, Tryptophan, Ubenimex, Vapreotid, Yttrium-90- Glasmikrokugeln, Zinostatin, Zinostatin-Stimalamer. In general, 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, interferons, corticosteroids (eg, prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine and sulfasalazine; Paracetamol, non-steroidal anti-inflammatory substances (NSAIDS) (eg aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine). For tumor therapy, mention should be made of: 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, asparaginase, bleomycin, busulfan, Dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, obinutuzumab, ofatumumab, toositumomab, aromatase inhibitors (eg exemestane, fadrozole, formestan, letrozole, anastrozole, vorozole), antiestrogens (eg chlormadinone, fulvestrant, mepitiostane, tamoxifen, raloxifene, toremifene) , Estrogens (eg, estradiol, polyestradiol phosphate), progestagens (eg, medroxyprogesterone, megestrol), topoisomerase I In hibitors (eg irinotecan, topotecan), topoisomerases II inhibitors (eg amrubicin, daunorubicin, elliptinium acetate, etoposide, idarubicin, mitoxantrone, teniposide), microtubule-active substances (eg cabazitaxel, eribulin, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine), telomerase inhibitors (eg imetelstat), alkylating agents and histone deacetylases inhibitors (eg bendamustine, carmustine, chlormethine, dacarbazine, estramustine, ifosfamide, lomustine, mitobronitol, mitolactol, nimustine prednimustine, procarbazine, ranimustine, streptozotocin, temozolomide, thiotepa, treosulfan, trofosfamide, vorinostat , Romidepsin, panobinostat); Substances that influence processes of cell differentiation such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptide mimetics, non-peptide mimetics and tetracyclines such as marimastat, BAY 12-9566, BMS-275291, clodronate, prinomastate, doxycycline), mTOR inhibitors (eg sirolimus, Everolimus, temsirolimus, zotarolimus), antimetabolites (eg clofarabine, doxifluridine, methotrexate, 5-fluorouracil, cladribine, tarabin, fludarabine, mercaptopurine, methotrexate, pemetrexed, raltitrexed, tegafur, tioguanine), platinum compounds (eg carboplatin, cisplatin, cisplatinum, Eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin); Antiangiogenic compounds (eg bevacizumab), antiandrogenic compounds (eg bevacizumab, enzalutamide, flutamide, nilutamide, bicalutamide, cyproterone, cyproterone acetate), proteasome inhibitors (eg bortezomib, carfilzomib, oprozomib, ONYX0914), gonadoliberin agonists and antagonists (eg abarelix, buserelin, Deslorelin, ganirelix, goserelin, histrelin, triptorelin, degarelix, leuprorelin), methionine aminopeptidase inhibitors (eg bengamide derivatives, TNP-470, PPI-2458), heparanase inhibitors (eg SSTOOOI, PI-88); Inhibitors against genetically modified ras protein (eg farnesyl-transferase inhibitors such as lonafarnib, tipifarnib), HSP90 inhibitors (eg geldamycin derivatives such as 17-allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17-DMAG, retaspimycin hydrochloride, IPI-493, AUY922 , BIIB028, STA-9090, KW-2478), kinesin spindie protein inhibitors (eg SB715992, SB743921, pentamidine / chlorpromazine), MEK (mitogen-activated protein kinase kinase) inhibitors (eg trametinib, BAY 86-9766 (Refametinib), AZD6244) , Kinase inhibitors (eg: sorafenib, regorafenib, lapatinib, sutent, dasatinib, Cetuximab, BMS-908662, GSK2118436, AMG 706, erlotinib, gefitinib, imatinib, nilotinib, pazopanib, roniciclib, sunitinib, vandetanib, vemurafenib), hedgehog signal inhibitors (eg, cyclopamine, vismodegib), BTK (Bruton's tyrosine kinase) inhibitor (eg, ibrutinib) , JAK / pan-JAK (Janus kinase) inhibitor (eg SB-1578, baricitinib, tofacitinib, pacritinib, momelotinib, ruxolitinib, VX-509, AZD-1480, TG-101348), PI3K inhibitor (eg BAY 1082439, BAY 80- 6946 (copanlisib), ATU-027, SF-1126, DS-7423, GSK-2126458, buparlisib, PF-4691502, BYL-719, XL-147, XL-765, idelalisib), SYK (spleen tyrosine kinase) inhibitor ( eg fostamatinib, Excellair, PRT-062607), p53 gene therapy, bisphosphonates (eg, etridonate, clodronate, tiludronate, pamidronate, alendronic acid, ibandronate, risedronate, zoledronate). Also to be mentioned by way of example, but not exclusively, 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 dihydrochloride, hydroxycarbamide, improversulfan, Ixabepilone, Lanreotide, Lentinan, Levamisole, Lisuride, Lonidamine, Masoprocol, Methyltestosterone, Methoxsalen, Methylaminolevulinate, Miltefosine, Mitoguazone, Mitomycin, Mitotane, Nelarabine, Nimotuzumab, Nitracrin, Omeprazole, Palifermin, Panitumumab, Pegaspargase, PEG-epoetin-beta (Methoxy) PEG-epoetin-beta), pegfilgrastim, peg-interferon-alfa-2b, P entazocin, pentostatin, perfosfamide, pirarubicin, plicamycin, poliglusam, porfimer sodium, pralatrexate, quinagolide, razoxan, sizofiran, sobuzoxan, sodium glycididazole, tamibaroten, the combination of tegafur and gimeracil and oteracil, testosterone, tetrofosmin, thalidomide, thymalfasin, trabectedin, tretinoin , Trilostane, Tryptophan, Ubenimex, Vapreotide, Yttrium-90 Glass Microspheres, Zinostatin, Zinostatin Stimalamer.
Für die Tumortherapie geeignet ist auch eine Kombination aus nicht-medikamentöser Therapie wie Chemotherapie (z.B. Azacitidin, Belotecan, Enocitabine, Melphalan, Valrubicin, Vinflunin, Zorubicin), Radiotherapie (z.B. I-125-Seeds, Palladium-103-Seed, Radium-223-chlorid) oder Phototherapie (z.B. Temoporfin, Talaporfin), die von einer medikamentösen Behandlung mit den erfindungsgemäßen IRAK4 Inhibitoren begleitet werden oder die nach Beendigung der nichtmedikamentösen Tumortherapie wie Chemotherapie, Radiotherapie oder Phototherapie durch eine medikamentöse Behandlung mit den erfindungsgemäßen IRAK4 Inhibitoren ergänzt werden. Also suitable for tumor therapy is a combination of 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.
Die erfindungsgemäßen IRAK4 Inhibitoren können außer mit den bereits genannten auch mit folgenden Wirkstoffen kombiniert werden: The IRAK4 inhibitors according to the invention can, in addition to those already mentioned, also be combined with the following active substances:
Wirkstoffe für die Alzheimertherapie wie beispielsweise Acetylcholinesterase-Hemmern (z.B. Donepezil, Rivastigmine, Galantamin, Tacrin), NMDA (N-Methyl-D-Aspartat)-Rezeptorantagonisten (z.B. Memantine); L-DOPA/Carbidopa (L-3,4-Dihydroxyphenylalanin), COMT (Catechol-O- Methyl transferase) -Hemmer (z.B. Entacapon), Dopaminagonisten (z.B. Ropinrol, Pramipexol, Bromocriptin), MAO-B (Monoaminooxidase-B)-Hemmer (z.B. Selegilin), Anticholinergika (z.B. Trihexyphenidyl) und NMDA- Antagonisten (z.B. Amantadin) zur Behandlung von Parkinson; Beta- Interferon (IFN-beta) (z.B. IFN beta-lb, IFN beta-la Avonex® und Betaferon®), Glatirameracetat, Immunglobuline, Natalizumab, Fingolimod und Immunsuppressiva wie Mitoxantron, Azathioprin und Cyclophosphamid zur Behandlung der Multiplen Sklerose; Substanzen zur Behandlung von pulmonalen Erkrankungen wie beispielsweise Beta-2-Sympathomimetika (z.B. Salbutamol), Anticholinergika (z.B. Glycopyrronium), Methylxanthine (z.B. Theophyllin), Leukotrienrezeptor- Antagonist (z.B. Montelukast), PDE-4 (Phosphodiesterase Typ 4)-Hemmer (z.B. Roflumilast), Methotrexat, IgE Antikörper, Azathioprin und Cyclophosphamid, Kortisolhaltige Präparate; Substanzen zur Behandlung von Osteoarthritis wie non-steroidale anti-inflammatorische Substanzen (NSAIDs). Neben den zwei genannten Therapien sind für rheumatoide Erkrankungen wie beispielsweise rheumatoide Arthritis, Spondyloarthritiden und juvenile idiopathische Arthritis Methotrexat Leflunomid, Jak/STAT Inhibitoren (z.B. Tofacitinib, Baricitinib, GLPG0634), TNF- Antagonisten (z.B. Humira®,, Etanercept, Infliximab), IL-1 Inhibitoren (z.B. Anakinra, Canakinumab, Rilonacept), und Biologika zur B-Zell- und T-Zell-Therapie (z.B. Rituximab, Abatacept) zu nennen. Neurotrophe Substanzen wie Acetylcholinesterase Inhibitoren (z.B. Donepezil), MAO (Monoaminooxidase) Inhibitoren (z.B. Selegilin), Interferone und Antikonvulsivum (z.B. Gabapentin); Wirkstoffe zur Behandlung von kardiovaskulären Erkrankungen wie beta-Blocker (z.B. Metoprolol), ACE Inhibitoren (z.B. Benazepril), Angiotensin-Rezeptorblocker (z.B. Losartan, Valsartan), Diuretika (z.B. Hydrochlorothiazid), Calciumkanal-Blocker (z.B. Nifedipin), Statine (z.B. Simvastatin, Fluvastatin); Anti-Diabetika wie z.B. Metformin, Glinide (z.B. Nateglinid), DPP-4 (Dipeptidyl-Peptidase-4)-Inhibitoren (z.B. Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin), SGLT2 (sodium/glucose cotransporter 2)-Inhibitoren/ Gliflozin (z.B. Dapagliflozin, Empagliflozin), Inkretinmimetika (Hormone Glukoseabhängiges insulinotropes Peptid (GIP)- und Glucagon-like Peptid 1 (GLP-l)-Analoga/Agonisten) (z.B. Exenatid, Liraglutid, Lixisenatide), a-Glucosidase- Hemmer (z.B. Acarbose, Miglitol, Voglibiose) und Sulfonylharnstoffe (z.B. Glibenclamid, Tolbutamid), Insulin-Sensitizer (z.B. Pioglitazon) und Insulintherapie (z.B. NPH-Insulin, Insulin lispro), Substanzen zur Behandlung einer Hypoglykämie zur Behandlung von Diabetes und metabolischem Syndrom. Lipidsenker wie beispielsweise Fibrate (z.B. Bezafibrat, Etofibrat, Fenofibrat, Gemfibrozil), Nikotinsäurederivate (z.B. Nicotinsäure/Laropiprant), Ezetimib, Statine (z.B. Simvastatin, Fluvastatin), Anionenaustauscher (z.B. Colestyramin, Colestipol, Colesevelam). Wirkstoffe wie Mesalazin, Sulfasalazin, Azathioprin, 6-Mercaptopurin oder Methotrexat, probiotische Bakterien (Mutaflor, VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), Antibiotika wie beispielsweise Ciprofloxacin und Metronidazol, Antidiarrhoika wie z.B. Loperamid oder Laxativa (Bisacodyl) zur Behandlung von chronisch-entzündlichen Darmerkrankungen. Immunsuppressiva wie Glucocorticoide und non-steroidale anti-inflammatorische Substanzen (NSAIDs), Cortison, Chloroquin, Cyclosporin, Azathioprin, Belimumab, Rituximab, Cyclophosphamid zur Behandlung von Lupus erythematodes. Beispielhaft aber nicht ausschließlich Calcineurinhemmer (z.B. Tacrolimus und Ciclosporin), Zellteilungshemmer (z.B. Azathioprin, Mycophenolat Mofetil, Mycophenolsäure, Everolimus oder Sirolimus), Rapamycin, Basiliximab, Daclizumab, Anti-CD3-Antikörper, Anti-T-Lymphozytenglobulin/Anti-Lymphozytenglobulin bei Organtransplantation. Vitamin D3-Analoga wie beispielsweise Calcipotriol, Tacalcitol oder Calcitriol; Salicylsäure, Harnstoff, Ciclosporin, Methotrexat, Efalizumab bei dermatologischen Erkrankungen. Glucocorticoide (z.B. Prednisone), immunosupressive Substanzen wie beispielsweise Azathioprine, Cyclophosphamid, Mycophenolat Mofetil; Hydro xychloroquin, ACE Inhibitoren (z.B. Captopril, Benazepril, Enalapril, Fosinopril), Angiotensin-Rezeptorblocker (z.B. Losartan, Valsartan), beta- Blocker (z.B. Metoprolol), Calciumkanal-Blocker (z.B. Nifedipin), und Immunsuppressiva wie z.B. Ciclosporin zur Behandlung von Nierenerkrankungen, Nephropathien und glomeruläre Krankheiten. Weiterhin seien Arzneimittel genannt, die mindestens eine der erfindungsgemäßen Verbindungen und einen oder mehrere weitere Wirkstoffe enthalten, insbesondere EP4-Inhibitoren (Prostaglandin E2 Receptor 4 Inhibitoren), P2X3- Inhibitoren (P2X Purinoceptor 3), PTGES -Inhibitoren (Prostaglandin E Synthase Inhibitoren) oder AKRlC3-Inhibitoren (Aldo-keto reductase family 1 member C3 Inhibitoren), zur Behandlung und/oder Prävention der zuvor genannten Erkrankungen. 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®), glatiramer acetate, immunoglobulins, natalizumab, fingolimod and immunosuppressants such as mitoxantrone, azathioprine and cyclophosphamide for the treatment of multiple sclerosis; Substances for the treatment of pulmonary diseases such as beta-2-sympathomimetics (eg salbutamol), anticholinergics (eg glycopyrronium), methylxanthines (eg theophylline), leukotriene receptor antagonist (eg montelukast), PDE-4 (phosphodiesterase type 4) inhibitors (eg Roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, cortisol containing preparations; Substances for the treatment of osteoarthritis such as non-steroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned above, for 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). 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), SGLT2 (sodium / glucose cotransporter 2) inhibitors / gliflozin (eg Dapagliflozin, empagliflozin), incretin mimetics (hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) analogs / agonists) (eg exenatide, liraglutide, lixisenatide), a-glucosidase inhibitors (eg acarbose, miglitol , Voglibiose) and sulfonylureas (eg glibenclamide, tolbutamide), insulin sensitizers (eg pioglitazone) and insulin therapy (eg NPH insulin, insulin lispro), substances for the treatment of hypoglycaemia for the treatment of diabetes and metabolic syndrome. 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. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics such as ciprofloxacin and metronidazole, antidiarrheals such as loperamide or laxatives (bisacodyl) for the treatment of chronic inflammatory Intestinal diseases. Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus. Exemplary but not limited to 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. Furthermore, drugs may be mentioned 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.
Die erfindungsgemäßen Verbindungen können systemisch und/oder lokal wirken. Zu diesem Zweck können sie auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, über das Ohr oder als Implantat bzw. Stent. Für diese Applikationswege können die erfindungsgemäßen Verbindungen in geeigneten Applikationsformen verabreicht werden. 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.
Für die orale Applikation eignen sich nach dem Stand der Technik funktionierende, die erfindungsgemäßen Verbindungen schnell und/oder modifiziert abgebende Applikationsformen, die die erfindungsgemäßen Verbindungen in kristalliner und/oder amorphisierter und/oder gelöster Form enthalten, wie z.B. Tabletten (nicht-überzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfindungsgemäßen Verbindung kontrollieren), in der Mundhöhle schnell zerfallende Tabletten oder Filme/Oblaten, Filme/Lyophylisate, Kapseln (beispielsweise Hart- oder Weichgelatinekapseln), Dragees, Granulate, Pellets, Pulver, Emulsionen, Suspensionen, Aerosole oder Lösungen. Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes geschehen (z.B. intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (z.B. intramuskulär, subcutan, intracutan, percutan oder intraperitoneal). Für die parenterale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszubereitungen in Form von Lösungen, Suspensionen, Emulsionen, Lyophilisaten oder sterilen Pulvern. For oral administration are according to the prior art functioning, 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. The 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). For parenteral administration, suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhalatoren, Nebulizer), Nasentropfen, -lösungen oder -sprays, lingual, sublingual oder buccal zu applizierende Tabletten, Filme/Oblaten oder Kapseln, Suppositorien, Ohren- oder Augenpräparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, transdermale therapeutische Systeme (z.B. Pflaster), Milch, Pasten, Schäume, Streupuder, Implantate oder Stents. For the other routes of administration are suitable, for example 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.
Bevorzugt sind die orale oder parenterale Applikation, insbesondere die orale Applikation. Preference is given to oral or parenteral administration, in particular oral administration.
Die erfindungsgemäßen Verbindungen können in die angeführten Applikationsformen überführt werden. Dies kann in an sich bekannter Weise durch Mischen mit inerten, nichttoxischen, pharma- zeutisch geeigneten Hilfsstoffen geschehen. Zu diesen Hilfsstoffen zählen u.a. Trägerstoffe (beispielsweise mikrokristalline Cellulose, Lactose, Mannitol), Lösungsmittel (z.B. flüssige Polyethylen - glycole), Emulgatoren und Dispergier- oder Netzmittel (beispielsweise Natriumdodecylsulfat, Polyoxysorbitanoleat), Bindemittel (beispielsweise Polyvinylpyrrolidon), synthetische und natürliche Polymere (beispielsweise Albumin), Stabilisatoren (z.B. Antioxidantien wie beispielsweise Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie beispielsweise Eisenoxide) und Geschmacks- und/oder Geruchskorrigentien. 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. These adjuvants include, among others. 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) and flavor and / or odoriferous.
Ein weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, die mindestens eine erfindungsgemäße Verbindung, üblicherweise zusammen mit einem oder mehreren inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoffen enthalten, sowie deren Verwendung zu den zuvor genannten Zwecken. Another object of the present invention are pharmaceutical 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.
Im Allgemeinen ist es vorteilhaft, bei parenteraler Applikation Mengen von etwa 0.001 bis 1 mg/kg, vorzugsweise etwa 0.01 bis 0.5 mg/kg Körpergewicht zur Erzielung wirksamer Ergebnisse zu verabreichen. Bei oraler Applikation beträgt die Dosierung etwa 0.01 bis 100 mg/kg, vorzugsweise etwa 0.01 bis 20 mg/kg und ganz besonders bevorzugt 0.1 bis 10 mg kg Körpergewicht. Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen. In general, it is advantageous to administer 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. When administered orally, 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. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. So it may be sufficient in some cases, with less than the aforementioned minimum amount while in other cases the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
Die nachfolgenden Ausführungsbeispiele erläutern die Erfindung. Die Erfindung ist nicht auf die Beispiele beschränkt. The following embodiments illustrate the invention. The invention is not limited to the examples.
Die Prozentangaben in den folgenden Tests und Beispielen sind, sofern nicht anders angegeben, Gewichtsprozente; Teile sind Gewichtsteile. Lösungsmittelverhältnisse, Verdünnungsverhältnisse und Konzentrationsangaben von flüssig/flüssig-Lösungen beziehen sich jeweils auf das Volumen. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.
Die Herstellung der erfindungsgemäßen Verbindungen wird durch die folgenden Syntheseschemata verdeutlicht. The preparation of the compounds according to the invention is illustrated by the following synthesis schemes.
Als Ausgangsmaterial zur Synthese der erfindungsgemäßen Verbindungen werden Carbonsäuren (Intermediat V3) verwendet, welche kommerziell erhältlich sind oder auf literaturbekannten oder analog zu literaturbekannten Wegen (siehe zum Beispiel European Journal of Organic Chemistry 2003, 8, 1559 - 1568, Chemical and Pharmaceutical Bulletin, 1990, 38, 9, 2446 - 2458, Synthetic Communications 2012, 42, 658 - 666, Tetrahedron, 2004, 60, 51, 11869 - 11874) hergestellt werden können (siehe beispielsweise Syntheseschema 1). Einige Carbonsäuren V3 können ausgehend von Carbonsäureestern (Intermediat V2) durch Verseifung (vergleiche zum Beispiel die Umsetzung von Ethyl-6-(hydroxymethyl)pyridin-2-carboxylat mit wässriger Natriumhydroxidlösung in Methanol, WO2004113281) oder - in dem Fall, dass es sich um einen ieri-Butylester handelt - durch Reaktion mit einer Säure wie zum Beispiel Chlorwasserstoff oder Trifluoressigsäure (vergleiche zum Beispiel Dalton Transactions, 2014 , 43, 19, 7176 - 7190) hergestellt werden. Die Carbonsäuren V3 können auch in Form ihrer Alkalimetallsalze verwendet werden. Die Herstellung der Intermediate V2 kann gegebenenfalls aus den Intermediaten VI erfolgen, welche als Substituent X1 ein Chlor, Brom oder lod tragen, durch Umsetzung in einer Kohlenmonoxid-Atmosphäre gegebenenfalls unter Überdruck in Gegenwart eines Phosphinliganden wie zum Beispiel l,3-Bis(diphenylphoshino)propan, einer Palladium- Verbindung wie zum Beispiel Palladium(II)acetat und einer Base wie zum Beispiel Triethylamin unter Zusatz von Ethanol oder Methanol in einem Lösemittel wie zum Beispiel Dimethylsulfoxid (für Herstellungsmethoden vergleiche zum Beispiel WO2012112743, WO 2005082866, Chemical Communications (Cambridge, England), 2003, 15, 1948 - 1949, WO200661715). Die Intermediate VI sind entweder kommerziell erhältlich oder können auf literaturbekannten Wegen hergestellt werden. Beispielhafte Herstellungsmethoden sind in WO 2012061926, European Journal of Organic Chemistry, 2002, 2, 327 - 330, Synthesis, 2004, 10, 1619 - 1 24, Journal of the American Chemical Society, 2013, 135, 32, 12122 - 12134, Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039 - 4043, US2007185058, WO2009117421 aufgeführt.
Figure imgf000028_0001
As starting material for the synthesis of the compounds according to the invention, carboxylic acids (intermediate V3) which are commercially available or are known from the literature or analogous to the literature (see, for example, European Journal of Organic Chemistry 2003, 8, 1559-1568, Chemical and Pharmaceutical Bulletin, 1990 , 38, 9, 2446-2458, Synthetic Communications 2012, 42, 658-666, Tetrahedron, 2004, 60, 51, 11869-11874) (see for example Synthetic Scheme 1). Some 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). 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.
Figure imgf000028_0001
Intermediat V1 Intermediat V2 Intermediat V3  Intermediate V1 Intermediate V2 Intermediate V3
Syntheseschema 1 Synthetic Scheme 1
X bedeutet Chlor, Brom oder Iod.  X is chlorine, bromine or iodine.
Rd bedeutet Methyl, Ethyl, Benzyl oder ieri-Butyl. R d is methyl, ethyl, benzyl or ieri-butyl.
R3, R4 haben die in der allgemeinen Formel (I) beschriebenen Definitionen. R 3 , R 4 have the definitions described in the general formula (I).
Teilmengen (I)-l und (I)-2 der erfindungsgemäßen Verbindungen der Formel (I) können nach Syntheseschema 2 hergestellt werden. Aliquots of (I) -1 and (I) -2 of the compounds of the formula (I) according to the invention can be prepared according to synthesis scheme 2.
Intermediate 1 können durch Alkylierung der Phenolgruppe von 2-Amino-4-chlor-5-nitrophenol (CAS-RN6358-07-2) nach den dem Fachmann bekannten Methoden (vergleich zum Beispiel Science of Synthesis, Georg Thieme Verlag) hergestellt werden. Die Alkylierung kann mit Alkylhalogeniden oder Alkylsulfonaten erfolgen. Bevorzugt ist dabei die Verwendung der Alkylierungsreaktion mit Alkylbromiden/Alkyliodiden und Kaliumcarbonat in DMF. 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.
Intermediate 2 werden aus den Intermediaten 1 durch Einführung einer„Boc" (tert-Butoxycarbonyl Gruppe) Aminoschutzgruppe erhalten. Die tert-Butoxycarbonyl Gruppe kann nach den dem Fachmann bekannten Methoden (vergleiche auch P. G. M. Wuts, T. W. Greene, Greene 's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) eingeführt werden. Vorzugsweise durch Behandlung mit Di-tert-butyldicarbonat, 4-Dimethylaminopyridin und Triethylamin in Dichlormethan. Die Intermediate 3 werden aus den Intermediaten 2 durch Reaktion mit Methylamin erhalten (siehe auch WO2008/5457). Vorzugsweise wird die Reaktion in Ethanol mit Methylamin (beispielsweise im verschlossenen Gefäß unter Druck bei einer Badtemperatur von 70°C) durchgeführt. 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). Preferably, the reaction is carried out in ethanol with methylamine (for example in a sealed vessel under pressure at a bath temperature of 70 ° C).
Die Intermediate 4 werden durch Reduktion der Nitrogruppe aus den Intermediaten 3 erhalten. Die Reduktion kann nach den dem Fachmann bekannten Methoden (vergleiche zum Beispiel Science of Synthesis, Georg Thieme Verlag) erfolgen. Beispielsweise kann die Nitrogruppe mit Palladium auf Kohlenstoff unter einer Wasserstoffatmosphäre, durch die Verwendung von Palladium auf Kohlenstoff und Ammoniumformiat in Methanol, durch die Verwendung von Eisen und Ammoniumchlorid in Wasser und Ethanol bzw. Methanol (Journal of the Chemical Society, 1955, 2412 -2419) reduziert werden. 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). For example, 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.
Die Intermediate 5 werden in zwei Stufen ausgehend von den Intermediaten 4 erhalten. Zuerst erfolgt eine Acylierung mit 5-Methoxy-4,4-dimethyl-5-oxopentansäure (CAS-RN 2840-71-3). Hierfür können verschiedene in der Literatur bekannte Kupplungsreagenzien eingesetzt werden (Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.3-Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Kapitel 12 - Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606). Beispielsweise können l-(3-Dimefhylaminopropyl)-3- ethylcarbodiimidhydrochlorid in Kombination mit 1-Hydroxy-lH-benzotriazol Hydrat (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, 2093), (lH-Benzotriazol-1- yloxy)(dimethylamino)-N,N-dimethylmethaniminiumtetrafluoroborat (TBTU, CAS-RN 125700-67-6), (Dimethylamino)-N,N-dimethyl(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminiumhexa- fluorophosphat (HATU, CAS-RN 148893-10- 1), Propanphosphonsäureanhydrid (als Lösung in Ethylacetat oder DMF, CAS-RN 68957-94-8) oder Di-lH-imidazol-l-ylmethanon (CDI) als Kupplungsreagenzien verwendet werden, wobei jeweils zur Reaktionsmischung noch eine Base wie Triethylamin oder N-Ethyl-N-isopropylpropan-2-amin gegeben wird. Bevorzugt ist das Kupplungsreagenz HATU in Kombination mit Triethylamin in DMF. The intermediates 5 are obtained in two stages starting from the intermediates 4. First, an acylation with 5-methoxy-4,4-dimethyl-5-oxopentanoic acid (CAS-RN 2840-71-3). For this purpose, 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). For example, 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). 1-yloxy) (dimethylamino) -N, N-dimethylmethaniminium tetrafluoroborate (TBTU, CAS-RN 125700-67-6), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5 -b] pyridin-3-yloxy) methaneiminium hexafluorophosphate (HATU, CAS-RN 148893-10-1), propanephosphonic anhydride (as a solution in ethyl acetate or DMF, CAS-RN 68957-94-8) or di-1H-imidazole L-ylmethanone (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. Preferably, the coupling reagent is HATU in combination with triethylamine in DMF.
Danach erfolgt eine Behandlung mit Säuren, optional unter Erwärmen (siehe auch Chem. Rev., 1951, 48 (3), 397-541). Vorzugsweise wird Essigsäure verwendet. Die Säure kann als Lösungsmittel verwendet oder gegebenenfalls kann die Reaktion auch in einem Lösemittel wie Dichlormethan durchgeführt werden.  This is followed by treatment with acids, optionally with heating (see also Chem. Rev., 1951, 48 (3), 397-541). Preferably, 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.
Durch Abspaltung der tert-Butoxycarbonyl Gruppe erhält man aus den Intermediaten 5 die Intermediate 6. Hierfür kommen dem Fachmann bekannte Methoden (vergleiche auch P. G. M. Wuts, T. W. Greene, Greene ' s Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) in Betracht. Vorzugsweise kann die Abspaltung durch Behandlung mit Trifluoressigsäure in Dichlormethan erfolgen.  By cleavage of the tert-butoxycarbonyl group is obtained from the intermediates 5, the intermediates 6. For this purpose, methods known in the art (see also PGM Wuts, TW Greene, Greene's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) into consideration , Preferably, the cleavage can be effected by treatment with trifluoroacetic acid in dichloromethane.
Eine Teilmenge (I)-l der erfindungsgemäßen Verbindungen (I) wird durch Acylierung der Intermediate 6 mit geeigneten Carbonsäuren erhalten. Hierfür können verschiedene in der Literatur bekannte Kupplungsreagenzien eingesetzt werden (Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.3-Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Kapitel 12 - Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606). Beispielsweise können l-(3-Dimethylaminopropyl)-3-ethylcarbodiimidhydrochlorid in Kombination mit 1-Hydroxy- lH-benzotriazol Hydrat (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, 2093), (1H- Benzotriazol- l-yloxy)(dimethylamino)-N,N-dimethylmethaniminiumtetrafluoroborat (TBTU, CAS- RN 125700-67-6), (Dimethylamino)-N,N-dimethyl(3H-[l,2,3]triazolo[4,5-b]pyridin-3- yloxy)methaneiminiumhexafluorophosphat (HATU, CAS-RN 148893-10-1), A subset (I) -1 of the compounds (I) according to the invention is obtained by acylation of the intermediates 6 with 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). For example, 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) 1-yloxy) (dimethylamino) -N, N-dimethylmethaniminium tetrafluoroborate (TBTU, CAS RN 125700-67-6), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5 -b] pyridin-3-yloxy) methaneiminium hexafluorophosphate (HATU, CAS-RN 148893-10-1),
Propanphosphonsäureanhydrid (als Lösung in Ethylacetat oder DMF, CAS-RN 68957-94-8) oder Di- lH-imidazol-l-ylmethanon (CDI) als Kupplungsreagenzien verwendet werden, wobei jeweils zur Reaktionsmischung noch eine Base wie Triethylamin oder N-Ethyl-N-isopropylpropan-2-amin gegeben wird. Bevorzugt ist das Kupplungsreagenz HATU in Kombination mit der Base Triethylamin Als Lösemittel eignen sich Beispielsweise THF oder DMF. Bevorzugt ist das Lösemittel DMF. Propanphosphonsäureanhydrid (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. Preferably, the solvent is DMF.
Durch Verseifung des Methylesters in den Verbindungen (I)-l gelangt man zu den Ziel Verbindungen (I)-2 (die Verbindungen (I)-2 repräsentieren eine Teilmenge der erfindungsgemäßen Verbindungen (I)) (siehe auch P. G. M. Wuts, T. W. Greene, Greene ' s Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541). Die Hydrolyse des Methylesters kann durch geeignete Basen wie Natriumhydroxid, Kaliumhydroxid oder Lithiumhydroxid, in einem Lösungsmittel wie zum Beispiel Methanol, Ethanol, Tetrahydrofuran oder Dioxan unter Zusatz von Wasser erfolgen. Bevorzugt ist die Verwendung von Lithiumhydroxid in einer Lösung aus Wasser und THF bei 60°C. By saponification of the methyl ester in the compounds (I) -l, 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. Preferred is the use of lithium hydroxide in a solution of water and THF at 60 ° C.
Figure imgf000030_0001
Figure imgf000030_0001
Syntheseschema 2  Synthesis Scheme 2
Die Substituenten R2, R3, R4 haben die in der allgemeinen Formel (I) angegebenen Definitionen. Die Verbindungen (I)-l und (I)-2 entsprechen jeweils Teilmengen der erfindungsgemäßen Verbindungen (D- The substituents R 2 , R 3 , R 4 have the definitions given in the general formula (I). The compounds (I) -l and (I) -2 correspond in each case to portions of the compounds according to the invention (D-
Weitere Teilmengen (I)-3 und (I)-4 der erfindungsgemäßen Verbindungen (I) werden gemäß Syntheseschema 3 erhalten. Die Intermediate 7 werden aus den Intermediaten 4 analog zu Syntheseschema 2 (Herstellung der Intermediate 5 aus den Intermediaten 4) erhalten. Zuerst erfolgt die Umsetzung der Intermediate 4 mit 4-Methoxy-4-oxobutansäure (CAS RN 3878-55-5). Bevorzugt ist die Verwendung von HATU und Triethylamin in DMF. Danach wird mit Essigsäure behandelt, wodurch die Intermediate 7 erhalten werden. Intermediate 8 werden aus den Intermediaten 7 analog zu Syntheseschema 2 hergestellt. Eine Teilmenge (I)-3 der erfindungsgemäßen Verbindungen (I) wird ausgehend von den Intermediaten 8 durch Acylierung mit den geeigneten Carbonsäuren hergestellt (vergleiche die analoge Herstellung von (I)-l aus den Intermediaten 6 wie in Syntheseschema 2). Ausgehend von den Verbindungen (I)-3 können durch Grignard Reaktion mit beispielsweise Methylmagnesiumbromid die Verbindungen (I)-4 hergestellt werden (I)-4 entspricht einer Teilmenge der erfindungsgemäßen Verbindungen (I)). Die Reaktion kann in einem geeigneten Lösungsmittel wie zum Beispiel Tetrahydrofuran oder 2-Methyltetrahydrofuran oder in einer Mischung aus Tetrahydrofuran und 2-Methyltetrahydrofuran erfolgen. Further subsets of (I) -3 and (I) -4 of the compounds (I) according to the invention are obtained according to Synthetic Scheme 3. The intermediates 7 are obtained from the intermediates 4 analogously to synthesis scheme 2 (preparation of the intermediates 5 from the intermediates 4). First, the reaction of the intermediates 4 with 4-methoxy-4-oxobutanoic acid (CAS RN 3878-55-5). Preference is given to the use of HATU and triethylamine in DMF. Thereafter, it is treated with acetic acid, whereby the intermediates 7 are obtained. Intermediates 8 are prepared from intermediates 7 analogously to synthesis scheme 2. 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). Starting from the compounds (I) -3, 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.
Figure imgf000031_0001
Figure imgf000031_0001
Intermediat 8  Intermediate 8
(l)-3 (l)-4 Syntheseschema 3  (l) -3 (l) -4 Synthesis Scheme 3
Die Substituenten R2, R3, R4 haben die in der allgemeinen Formel (I) angegebenen Definitionen. The substituents R 2 , R 3 , R 4 have the definitions given in the general formula (I).
Eine weitere Teilmenge (I)-5 der erfindungsgemäßen Verbindungen (I) wird gemäß Syntheseschema 4 erhalten. A further subset (I) -5 of the compounds (I) according to the invention is obtained according to synthesis scheme 4.
Intermediat 4 wird dazu analog zu Syntheseschema 2 mit einer geeigneten Carbonsäure im Rahmen einer Amidsynthese umgesetzt. Geeignete Carbonsäuren sind kommerziell erhältlich oder können nach literaturbekannten Methoden hergestellt werden (siehe zum Beispiel Bioorganic and Medicinal Chemistry, 2011, vol. 19, 17, 5093 - 5102). Bevorzugt für die Amidsynthese ist die Verwendung von HATU in Gegenwart von Triethylamin in DMF. Danach erhält man durch Behandeln mit Essigsäure die Intermediate 9. Intermediate 10 werden durch die Umsetzung mit Trifluoressigsäure in Dichlormethan erhalten. Ausgehend von Intermediaten 10 werden dann durch Umsetzung mit Carbonsäuren die Verbindungen (I)-5 erhalten. Hierfür kommen die bei Syntheseschema 2 beschriebenen Methoden in Betracht. Bevorzugt ist die Verwendung von HATU und Triethylamin in DMF.
Figure imgf000032_0001
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. Thereafter, the intermediates 9 are obtained by treatment with acetic acid. Intermediate 10 are obtained by the reaction with trifluoroacetic acid in dichloromethane. Starting from intermediates 10, the compounds (I) -5 are then obtained by reaction with carboxylic acids. For this purpose, the methods described in Synthetic Scheme 2 come into consideration. Preference is given to the use of HATU and triethylamine in DMF.
Figure imgf000032_0001
Intermediat 9  Intermediate 9
Intermediat 4  Intermediate 4
Figure imgf000032_0002
Figure imgf000032_0002
(0-5  (0-5
Syntheseschema 4  Synthesis Scheme 4
Die Substituenten R2, R3, R4 und R6 haben die in der allgemeinen Formel (I) angegebenen Die Teilmenge (I)-4 der erfindungsgemäßen Verbindungen (I) wird alternativ gemäß Syntheseschema 5 erhalten. Die Intermediate 11 werden aus den Intermediaten 4 analog zu Syntheseschema 2 (Herstellung der Intermediate 5 aus den Intermediaten 4) erhalten, wobei die verwendete Carbonsäure 4-Hydroxy-4-methylpentansäure hergestellt wird durch basische Hydrolyse von 5,5- Dimefhyldihydrofuran-2(3//)-on (CAS RN 3123-97-5, siehe zum Beispiel J. Org. Chem., 2001, vol. 66, 23, 7832 - 7840). . Die Intermediate 12 werden aus den Intermediaten 11 analog zu Syntheseschema 2 hergestellt. Die Teilmenge (I)-4 der erfindungsgemäßen Verbindungen (I) wird ausgehend von den Intermediaten 12 durch Acylierung mit den geeigneten Carbonsäuren hergestellt (vergleiche die analoge Herstellung von (I)-l aus den Intermediaten 6 wie in Syntheseschema 2). 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. 5 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).
Figure imgf000032_0003
Die Substituenten R2, R3, R4 haben die in der allgemeinen Formel (I) angegebenen Definitionen.
Figure imgf000032_0003
The substituents R 2 , R 3 , R 4 have the definitions given in the general formula (I).
Ein weiterer Gegenstand der Erfindung sind Verbindungen der allgemeinen Formel (II), Another object of the invention are compounds of general formula (II),
Figure imgf000033_0001
Figure imgf000033_0001
worin wherein
R2 für Cyclopropylmethyl oder Ci-Cö-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann, steht; R 2 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
R6 für Cyclopropylmethyl oder Ci-Cö-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann, steht; R 6 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
und ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze. and their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
Bevorzugt ist insbesondere folgende Verbindung der allgemeinen Formel (II), nämlich  In particular, the following compound of the general formula (II) is preferred, namely
5-Methoxy- 1 -methyl-2-[2-(methylsulfonyl)ethyl] - lH-benzimidazol-6-amin. 5-Methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6-amine.
Die Verbindungen der allgemeinen Formel (II) sind geeignet zur Herstellung einer Teilmenge der Verbindungen der allgemeinen Formel (I). The compounds of general formula (II) are suitable for the preparation of a subset of the compounds of general formula (I).
Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung einer Teilmenge (I)-5 der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) aus Verbindungen der Formel (II) 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)
Figure imgf000034_0001
Figure imgf000034_0001
worin wherein
R2 für Cyclopropylmethyl oder Ci-Cö-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann, steht; R 2 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
R3 für C3-C6-Cycloalkyl oder Ci-Cö-Alkyl, welches ein- bis fünffach mit Fluor substituiert sein kann, steht; R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 6 -alkyl which may be substituted one to five times by fluorine;
R4 für Wasserstoff oder Fluor steht; R 4 is hydrogen or fluorine;
R6 für O-C t-Alkyl, Cyclopropyl, Cylopropylmethyl oder 2,2,2-Trifluorethyl steht; R 6 is OC t -alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl;
durch eine Amidsynthese, bevorzugt mit einer geeigneten Carbonsäure unter Verwendung von HATU. by an amide synthesis, preferably with a suitable carboxylic acid using HATU.
Definitionen: definitions:
Figure imgf000034_0002
h Stunde(n) min Minute(n) s Singlet sbr Singlet breit d Doublet m Multiplet q Qu artet t Triplet
Figure imgf000034_0002
h Hour (s) min Minute (s) Singlet sbr Singlet wide d Doublet m Multiplet q Qu artet t Triplet
UPLC Ultra-Hochleistungsflüssigchromatographie UPLC Ultra High Performance Liquid Chromatography
DAD Diodenarraydetektor DAD diode array detector
ELSD Verdampfungslichtstreudetektor ELSD evaporation light scattering detector
ESI Elektronenspray-Ionisation ESI electron spray ionization
SQD Single Quadrupole Detektor SQD single quadrupole detector
Methoden methods
Die erfindungsgemäßen Verbindungen sowie deren Vor- und/ oder Zwischenstufen wurden durch LC- MS analysiert: LC-MS Methoden (analytisch): The compounds according to the invention and their precursors and / or intermediates were analyzed by LC-MS: LC-MS methods (analytical):
UPLC-MS Methode A UPLC-MS method A
Instrument: Waters Acquity UPLC-MS SQD 3001; Säule: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: Wasser+ 0.1% Ameisensäure , Eluent B: Acetonitril; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Fluss 0.8 mL/min; Temperatur: 60 °C; Injektion: 2 μΕ; DAD scan: 210-400 nm. UPLC-MS Methode B Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.1% formic acid, 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 μΕ; DAD scan: 210-400 nm. UPLC-MS Method B
Instrument: Waters Acquity UPLC-MS SQD 3001; Säule: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: Wasser + 0.2% Ammoniak (32%), Eluent B: Acetonitril; Gradient: 0-1.6 min 1-99% B, 1.6- 2.0 min 99% B; Fluss 0.8 mL/min; Temperature: 60 °C; Injektion: 2 L; DAD scan: 210-400 nm; ELSD. Instrument: Waters Acquity UPLC-MS SQD 3001; 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 minutes 99% B; Flow 0.8 mL / min; Temperature: 60 ° C; Injection: 2 L; DAD scan: 210-400 nm; ELSD.
UPLC-MS Methode C Instrument: Waters Acquity UPLC-MS ZQ4000; Säule: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: Wasser + 0.05% Ameisensäure, Eluent B: Acetonitrile + 0.05% Ameisensäure; Gradient: 0- 1.6 min 1-99% B, 1.6-2.0 min 99% B; Fluss 0.8 mL/min; Temperatur: 60 °C; Injektion: 2 μΕ; DAD scan: 210-400 nm. 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 μΕ; DAD scan: 210-400 nm.
UPLC-MS Methode D Instrument: Waters Acquity UPLC-MS ZQ4000; Säule: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: Wasser + 0.2% Ammoniak (32%), Eluent B: Acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Fluss 0.8 mL/min; Temperatur: 60 °C; Injektion: 2 μΕ; DAD scan: 210-400 nm; ELSD. 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 μΕ; DAD scan: 210-400 nm; ELSD.
UPLC-MS Methode E Instrument: Waters Acquity UPLC-MS ZQ2000; Säule: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: Wasser + 0.1 % Ameisensäure, Eluent B: Acetonitril; Gradient: 0-1.6 min 1-99% B, 1.6- 2.0 min 99% B; Fluss 0.8 mL/min; Temperatur: 60 °C; Injektion: 1 μΕ; DAD scan: 210-400 nm; ELSD. UPLC-MS Methode F UPLC-MS Method E Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1% formic acid, 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: 1 μΕ; DAD scan: 210-400 nm; ELSD. UPLC-MS method F
Instrument: Waters Acquity UPLC-MS ZQ2000; Säule: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: Wasser + 0.2% Ammoniak (32%), Eluent B: Acetonitril; Gradient: 0-1.6 min 1-99% B, 1.6- 2.0 min 99% B; Fluss 0.8 mL/min; Temperatur: 60 °C; Injection: 1 μΕ; DAD scan: 210-400 nm; ELSD. Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; 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: 1 μΕ; DAD scan: 210-400 nm; ELSD.
In einigen Fällen erfolgte die Aufreinigung von Substanzgemischen durch Säulenchromatographie an Kieselgel. In some cases, the purification of substance mixtures by column chromatography on silica gel.
Zur Herstellung einiger der erfindungsgemäßen Verbindungen sowie deren Vorstufen und/ oder Zwischenstufen wurde eine säulenchromatographische Reinigung („Flash-Chromatographie") an Kieselgel durchgeführt unter Verwendung von Geräten Isolera® der Firma Biotage. Hierbei kamen Kartuschen der Firma Biotage wie zum Beispiel die Kartusche „SNAP Cartridge, KP_SIL" unterschiedlicher Größe zum Einsatz. Intermediat 1-1 For the production of some of the inventive compounds and their precursors and / or intermediates purification by column chromatography ( "flash chromatography") on silica gel was carried out using equipment Isolera ® from Biotage. These cartridges were the Biotage such as the cartridge "SNAP Cartridge, KP_SIL "different size used. Intermediate 1-1
5-Chlor-2-methoxy-4-nitroanilin 5-chloro-2-methoxy-4-nitroaniline
Figure imgf000037_0001
10 g (53 mmol) 2-Amino-4-chlor-5-nitrophenol wurden in 200 ml DMF gelöst und mit 3.3 ml (53 mmol) lodmethan sowie 11 g (79 mmol) Kaliumcarbonat versetzt und bei Raumtemperatur über Nacht gerührt. Die Reaktionsmischung wurde eingeengt, der Rückstand wurde in 500 ml Wasser und 500 ml Ethylacetat aufgenommen. Die organische Phase wurde abgetrennt und die wässrige Phase mit 500 ml Ethylacetat nachextrahiert. Die vereinigten organischen Phasen wurden mit zweimal 500 ml Wasser, 300 ml gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt 10.5 g ( 98%) der Titelverbindung.
Figure imgf000037_0001
10 g (53 mmol) of 2-amino-4-chloro-5-nitrophenol were dissolved in 200 ml of DMF and admixed with 3.3 ml (53 mmol) of iodomethane and 11 g (79 mmol) of potassium carbonate and stirred at room temperature overnight. The reaction mixture was concentrated, the residue was taken up in 500 ml of water and 500 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was back-extracted with 500 ml of ethyl acetate. The combined organic phases were washed twice with 500 ml of water, 300 ml of saturated brine, dried over magnesium sulfate and concentrated. 10.5 g (98%) of the title compound were obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 3.87 (s, 3H), 6.54 (sbr, 2H), 6.72 (s, 1H), 7.57 (s, 1H),. UPLC-MS (ESI+): [M + H]+ = 203; Rt = 0.97 min (Methode D) . Ή-NMR (400MHz, DMSO-d 6 ): δ [ppm] = 3.87 (s, 3H), 6.54 (sbr, 2H), 6.72 (s, 1H), 7.57 (s, 1H) ,. UPLC-MS (ESI +): [M + H] + = 203; R t = 0.97 min (method D).
Intermediat 1-2 Intermediate 1-2
5-Chlor-2-ethoxy-4-nitroanilin 5-chloro-2-ethoxy-4-nitroaniline
Figure imgf000037_0002
Figure imgf000037_0002
20 g (106 mmol) 2-Amino-4-chlor-5-nitrophenol wurden in 400 ml DMF gelöst und mit 7.92 ml (53 mmol) Bromethan sowie 22 g (160 mmol) Kaliumcarbonat versetzt und bei Raumtemperatur über Nacht gerührt. Die Reaktionsmischung wurde eingeengt, der Rückstand wurde in 500 ml Wasser und 500 ml Ethylacetat aufgenommen. Die organische Phase wurde abgetrennt und die wässrige Phase mit 500 ml Ethylacetat nachextrahiert. Die vereinigten organischen Phasen wurden mit zweimal 500 ml Wasser, 400 ml gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt 22.6 g (98%) der Titelvebindung. 20 g (106 mmol) of 2-amino-4-chloro-5-nitrophenol were dissolved in 400 ml of DMF and treated with 7.92 ml (53 mmol) of bromoethane and 22 g (160 mmol) of potassium carbonate and stirred at room temperature overnight. The reaction mixture was concentrated, the residue was taken up in 500 ml of water and 500 ml of ethyl acetate. The organic phase was separated and the aqueous phase with 500 ml of ethyl acetate extracted. The combined organic phases were washed twice with 500 ml of water, 400 ml of saturated brine, dried over magnesium sulfate and concentrated. 22.6 g (98%) of the title compound were obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.36 (t, 3H), 4.10 (q, 2H), 6.47 (sbr, 2H), 6.73 (s, 1H), 7.55 (s, 1H),. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.36 (t, 3H), 4.10 (q, 2H), 6.47 (sbr, 2H), 6.73 (s, 1H), 7.55 (s, 1H ) ,.
UPLC-MS (ESI+): [M + H]+ = 217; Rt = 1.07 min (Methode D) . UPLC-MS (ESI +): [M + H] + = 217; R t = 1.07 min (method D).
Intermediat 2-1 tert-Butyl-(5-chlor-2-methoxy-4-nitrophenyl)carbamat Intermediate 2-1 tert -butyl- (5-chloro-2-methoxy-4-nitrophenyl) carbamate
Figure imgf000038_0001
Figure imgf000038_0001
10.5 g (52 mmol) 5-Chlor-2-methoxy-4-nitroanilin (Intermediat 1-1) wurden mit 13.5 g (62 mmol) Di- tert-butyldicarbonat, 22 mg (0.17 mmol) 4-Dimethylaminopyridin in 105 ml Dichlormethan 3 h bei 45 °C gerührt. Dann wurde eingeengt und der Rückstand (17 g) ohne weitere Reinigung in der Folgestufe weiterverarbeitet. 10.5 g (52 mmol) of 5-chloro-2-methoxy-4-nitroaniline (Intermediate 1-1) were mixed with 13.5 g (62 mmol) of di-tert-butyldicarbonate, 22 mg (0.17 mmol) of 4-dimethylaminopyridine in 105 ml of dichloromethane Stirred at 45 ° C for 3 h. It was then concentrated and the residue (17 g) without further purification in the next step processed.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.48 (s, 9H), 3.91 (s, 3H), 7.73 (s, 1H), 8.15 (s, 1H), 8.78 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.48 (s, 9H), 3.91 (s, 3H), 7.73 (s, 1H), 8.15 (s, 1H), 8.78 (s, 1H ).
UPLC-MS (ESI+): [M + H]+ = 302; Rt = 1.44 min (Methode D) . UPLC MS (ESI +): [M + H] + = 302; R t = 1.44 min (method D).
Intermediat 2-2 tert-Butyl-(5-chlor-2-ethoxy-4-nitrophenyl)carbamat Intermediate 2-2 tert -Butyl (5-chloro-2-ethoxy-4-nitrophenyl) carbamate
Figure imgf000039_0001
Figure imgf000039_0001
22.6 g (104 mmol) 5-Chlor-2-ethoxy-4-nitroanilin wurden mit 27.5 g (125 mmol) Di-tert- butyldicarbonat, 45 mg (0.34 mmol) 4-Dimethylaminopyridin in 225 ml Dichlormethan 3 h bei 45 °C gerührt. Dann wurde eingeengt und der Rückstand (35 g) ohne weitere Reinigung in der Folgestufe weiterverarbeitet. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.38 (t, 3H), 1.49 (s, 9H), 4.18 (q, 2H), 7.70 (s, 1H), 8.15 (s, 1H), 8.67 (s, 1H). 22.6 g (104 mmol) of 5-chloro-2-ethoxy-4-nitroaniline were treated with 27.5 g (125 mmol) of di-tert-butyldicarbonate, 45 mg (0.34 mmol) of 4-dimethylaminopyridine in 225 ml of dichloromethane at 45 ° C. for 3 h touched. It was then concentrated and the residue (35 g) without further purification in the next step further processed. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.38 (t, 3H), 1.49 (s, 9H), 4.18 (q, 2H), 7.70 (s, 1H), 8.15 (s, 1H ), 8.67 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 317; Rt = 1.48 min (Methode D) . UPLC MS (ESI +): [M + H] + = 317; R t = 1.48 min (method D).
Intermediat 3-1 tert-Butyl-[2-methoxy-5-(methylamino)-4-nitrophenyl]carbamat Intermediate 3-1 tert -Butyl [2-methoxy-5- (methylamino) -4-nitrophenyl] carbamate
Figure imgf000039_0002
Figure imgf000039_0002
16 g (52 mmol) tert-Butyl-(5-chlor-2-methoxy-4-nitrophenyl)carbamat wurden in 160 ml Methylaminlösung (33% in Ethanol) gelöst und im verschlossenem Druckgefäß über Nacht bei 70°C gerührt. Nach Abkühlen wurde die Reaktionsmischung eingeengt und der Rückstand durch Chromatographie an Kieselgel (Eluent Dichlormethan) gereinigt. Man erhielt 8.4 g (54%) der Titelverbindung. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.49 (s, 9H), 2.93 (d, 3H), 3.81 (s, 3H), 7.49 (s, 1H), 7.61 (s, 1H), 8.33 - 8.41 (m, 2H). 16 g (52 mmol) of tert-butyl (5-chloro-2-methoxy-4-nitrophenyl) carbamate were dissolved in 160 ml of methylamine solution (33% in ethanol) and stirred in a sealed pressure vessel at 70 ° C. overnight. After cooling, the reaction mixture was concentrated and the residue was purified by chromatography on silica gel (eluent dichloromethane). 8.4 g (54%) of the title compound were obtained. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.49 (s, 9H), 2.93 (d, 3H), 3.81 (s, 3H), 7.49 (s, 1H), 7.61 (s, 1H ), 8.33 - 8.41 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 298; Rt = 1.35 min (Methode B) . UPLC MS (ESI +): [M + H] + = 298; R t = 1.35 min (method B).
Intermediat 3-2 tert-Butyl-[2-ethoxy-5-(methylamino)-4-nitrophenyl]carbamat Intermediate 3-2 tert -Butyl [2-ethoxy-5- (methylamino) -4-nitrophenyl] carbamate
Figure imgf000040_0001
Figure imgf000040_0001
33 g (104 mmol) tert-Butyl-(5-chlor-2-ethoxy-4-nitrophenyl)carbamat wurden in 320 ml Methylaminlösung (33% in Ethanol) gelöst und im verschlossenem Druckgefäß über Nacht bei 70 °C gerührt. Nach Abkühlen wurde die Reaktionsmischung eingeengt und der Rückstand durch Chromatographie an Kieselgel gereinigt. Man erhielt 4.2 g (13 %) der Titelverbindung. 33 g (104 mmol) of tert-butyl (5-chloro-2-ethoxy-4-nitrophenyl) carbamate were dissolved in 320 ml of methylamine solution (33% in ethanol) and stirred in a sealed pressure vessel at 70 ° C. overnight. After cooling, the reaction mixture was concentrated and the residue was purified by chromatography on silica gel. This gave 4.2 g (13%) of the title compound.
'H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.36 (t, 3H), 1.49 (s, 9H), 2.93 (d, 3H), 4.06 (q, 2H), 7.49 (s, 1H), 7.62 (s, 1H), 8.22 (s, 1H), 8.32 - 8.39 (m, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:36 (t, 3H), 1:49 (s, 9H), 2.93 (d, 3H), 4:06 (q, 2H), 7:49 (s, 1H), 7.62 (s, 1H), 8.22 (s, 1H), 8.32 - 8.39 (m, 1H).
UPLC-MS (ESI+): [M + H]+ = 312; Rt = 1.40 min (Methode D) . UPLC MS (ESI +): [M + H] + = 312; R t = 1.40 min (method D).
Intermediat 4-1 tert-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat Intermediate 4-1 tert -Butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate
Figure imgf000041_0001
Figure imgf000041_0001
4.9 g (16 mmol) tert-Butyl-[2-methoxy-5-(methylamino)-4-nitrophenyl]carbamat wurden mit 3.34 g Pd-Kohle (10% Pd), 5.2 g (82 mmol) Ammoniumformiat in 120 ml Methanol für eine Stunde bei 60 °C gerührt. Dann wurde abgesaugt und das Filtrat eingeengt. Der Rückstand wurde in 100 ml Wasser und 150 ml Ethylacetat aufgenommen. Die organische Phase wurde abgetrennt und die wässrige Phase mit 150 ml Ethylacetat nachextrahiert. Die vereinigten organischen Phasen wurden mit zweimal 100 ml Wasser, 100 ml gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt 4.23 g (96%) der Titelvebindung. 4.9 g (16 mmol) of tert-butyl [2-methoxy-5- (methylamino) -4-nitrophenyl] carbamate were mixed with 3.34 g of Pd-carbon (10% Pd), 5.2 g (82 mmol) of ammonium formate in 120 ml of methanol stirred for one hour at 60 ° C. It was then filtered off with suction and the filtrate was concentrated. The residue was taken up in 100 ml of water and 150 ml of ethyl acetate. The organic phase was separated and the aqueous phase was back-extracted with 150 ml of ethyl acetate. The combined organic phases were washed twice with 100 ml of water, 100 ml of saturated brine, dried over magnesium sulfate and concentrated. 4.23 g (96%) of the title compound were obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.41 (s, 9H), 2.63 (d, 3H), 3.62 (s, 3H), 4.14 - 4.23 (m, 1H), 4.39 (s, 2H), 6.32 (s, 1H), 6.63 (sbr, 1H), 7.46 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.41 (s, 9H), 2.63 (d, 3H), 3.62 (s, 3H), 4.14-4.23 (m, 1H), 4.39 (s , 2H), 6.32 (s, 1H), 6.63 (sbr, 1H), 7.46 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 268; Rt = 0.72 min (Methode A) . UPLC-MS (ESI +): [M + H] + = 268; R t = 0.72 min (method A).
Intermediat 4-2 tert-Butyl-[4-amino-2-ethoxy-5-(methylamino)phenyl]carbamat Intermediate 4-2 tert -Butyl [4-amino-2-ethoxy-5- (methylamino) phenyl] carbamate
Figure imgf000041_0002
4.2 g (13.5 mmol) tert-Butyl-[2-ethoxy-5-(methylamino)-4-nitrophenyl]carbamat wurden mit 3.4 g (61 mmol) Eisenpulver, 164 mg (3 mmol) Ammoniumchlorid in 85 ml Methanol und 17 ml Wasser für 3.5 h bei 90 °C gerührt. Dann wurde abgesaugt und das Filtrat eingeengt. Der Rückstand wurde durch Chromatographie gereinigt. Man erhielt 1.12 g ( 29%) der Titelverbindung. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.26 (t, 3H), 1.42 (s, 9H), 2.63 (s, 3H), 3.85 (q, 2H), 4.14 - 4.23 (m, 1H), 4.37 (s, 2H), 6.31 (s, 1H), 6.62 (sbr, 1H), 7.42 (s, 1H).
Figure imgf000041_0002
4.2 g (13.5 mmol) of tert-butyl [2-ethoxy-5- (methylamino) -4-nitrophenyl] carbamate were mixed with 3.4 g (61 mmol) of iron powder, 164 mg (3 mmol) of ammonium chloride in 85 ml of methanol and 17 ml Water for 3.5 h at 90 ° C stirred. It was then filtered off with suction and the filtrate was concentrated. The residue was purified by chromatography. 1.12 g (29%) of the title compound were obtained. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.26 (t, 3H), 1.42 (s, 9H), 2.63 (s, 3H), 3.85 (q, 2H), 4.14 - 4.23 (m , 1H), 4.37 (s, 2H), 6.31 (s, 1H), 6.62 (sbr, 1H), 7.42 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 282; Rt = 0.82 min (Methode A) . UPLC MS (ESI +): [M + H] + = 282; R t = 0.82 min (method A).
Intermediat 5-1 Methyl-4-{6 (tert-butoxycarbonyl)amino]-5-methoxy-l-methyl-lH-benzimidazol-2-yl}-2,2- dimethylbutanoat Intermediate 5-1 Methyl 4- {6 (tert-butoxycarbonyl) amino] -5-methoxy-1-methyl-1H-benzimidazol-2-yl} -2,2-dimethylbutanoate
Figure imgf000042_0001
Figure imgf000042_0001
2.3 g (8.6 mmol) tert-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat und 1.5 g (8.6 mmol) 5-Methoxy-4,4-dimethyl-5-oxopentansäure wurden mit 4.9 g (13 mmol) HATU in der Gegenwart von 3 ml (21 mmol) Triethylamin in 50 ml DMF bei Raumtemperatur über Nacht gerührt. Dann wurde eingeengt und 8.4 g eines Rückstands erhalten. 2.3 g (8.6 mmol) of tert-butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate and 1.5 g (8.6 mmol) of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid were treated with 4.9 g (13 mmol) of HATU in the presence of 3 ml (21 mmol) of triethylamine in 50 ml of DMF at room temperature overnight. It was then concentrated and 8.4 g of a residue was obtained.
8.4 g des Rückstands wurden in 20 ml Essigsäure 3 h bei Raumtemperatur gerührt. Es wurde eingeengt und der Rückstand wurde durch Chromatographie gereinigt. Man erhielt 2.39 g der Titelverbindung. UPLC-MS (ESI+): [M + H]+ = 406; Rt = 1.29 min (Methode F) Intermediat 6-1 8.4 g of the residue were stirred in 20 ml of acetic acid for 3 h at room temperature. It was concentrated and the residue was purified by chromatography. This gave 2.39 g of the title compound. UPLC MS (ESI +): [M + H] + = 406; R t = 1.29 min (method F) Intermediate 6-1
Methyl-4-(6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl)-2,2-dimethylbutanoat Methyl-4- (6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl) -2,2-dimethylbutanoate
Figure imgf000043_0001
Figure imgf000043_0001
2.37 g (5.8 mmol) Methyl-4-{6-[(tert-butoxycarbonyl)amino]-5-methoxy-l-methyl-lH-benzimidazol- 2-yl}-2,2-dimethylbutanoat wurden in 35 ml Dichlormethan mit 3.4 ml (44 mmol) Trifluoressigsäure über Nacht bei Raumtemperatur gerührt. Dann wurden 25 ml Wasser zugegeben und der pH Wert auf 8-9 durch Zugabe von gesättigter Natriumhydrogencarbonatlösung eingestellt. Das Dichlormethan wurde im Vakuum abdestilliert. Der wässrige Rückstand wurde mit zweimal 40 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurde 1 g (56 %) der Titelverbindung erhalten. 2.37 g (5.8 mmol) of methyl 4- {6 - [(tert-butoxycarbonyl) amino] -5-methoxy-1-methyl-1H-benzimidazol-2-yl} -2,2-dimethylbutanoate were dissolved in 35 ml of dichloromethane 3.4 ml (44 mmol) of trifluoroacetic acid are stirred overnight at room temperature. Then, 25 ml of water was added and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution. The dichloromethane was distilled off in vacuo. The aqueous residue was extracted twice with 40 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There was obtained 1 g (56%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.20 (s, 6H), 1.89 - 1.98 (m, 2H), 2.63 - 2.70 (m, 2H), 3.55 (s, 3H), 3.59 (s, 3H), 3.77 (s, 3H), 4.70 (sbr, 2H), 6.62 (s, 1H), 6.95 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.20 (s, 6H), 1.89-1.98 (m, 2H), 2.63-2.70 (m, 2H), 3.55 (s, 3H), 3.59 (s, 3H), 3.77 (s, 3H), 4.70 (sbr, 2H), 6.62 (s, 1H), 6.95 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 306; Rt = 0.89 min (Methode F) . UPLC-MS (ESI +): [M + H] + = 306; R t = 0.89 min (method F).
Intermediat 7-1 Intermediate 7-1
Methyl-3-{6-[(tert-butoxycarbonyl)amino]-5-methoxy-l-methyl-lH-benzimidazol-2- yljpropanoat Methyl 3- {6 - [(tert-butoxycarbonyl) amino] -5-methoxy-1-methyl-1H-benzimidazol-2-yl-propanoate
Figure imgf000043_0002
Figure imgf000043_0002
1 g (3.7 mmol) tert-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat und 0.49 g (3.7 mmol) 4-Methoxy-4-oxobutansäure (CAS-RN 3878-55-5) wurden mit 2.1 g (5.6 mmol) HATU in der Gegenwart von 2 ml (15 mmol) Triethylamin in 20 ml DMF bei Raumtemperatur über Nacht gerührt. Danach wurde auf 10 ml Wasser gegeben, mit gesättigter Natriumhydrogencarbonatlösung auf pH 8-9 eingestellt und mit 250 ml Ethylacetat extrahiert. Die organische Phase wurde mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurde 1.46 g eines Rückstands erhalten, welcher ohne weitere Reinigung in der Folgestufe eingesetzt wurde. 1.43 g des Rückstandes wurden in 20 ml Essigsäure bei Raumtemperatur über Nacht gerührt. Es wurde eingeengt und der Rückstand wurde durch Chromatographie gereinigt. Man erhielt 0.69 g (50%) der Titel Verbindung. 1 g (3.7 mmol) of tert-butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate and 0.49 g (3.7 mmol) of 4-methoxy-4-oxobutanoic acid (CAS-RN 3878-55-5 ) were treated with 2.1 g (5.6 mmol) of HATU in the presence of 2 ml (15 mmol) of triethylamine in 20 ml of DMF at room temperature overnight touched. It was then added to 10 ml of water, adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. There was obtained 1.46 g of a residue which was used without further purification in the subsequent stage. 1.43 g of the residue was stirred in 20 ml of acetic acid at room temperature overnight. It was concentrated and the residue was purified by chromatography. 0.69 g (50%) of the title compound was obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.49 (s, 9H), 2.84 - 2.91 (m, 2H), 3.04 - 3.10 (m, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.81 (s, 3H), 7.17 (s, 1H), 7.77 (sbr, 1H), 7.85 (s, 1H). UPLC-MS (ESI+): [M + H]+ = 364; Rt = 1.17 min (Methode F) Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.49 (s, 9H), 2.84-2.91 (m, 2H), 3.04-3.10 (m, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.81 (s, 3H), 7.17 (s, 1H), 7.77 (sbr, 1H), 7.85 (s, 1H). UPLC-MS (ESI +): [M + H] + = 364; R t = 1.17 min (method F)
Intermediat 7-2 Intermediate 7-2
Methyl-3-{6 (tert-butoxycarbonyl)amino]-5-ethoxy-l-methyl-lH-benzimidazol-2-yl}propanoat Methyl 3- {6 (tert-butoxycarbonyl) amino] -5-ethoxy-1-methyl-1H-benzimidazol-2-yl} propanoate
Figure imgf000044_0001
l g (3.8 mmol) tert-Butyl-[4-amino-2-ethoxy-5-(methylamino)phenyl]carbamat und 0.50 g (3.8 mmol) 4-Methoxy-4-oxobutansäure (CAS-RN 3878-55-5) wurden mit 2.2 g (5.7 mmol) HATU in der Gegenwart von 2.1 ml (15 mmol) Triethylamin in 20 ml DMF bei Raumtemperatur über Nacht gerührt. Danach wurde auf 10 ml Wasser gegeben, mit gesättigter Natriumhydrogencarbonatlösung auf pH 8-9 eingestellt und mit 250 ml Ethylacetat extrahiert. Die organische Phase wurde mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurde 1.86 g eines Rückstands erhalten. Der Rückstand wurde in 10 ml Essigsäure bei 40°C über Nacht gerührt. Es wurde eingeengt und der Rückstand wurde durch Chromatographie gereinigt. Man erhielt 433 mg (24%) der Titelverbindung.
Figure imgf000044_0001
1 g (3.8 mmol) of tert-butyl [4-amino-2-ethoxy-5- (methylamino) phenyl] carbamate and 0.50 g (3.8 mmol) of 4-methoxy-4-oxobutanoic acid (CAS-RN 3878-55-5). were stirred with 2.2 g (5.7 mmol) of HATU in the presence of 2.1 ml (15 mmol) of triethylamine in 20 ml of DMF at room temperature overnight. It was then added to 10 ml of water, adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. There was obtained 1.86 g of a residue. The residue was stirred in 10 ml of acetic acid at 40 ° C overnight. It was concentrated and the residue was purified by chromatography. 433 mg (24%) of the title compound were obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.36 (t, 3H), 1.48 (s, 9H), 2.84 - 2.91 (m, 2H), 3.03 - 3.10 (m, 2H), 3.61 (s, 3H), 3.67 (s, 3H), 4.06 (q, 2H), 7.16 (s, 1H), 7.74 - 7.82 (m, 2H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.36 (t, 3H), 1.48 (s, 9H), 2.84-2.91 (m, 2H), 3.03-3.10 (m, 2H), 3.61 (s, 3H), 3.67 (s, 3H), 4.06 (q, 2H), 7.16 (s, 1H), 7.74 - 7.82 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 378; Rt = 0.98 min (Methode A) Intermediat 8-1 UPLC MS (ESI +): [M + H] + = 378; R t = 0.98 min (method A) Intermediate 8-1
Methyl-3-(6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl)propanoat Methyl 3- (6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl) propanoate
Figure imgf000045_0001
0.68 g (1.9 mmol) Methyl-3-{6-[(tert-butoxycarbonyl)amino]-5-methoxy-l-methyl-lH-benzimidazol- 2-yl Jpropanoat wurden in 12 ml Dichlormethan mit 1.6 ml (21 mmol) Trifluoressigsäure über Nacht bei Raumtemperatur gerührt. Dann wurden 25 ml Wasser zugegeben und der pH Wert auf 8-9 durch Zugabe von gesättigter Natriumhydrogencarbonatlösung eingestellt.Es wurde mit zweimal 15 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurden 322 mg (65%)der Titelverbindung erhalten.
Figure imgf000045_0001
0.68 g (1.9 mmol) of methyl 3- {6 - [(tert-butoxycarbonyl) amino] -5-methoxy-1-methyl-1H-benzimidazol-2-yl-propanoate were dissolved in 12 ml of dichloromethane with 1.6 ml (21 mmol). Trifluoroacetic acid stirred overnight at room temperature. Then, 25 ml of water was added and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution. It was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There were obtained 322 mg (65%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 2.80 - 2.89 (m, 2H), 2.97 - 3.04 (m, 2H), 3.58 (s, 3H), 3.60 (s, 3H), 3.77 (s, 3H), 4.72 (sbr, 2H), 6.63 (s, 1H), 6.97 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 2.80-2.89 (m, 2H), 2.97-3.04 (m, 2H), 3.58 (s, 3H), 3.60 (s, 3H), 3.77 (s, 3H), 4.72 (sbr, 2H), 6.63 (s, 1H), 6.97 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 264; Rt = 0.69 min (Methode F) . UPLC MS (ESI +): [M + H] + = 264; R t = 0.69 min (method F).
Intermediat 8-2 Intermediate 8-2
Methyl-3-(6-amino-5-ethoxy-l-methyl-lH-benzimidazol-2-yl)propanoat Methyl 3- (6-amino-5-ethoxy-l-methyl-lH-benzimidazol-2-yl) propanoate
Figure imgf000045_0002
Figure imgf000045_0002
430 mg (1.14 mmol) Methyl-3-{6-[(tert-butoxycarbonyl)amino]-5-ethoxy-l-methyl-lH- benzimidazol-2-yl}propanoat wurden in 8 ml Dichlormethan mit 1.15 ml (14.9 mmol) Trifluoressigsäure über Nacht bei Raumtemperatur gerührt. Dann wurden 10 ml Wasser zugegeben und der pH Wert auf 8-9 durch Zugabe von gesättigter Natriumhydrogencarbonatlösung eingestellt. Es wurde mit zweimal 15 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurden 286 mg (90%) der Titelverbindung erhalten. 430 mg (1.14 mmol) of methyl 3- {6 - [(tert-butoxycarbonyl) amino] -5-ethoxy-1-methyl-1H-benzimidazol-2-yl} -propanoate were dissolved in 8 ml of dichloromethane with 1.15 ml (14.9 mmol ) Trifluoroacetic acid stirred overnight at room temperature. Then, 10 ml of water was added and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution. It was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed with Washed water and brine, dried over magnesium sulfate and concentrated. There were obtained 286 mg (90%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.35 (t, 3H), 2.81 - 2.87 (m, 2H), 2.96 - 3.04 (m, 2H), 3.57 (s, 3H), 3.60 (s, 3H), 3.99 (q, 2H), 4.70 (sbr, 2H), 6.63 (s, 1H), 6.96 (s, 1H). UPLC-MS (ESI+): [M + H]+ = 278; Rt = 0.77 min (Methode F) . Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.35 (t, 3H), 2.81-2.87 (m, 2H), 2.96-3.04 (m, 2H), 3.57 (s, 3H), 3.60 (s, 3H), 3.99 (q, 2H), 4.70 (sbr, 2H), 6.63 (s, 1H), 6.96 (s, 1H). UPLC-MS (ESI +): [M + H] + = 278; R t = 0.77 min (method F).
Intermediat 9-1 tert-Butyl-{5-methoxy-l-methyl-2 2-(methylsulfonyl)ethyl]-lH-benzimidazol-6-yl}carbamat Intermediate 9-1 tert -butyl {5-methoxy-1-methyl-2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} carbamate
Figure imgf000046_0001
l g (3.1 mmol) tert-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat (Substanz ca. 80%ig) und 0.48 g (3.1 mmol) 3-(Methylsulfonyl)propansäure (CAS-RN 645-83-0) wurden mit 1.8 g (4.7 mmol) HATU in der Gegenwart von 0.65 ml (4.7 mmol) Triethylamin in 20 ml DMF bei Raumtemperatur über Nacht gerührt. Das Reaktionsgemisch wurde eingeengt. Der Rückstand (1.25 g) wurde in 8 ml Essigsäure bei 40°C über Nacht gerührt. Es wurde eingeengt und 3.3 g eines Rückstands erhalten , welcher ohne weitere Reinigung in der Folgestufe eingesetzt wurde.
Figure imgf000046_0001
1 g (3.1 mmol) of tert-butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate (substance about 80% strength) and 0.48 g (3.1 mmol) of 3- (methylsulfonyl) propanoic acid (CAS). RN 645-83-0) were stirred with 1.8 g (4.7 mmol) of HATU in the presence of 0.65 ml (4.7 mmol) of triethylamine in 20 ml of DMF at room temperature overnight. The reaction mixture was concentrated. The residue (1.25 g) was stirred in 8 ml of acetic acid at 40 ° C overnight. It was concentrated and 3.3 g of a residue obtained, which was used without further purification in the next stage.
UPLC-MS (ESI+): [M + H]+ = 384; Rt= 1.04 min (Methode B) UPLC-MS (ESI +): [M + H] + = 384; R t = 1.04 min (method B)
Intermediat 10-1 Intermediate 10-1
5-Methoxy-l-methyl-2-[2-(methylsulfonyl)ethyl]-lH-benzimidazol-6-amin 5-methoxy-l-methyl-2- [2- (methylsulfonyl) ethyl] -lH-benzimidazol-6-amine
Figure imgf000046_0002
1.2 g (3.1 mmol) tert-Butyl-{5-methoxy-l-methyl-2-[2-(methylsulfonyl)ethyl]-lH-benzimidazol-6- yljcarbamat wurden in 18 ml Dichlormethan mit 1.8 ml (23 mmol) Trifluoressigsäure über Nacht bei Raumtemperatur gerührt. Es wurden weitere 1.8 ml (23 mmol) Trifluoressigsäure zugegeben und 1 h bei Raumtemperatur gerührt. Dann wurden 10 ml Wasser zugegeben und der pH Wert auf 8-9 durch Zugabe von gesättigter Natriumhydrogencarbonatlösung eingestellt. Das Dichlormethan wurde abdestilliert und die verbliebene Lösung mit zweimal 15 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurden 725 mg (81 %)der Titelverbindung erhalten.
Figure imgf000046_0002
1.2 g (3.1 mmol) of tert-butyl {5-methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6-ylcarbamate were dissolved in 18 ml of dichloromethane with 1.8 ml (23 mmol) of trifluoroacetic acid stirred overnight at room temperature. Another 1.8 ml (23 mmol) of trifluoroacetic acid were added and the mixture was stirred at room temperature for 1 h. Then, 10 ml of water was added and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate solution. The dichloromethane was distilled off and the remaining solution was extracted twice with 15 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There were obtained 725 mg (81%) of the title compound.
UPLC-MS (ESI+): [M + H]+ = 284; Rt = 0.59 min (Methode B) . UPLC MS (ESI +): [M + H] + = 284; R t = 0.59 min (method B).
Intermediat 11-1 Intermediate 11-1
ieri-Butyl-[2-(3-hydroxy-3-methylbutyl)-5-methoxy-l-methyl-l//-benzimidazol-6-yl]carbamat ieri-butyl [2- (3-hydroxy-3-methylbutyl) -5-methoxy-l-methyl-l // - benzimidazol-6-yl] carbamate
Figure imgf000047_0001
Figure imgf000047_0001
Zu einer Lösung von 294 mg (7.36 mmol) Natriumhydroxid in 3 ml Wasser wurden nacheinander 6 ml Ethanol und 700 μΐ (6.1 mmol) 5,5-Dimethyldihydrofuran-2(3 /)-on gegeben. Das Reaktionsgemisch wurde für drei Stunden zum Rückfluss erhitzt, und anschließend im Vakuum eingeengt. Der Rückstand wurde in 4 ml Wasser aufgenommen, bei 0°C mit 574 mg Zitronensäure auf pH 4 bis 5 angesäuert, und dann mit einem Überschuss Natriumchlorid gesättigt. Die wässrige Phase wurde viermal mit Diethylether extrahiert. Die organische Phase wurde über wasserabweisendes Papier filtriert und eingeengt. Man erhielt 716 mg 4-Hydroxy-4-methylpentansäure als gelbes Öl, das sofort weiter umgesetzt wurde. To a solution of 294 mg (7.36 mmol) of sodium hydroxide in 3 ml of water was added successively 6 ml of ethanol and 700 μΐ (6.1 mmol) of 5,5-dimethyldihydrofuran-2 (3 /) -one. The reaction mixture was heated to reflux for three hours, then concentrated in vacuo. The residue was taken up in 4 ml of water, acidified to pH 4 to 5 with 574 mg of citric acid at 0 ° C., and then saturated with an excess of sodium chloride. The aqueous phase was extracted four times with diethyl ether. The organic phase was filtered over water-repellent paper and concentrated. 716 mg of 4-hydroxy-4-methylpentanoic acid were obtained as a yellow oil, which was immediately reacted further.
503 mg (1.4 mmol) ieri-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat und 373 mg (2.8 mmol) frisch hergestellte 4-Hydroxy-4-methylpentansäure wurden mit 1.17 g (3.08 mmol) HATU in Gegenwart von 537 μΐ (3.85 mmol) Triethylamin in 10 ml DMF bei Raumtemperatur über Nacht gerührt. Das Reaktionsgemisch wurde auf gesättigte Natriumhydrogencarbonatlösung gegeben und mit Ethylacetat extrahiert. Die organische Phase wurde mit gesättigter Kochsalzlösung gewaschen, über wasserabweisendes Papier filtriert und eingeengt. Es wurden 1.11 g eines Rückstands erhalten, welcher durch Flash-Chromatographie aufgereinigt wurde. Man erhielt 179 mg ieri-Butyl-{4-[(4- hydroxy-4-methylpentanoyl)amino] -2-methoxy-5-(methylamino)phenyl Jcarbamat als Rohprodukt, welches sofort in 1.1 ml (18 mmol) Essigsäure gelöst und über Nacht bei 40°C gerührt wurde. Es wurde eingeengt und 173 mg eines Rückstands erhalten, welcher ohne weitere Reinigung in der Folgestufe eingesetzt wurde. UPLC-MS (ESI+): [M + H]+ = 364; Rt = 1.10 min (Methode F) 503 mg (1.4 mmol) of iperi-butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate and 373 mg (2.8 mmol) of freshly prepared 4-hydroxy-4-methylpentanoic acid were mixed with 1.17 g (3.08 mmol ) HATU in the presence of 537 μΐ (3.85 mmol) of triethylamine in 10 ml of DMF at room temperature overnight. The reaction mixture was added to saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, filtered over water-repellent paper and concentrated. There was obtained 1.11 g of a residue, which was purified by flash chromatography. 179 mg of ieri-butyl {4 - [(4- Hydroxy-4-methylpentanoyl) amino] -2-methoxy-5- (methylamino) phenyl carbamate as a crude product, which was immediately dissolved in 1.1 ml (18 mmol) of acetic acid and stirred at 40 ° C overnight. It was concentrated and 173 mg of a residue obtained, which was used without further purification in the next step. UPLC-MS (ESI +): [M + H] + = 364; R t = 1.10 min (method F)
Intermediat 12-1 Intermediate 12-1
4-(6-Amino-5-methoxy-l-methyl-l//-benzimidazol-2-yl)-2-methylbutan-2-ol 4- (6-amino-5-methoxy-l-methyl-l // - benzimidazol-2-yl) -2-methyl-butan-2-ol
Figure imgf000048_0001
173 mg ieri-Butyl-[2-(3-hydroxy-3-methylbutyl)-5-methoxy-l-methyl-lii-benzimidazol-6-yl]- carbamat (Rohprodukt) wurden in 5 ml Dichlormethan mit 570 μΐ (7.4 mmol) Trifluoressigsäure über Nacht bei Raumtemperatur gerührt. Der Rückstand wurde mit Toluol im Vakuum eingeengt. Es wurden 216 mg der Titelverbindung als Rohprodukt erhalten.
Figure imgf000048_0001
173 mg of ieri-butyl [2- (3-hydroxy-3-methylbutyl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] carbamate (crude product) were dissolved in 5 ml of 570 μΐ dichloromethane (7.4 mmol) trifluoroacetic acid stirred overnight at room temperature. The residue was concentrated in vacuo with toluene. There were obtained 216 mg of the title compound as a crude product.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.18 (s, 6H), 1.82 (m, 2H), 3.11 (m, 2H), 3.55 (s, 3H), 3.80 (s, 3H), 3.89 (s, 3H), 5.44 (sbr, 2H), 6.96 (s, 1H), 7.08 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.18 (s, 6H), 1.82 (m, 2H), 3.11 (m, 2H), 3.55 (s, 3H), 3.80 (s, 3H ), 3.89 (s, 3H), 5.44 (sbr, 2H), 6.96 (s, 1H), 7.08 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 264; Rt = 0.66 min (Methode F). UPLC MS (ESI +): [M + H] + = 264; R t = 0.66 min (method F).
Beispiel 1 example 1
Methyl-3 5-methoxy-l-methyl-6-({[6-(trifluormethyl)pyridin-2-yl]carbonyl}amino)-lH- benzimidazol-2-yl]propanoat Methyl 3-5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] propanoate
Figure imgf000048_0002
0.32 g (1.2 mmol) Methyl-3-(6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl)propanoat und 232 mg (1.2 mmol) 6-(Trifluormethyl)pyridin-2-carbonsäure wurden mit 693 mg (1.8 mmol) HATU in der Gegenwart von 254 μΐ (1.8 mmol) Triethylamin in 5 ml DMF bei Raumtemperatur über Nacht gerührt. Es wurden 25 ml Wasser zugegeben und mit zweimal 70 ml Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es wurden 403 mg (76%)der Titelverbindung erhalten.
Figure imgf000048_0002
0.32 g (1.2 mmol) of methyl 3- (6-amino-5-methoxy-1-methyl-1H-benzimidazol-2-yl) -propanoate and 232 mg (1.2 mmol) of 6- (trifluoromethyl) -pyridine-2-carboxylic acid stirred with 693 mg (1.8 mmol) of HATU in the presence of 254 μΐ (1.8 mmol) of triethylamine in 5 ml of DMF at room temperature overnight. 25 ml of water were added and extracted with twice 70 ml of dichloromethane. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There were obtained 403 mg (76%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 2.86 - 2.95 (m, 2H), 3.07 - 3.14 (m, 2H), 3.61 (s, 3H), 3.73 (s, 3H), 3.96 (s, 3H), 7.34 (s, 1H), 8.19 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H). UPLC-MS (ESI+): [M + H]+ = 437; Rt = 1.17 min (Methode F) . Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 2.86-2.95 (m, 2H), 3.07-3.14 (m, 2H), 3.61 (s, 3H), 3.73 (s, 3H), 3.96 (s, 3H), 7.34 (s, 1H), 8.19 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H). UPLC MS (ESI +): [M + H] + = 437; R t = 1.17 min (method F).
Beispiel 2 Example 2
Methyl-3 5-ethoxy-l-methyl-6-({[6-(trifluormethyl)pyridin-2-yl]carbonyl}amino)-lH- benzimidazol-2-yl]propanoat Methyl 3 5-ethoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] propanoate
Figure imgf000049_0001
Figure imgf000049_0001
158 mg (0.57 mmol) Methyl-3-(6-amino-5-ethoxy-l-methyl-lH-benzimidazol-2-yl)propanoat und 163 mg (0.85 mmol) 6-(Trifluormethyl)pyridin-2-carbonsäure wurden mit 325 mg (0.85 mmol) HATU in der Gegenwart von 120 μΐ (0.85 mmol) Triethylamin in 2 ml DMF bei Raumtemperatur über Nacht gerührt. Es wurden 20 ml Wasser zugegeben und der Feststoff abgesaugt. Der Feststoff wurde in Dichlormethan gelöst, über Magnesiumsulfat getrocknet und eingeengt. Es wurden 241 mg (93%) der Titelverbindung erhalten.  158 mg (0.57 mmol) of methyl 3- (6-amino-5-ethoxy-1-methyl-1H-benzimidazol-2-yl) -propanoate and 163 mg (0.85 mmol) of 6- (trifluoromethyl) -pyridine-2-carboxylic acid with 325 mg (0.85 mmol) of HATU in the presence of 120 μΐ (0.85 mmol) of triethylamine in 2 ml of DMF at room temperature overnight. 20 ml of water were added and the solid was filtered off with suction. The solid was dissolved in dichloromethane, dried over magnesium sulfate and concentrated. There were obtained 241 mg (93%) of the title compound.
XH-NMR (400MHz, DMSO-d6): δ [ppm] = 1.52 (t, 3H), 2.93 - 3.00 (m, 2H), 3.64 (s, 3H), 3.95 (s, 3H), 4.28 (q, 2H), 7.40 (s, 1H), 8.24 - 8.29 (m, 1H), 8.40 - 8.50 (m, 2H), 8.81 (s, 1H), 10.81 (s, 1H). X H NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.52 (t, 3H), 2.93-3.00 (m, 2H), 3.64 (s, 3H), 3.95 (s, 3H), 4.28 ( q, 2H), 7.40 (s, 1H), 8.24 - 8.29 (m, 1H), 8.40 - 8.50 (m, 2H), 8.81 (s, 1H), 10.81 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 451; Rt = 1.24 min (Methode B). Beispiel 3 UPLC-MS (ESI +): [M + H] + = 451; R t = 1.24 min (method B). Example 3
Methyl-4 5-methoxy-l-methyl-6-({[6-(trifluormethyl)pyridin-2-yl]carbonyl}amino)-lH- benzimidazol-2-yl]-2,2-dimethylbutanoat Methyl 4 5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] -2,2-dimethylbutanoate
Figure imgf000050_0001
Figure imgf000050_0001
0.5 g (1.5 mmol) Methyl-4-(6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl)-2,2- dimethylbutanoat und 297 mg (1.5 mmol) 6-(Trifluormethyl)pyridin-2-carbonsäure wurden mit 887 mg (2.3 mmol) HATU in der Gegenwart von 325 μΐ (2.3 mmol) Triethylamin in 5 ml DMF bei Raumtemperatur über Nacht gerührt. Dann wurde eingeengt und der Rückstand mittels präparativer HPLC gereinigt. Es wurden 482 mg (64%) der Titelverbindung erhalten. 0.5 g (1.5 mmol) of methyl 4- (6-amino-5-methoxy-1-methyl-1H-benzimidazol-2-yl) -2,2-dimethylbutanoate and 297 mg (1.5 mmol) of 6- (trifluoromethyl) pyridine 2-carboxylic acid were stirred with 887 mg (2.3 mmol) of HATU in the presence of 325 μΐ (2.3 mmol) of triethylamine in 5 ml of DMF at room temperature overnight. It was then concentrated and the residue was purified by preparative HPLC. There were obtained 482 mg (64%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.23 (s, 6H), 1.96 - 2.03 (m, 2H), 2.73 - 2.81 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 7.31 (s, 1H), 8.20 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H). Ή-NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.23 (s, 6H), 1.96 - 2.03 (m, 2H), 2.73 - 2.81 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 7.31 (s, 1H), 8.20 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H ).
UPLC-MS (ESI+): [M + H]+ = 479; Rt = 1.31 min (Methode F) . UPLC-MS (ESI +): [M + H] + = 479; R t = 1.31 min (method F).
Beispiel 4 Example 4
Methyl-4 6-({[6-(l,l-difluorethyl)pyridin-2-yl]carbonyl}amino)-5-methoxy-l-methyl-lH- benzimidazol-2-yl]-2,2-dimethylbutanoat
Figure imgf000051_0001
Methyl 4,6 - ({[6- (1, 1-difluoroethyl) pyridin-2-yl] carbonyl} amino) -5-methoxy-1-methyl-1H-benzimidazol-2-yl] -2,2-dimethylbutanoate
Figure imgf000051_0001
0.5 g (1.5 mmol) Methyl-4-(6-amino-5-methoxy-l-methyl-lH-benzimidazol-2-yl)-2,2- dimethylbutanoat und 291 mg (1.5 mmol) 6-(l,l-Difluorethyl)pyridin-2-carbonsäure wurden mit 887 mg (2.3 mmol) HATU in der Gegenwart von 325 μΐ (2.3 mmol) Triethylamin in 5 mL DMF bei Raumtemperatur über Nacht gerührt. Dann wurde eingeengt und der Rückstand mittels präparativer HPLC gereinigt. Es wurden 451 mg (61%) der Titelverbindung erhalten. 0.5 g (1.5 mmol) of methyl 4- (6-amino-5-methoxy-1-methyl-1H-benzimidazol-2-yl) -2,2-dimethylbutanoate and 291 mg (1.5 mmol) of 6- (1, 1 -Difluoroethyl) pyridine-2-carboxylic acid were stirred with 887 mg (2.3 mmol) of HATU in the presence of 325 μΐ (2.3 mmol) of triethylamine in 5 mL of DMF at room temperature overnight. It was then concentrated and the residue was purified by preparative HPLC. There were obtained 451 mg (61%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.23 (s, 6H), 1.96 - 2.03 (m, 2H), 2.17 (t, 3H), 2.73 - 2.81 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 7.31 (s, 1H), 8.20 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H). UPLC-MS (ESI+): [M + H]+ = 479; Rt = 1.31 min (Methode F) . Ή-NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.23 (s, 6H), 1.96 - 2.03 (m, 2H), 2.17 (t, 3H), 2.73 - 2.81 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 3.96 (s, 3H), 7.31 (s, 1H), 8.20 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.53 (s, 1H ), 10.51 (s, 1H). UPLC-MS (ESI +): [M + H] + = 479; R t = 1.31 min (method F).
Beispiel 5 Example 5
4 5-Methoxy-l-methyl-6-({[6-(trifluormethyl)pyrid^ 4 5-Methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyrid]
yl]-2,2-dimethylbutansäure yl] -2,2-dimethylbutanoic
Figure imgf000051_0002
Figure imgf000051_0002
200 mg (0.41 mmol) Methyl-4-[5-methoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2- yl]carbonyl}amino)-lH-benzimidazol-2-yl]-2,2-dimethylbutanoat (Beispiel 3) wurden in 4.2 ml THF mit 4.2 ml Wasser mit 50 mg (2 mmol) Lithiumhydroxid über Nacht bei 60°C gerührt. Danach wurde mit 2 M HCl auf pH 4-5 angesäuert, mit Ethylacetat extrahiert und die Phasen wurden getrennt. Die wässrige Phase wurde 48 h stehengelassen wobei das Produkt ausfiel. Der Feststoff wurde abfiltriert, in Essigsäurethylester gelöst, über Magnesiumsulfat getrocknet und eingeengt. Man erhielt 102 mg (70%) der Titel Verbindung. 200 mg (0.41 mmol) of methyl 4- [5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] -2 , 2-Dimethylbutanoate (Example 3) were stirred in 4.2 ml of THF with 4.2 ml of water with 50 mg (2 mmol) of lithium hydroxide overnight at 60 ° C. It was then acidified to pH 4-5 with 2 M HCl, extracted with ethyl acetate, and the phases were separated. The aqueous phase was allowed to stand for 48 hours during which the product precipitated. The solid was filtered off, dissolved in ethyl acetate, dried over magnesium sulfate and concentrated. This gave 102 mg (70%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.20 (s, 6H), 1.89 - 2.02 (m, 2H), 2.75 - 2.86 (m, 2H), 3.72 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 8.17 - 8.27 (m, 1H), 8.36 - 8.48 (m, 2H), 8.54 (s, 1H), 10.51 (s, 1H), 12.24 (sbr, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.20 (s, 6H), 1.89-2.02 (m, 2H), 2.75-2.86 (m, 2H), 3.72 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 8.17 - 8.27 (m, 1H), 8.36 - 8.48 (m, 2H), 8.54 (s, 1H), 10.51 (s, 1H), 12.24 (sbr, 1H ).
UPLC-MS (ESI+): [M + H]+ = 465; Rt = 0.77 min (Methode F) . UPLC-MS (ESI +): [M + H] + = 465; R t = 0.77 min (method F).
Beispiel 6 Example 6
4 6-({[6-(l,l-Difluorethyl)pyridin-2-yl]carbonyl}amino)-5-methoxy-l-methyl-lH-benzimid^ 2-yl]-2,2-dimethylbutansäure 4 6 - ({[6- (1,1-Difluoroethyl) pyridin-2-yl] carbonyl} amino) -5-methoxy-1-methyl-1H-benzimid ^ 2-yl] -2,2-dimethylbutanoic acid
Figure imgf000053_0001
200 mg (0.41 mmol) Methyl-4 6-({ [6-(1 -difluorethyl)pyridin-2-yl]carbonyl}amino)-5-methoxy-l- methyl-lH-benzimidazol-2-yl]-2,2-dimethylbutanoat (Beispiel 4) wurden in 4.2 ml THF mit 4.2 ml Wasser mit 50 mg (2 mmol) Lithiumhydroxid über Nacht bei 60°C gerührt. Danach wurde mit 2 M HCl auf pH 4-5 angesäuert und mit Ethylacetat extrahiert. Die organische Phase wurde mit Wasser und gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde mittels präparativer HPLC gereinigt und 29 mg (19%) der Titelverbindung erhalten.
Figure imgf000053_0001
200 mg (0.41 mmol) of methyl 4,6 - ({[6- (1-difluoroethyl) pyridin-2-yl] carbonyl} amino) -5-methoxy-1-methyl-1H-benzimidazol-2-yl] -2 , 2-Dimethylbutanoate (Example 4) were stirred in 4.2 ml of THF with 4.2 ml of water with 50 mg (2 mmol) of lithium hydroxide overnight at 60 ° C. It was then acidified to pH 4-5 with 2 M HCl and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC to give 29 mg (19%) of the title compound.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.20 (s, 6H), 1.91 - 1.99 (m, 2H), 2.16 (t, 3H), 2.75 - 2.83 (m, 2H), 3.71 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 7.98 - 8.05 (m, 1H), 8.28 - 8.34 (m, 2H), 8.51 (s, 1H), 10.68 (s, 1H), 12.30 (sbr, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.20 (s, 6H), 1.91-1.99 (m, 2H), 2.16 (t, 3H), 2.75-2.83 (m, 2H), 3.71 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 7.98-8.05 (m, 1H), 8.28-8.34 (m, 2H), 8.51 (s, 1H), 10.68 (s, 1H ), 12.30 (sbr, 1H).
UPLC-MS (ESI+): [M + H]+ = 461; Rt = 0.75 min (Methode F) . UPLC-MS (ESI +): [M + H] + = 461; R t = 0.75 min (method F).
Beispiel 7 Example 7
N-[2-(3-Hydroxy-3-methylbutyl)-5-methoxy-l-methyl-lH-benzimidazol-6-yl]-6- (trifluormethyl)pyridin-2-carboxamid N- [2- (3-hydroxy-3-methylbutyl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
Figure imgf000053_0002
400 mg (0.2 mmol) Methyl-3-[5-methoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2- yl]carbonyl}amino)-lH-benzimidazol-2-yl]propanoat wurden in 32 ml THF gelöst und auf 0 - 5°C abgekühlt. Dann wurden 1.6 ml (5.5 mmol) einer Lösung von Methylmagnesiumbromid in 2- Methyltetrahydrofuran (3.4 mol/1) zugetropft. Danach wurde die Reaktionsmischung 1 h bei 5°C gerührt. Es wurden 12 ml gesättigte Ammoniumchloridlösung zugegeben und 5 min gerührt. Die organische Phase wurde abgetrennt, mit Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde mittels HPLC gereinigt.Man erhielt 134 mg (33%) der Titelverbindung.
Figure imgf000053_0002
400 mg (0.2 mmol) of methyl 3- [5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] -propanoate dissolved in 32 ml THF and cooled to 0-5 ° C. Then, 1.6 ml (5.5 mmol) of a solution of methylmagnesium bromide in 2-methyltetrahydrofuran (3.4 mol / l) was added dropwise. Thereafter, the reaction mixture was stirred at 5 ° C for 1 h. 12 ml of saturated ammonium chloride solution were added and the mixture was stirred for 5 minutes. The organic phase was separated, dried with magnesium sulfate and concentrated. The residue was purified by HPLC. 134 mg (33%) of the title compound were obtained.
Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.18 (s, 6H), 1.80 - 1.90 (m, 2H), 2.84 - 2.94 (m, 2H), 3.73 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 8.19 - 8.26 (m, 1H), 8.37 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H). Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.18 (s, 6H), 1.80-1.90 (m, 2H), 2.84-2.94 (m, 2H), 3.73 (s, 3H), 3.96 (s, 3H), 7.30 (s, 1H), 8.19 - 8.26 (m, 1H), 8.37 - 8.49 (m, 2H), 8.53 (s, 1H), 10.51 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 437; Rt = 1.15 min (Methode F). UPLC MS (ESI +): [M + H] + = 437; R t = 1.15 min (method F).
Beispiel 8 Example 8
N 5-Ethoxy-2-(3-hydroxy-3-methylbutyl)-l-methyl-lH-benzimidazol-6-yl]-6- (trifluormethyl)pyridin-2-carboxamid N 5-Ethoxy-2- (3-hydroxy-3-methylbutyl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
Figure imgf000054_0001
Figure imgf000054_0001
241 mg (0.53 mmol) Methyl-3-[5-ethoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2- yl]carbonyl}amino)-lH-benzimidazol-2-yl]propanoat wurden in 19 ml THF gelöst und auf 0 - 5°C abgekühlt. Dann wurden 0.994 ml (3.2 mmol) einer Lösung von Methylmagnesiumbromid in 2- Methyltetrahydrofuran (3.4 mol/1) zugetropft. Danach wurde die Reaktionsmischung 2.5 h bei Raumtemperatur gerührt. Es wurden 7 ml gesättigte Ammoniumchloridlösung zugegeben und 5 min gerührt. Die organische Phase wurde abgetrennt, mit Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde mittels HPLC gereinigt. Man erhielt 21 mg (9%) der Titelverbindung. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.17 (s, 6H), 1.47 (t, 3H), 1.80 - 1.88 (m, 2H), 2.84 - 2.93 (m, 2H), 3.72 (s, 3H), 4.17 (q, 2H), 4.47 (sbr, 1H), 7.28 (s, 1H), 8.19 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.56 (s, 1H), 10.74 (s, 1H). 241 mg (0.53 mmol) of methyl 3- [5-ethoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] -propanoate dissolved in 19 ml of THF and cooled to 0-5 ° C. Then 0.994 ml (3.2 mmol) of a solution of methylmagnesium bromide in 2-methyltetrahydrofuran (3.4 mol / l) were added dropwise. Thereafter, the reaction mixture was stirred for 2.5 h at room temperature. 7 ml of saturated ammonium chloride solution were added and stirred for 5 minutes. The organic phase was separated, dried with magnesium sulfate and concentrated. The residue was purified by HPLC. 21 mg (9%) of the title compound were obtained. Ή-NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.17 (s, 6H), 1.47 (t, 3H), 1.80 - 1.88 (m, 2H), 2.84 - 2.93 (m, 2H), 3.72 (s, 3H), 4.17 (q, 2H), 4.47 (sbr, 1H), 7.28 (s, 1H), 8.19 - 8.25 (m, 1H), 8.38 - 8.49 (m, 2H), 8.56 (s, 1H ), 10.74 (s, 1H).
Beispiel 9 Example 9
N-{5-Methoxy^-methyl-2 2-(methylsulfonyl)ethyl]-lH-benzimidazol-6-yl}-6- (trifluormethyl)pyridin-2-carboxamid N- {5-Methoxy-methyl-2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} -6- (trifluoromethyl) pyridine-2-carboxamide
Figure imgf000055_0001
Figure imgf000055_0001
240 mg 5-Methoxy-l-methyl-2-[2-(methylsulfonyl)ethyl]-lH-benzimidazol-6-amin und 113 mg (0.6 mmol) 6-(Trifluormethyl)pyridin-2-carbonsäure wurden mit 338 mg (0.89 mmol) HATU in der Gegenwart von 124 μΐ (0.89 mmol) Triethylamin in 3 ml DMF bei Raumtemperatur über Nacht gerührt. Es wurde abfiltriert und dabei 41 mg der Zielverbindung erhalten. Das Filtrat wurde mittels präparativer HPLC gereinigt. Es wurden weitere 18 mg der Titelverbindung erhalten. 240 mg of 5-methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6-amine and 113 mg (0.6 mmol) of 6- (trifluoromethyl) pyridine-2-carboxylic acid were combined with 338 mg of 0.89 mmol) of HATU in the presence of 124 μΐ (0.89 mmol) of triethylamine in 3 ml of DMF at room temperature overnight. It was filtered off to obtain 41 mg of the target compound. The filtrate was purified by preparative HPLC. An additional 18 mg of the title compound was obtained.
'H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.09 (s, 3H), 3.63 - 3.71 (m, 2H), 3.76 (s, 3H), 3.96 (s, 3H), 7.34 (s, 1H), 8.20 - 8.24 (m, 1H), 8.38 - 8.48 (m, 2H), 8.56 (s, 1H), 10.52 (s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 3:09 (s, 3H), 3.63 - 3.71 (m, 2H), 3.76 (s, 3H), 3.96 (s, 3H), 7:34 ( s, 1H), 8.20 - 8.24 (m, 1H), 8.38 - 8.48 (m, 2H), 8.56 (s, 1H), 10.52 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 457; Rt = 1.09 min (Methode B) . UPLC-MS (ESI +): [M + H] + = 457; R t = 1.09 min (method B).
Beispiel 10 Example 10
6-(l,l-Difluorethyl)-N-{5-methoxy-l-methyl-2 2-(methylsulfonyl)ethyl]-lH-benzimidazol-6- yl}pyridin-2-carboxamid 6- (1,1-Difluoroethyl) -N- {5-methoxy-1-methyl-2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} pyridine-2-carboxamide
Figure imgf000056_0001
240 mg 5-Methoxy- l-methyl-2-[2-(methylsulfonyl)ethyl]-lH-benzimidazol-6-amin und 1 11 mg (0.6 mmol) 6-(l,l-Difluoremyl)pyridin-2-carbonsäure wurden mit 338 mg (0.89 mmol) HATU in der Gegenwart von 124 μΐ (0.89 mmol) Triethylamin in 3 mL DMF bei Raumtemperatur über Nacht gerührt. Es wurde abfiltriert und dabei 77 mg der Zielverbindung erhalten. Das Filtrat wurde mittels präparativer HPLC gereinigt. Es wurden weitere 7 mg der Titelverbindung erhalten. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 2.17 (t, 3H), 3.09 (s, 3H), 3.63 - 3.72 (m, 2H), 3.76 (s, 3H), 3.98 (s, 3H), 7.34 (s, 1H), 7.98 - 8.06 (m, 1H), 8.29 - 8.35 (m, 2H), 8.55 (s, 1H), 10.70 (s, 1H).
Figure imgf000056_0001
240 mg of 5-methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazole-6-amine and 11 mg (0.6 mmol) of 6- (1,1-difluoro-methyl) -pyridine-2-carboxylic acid were stirred with 338 mg (0.89 mmol) HATU in the presence of 124 μΐ (0.89 mmol) triethylamine in 3 mL DMF at room temperature overnight. It was filtered off to give 77 mg of the target compound. The filtrate was purified by preparative HPLC. An additional 7 mg of the title compound was obtained. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 2.17 (t, 3H), 3.09 (s, 3H), 3.63-3.72 (m, 2H), 3.76 (s, 3H), 3.98 (s , 3H), 7.34 (s, 1H), 7.98 - 8.06 (m, 1H), 8.29 - 8.35 (m, 2H), 8.55 (s, 1H), 10.70 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 453; Rt = 1.08 min (Methode B) . UPLC-MS (ESI +): [M + H] + = 453; R t = 1.08 min (method B).
Beispiel 11 6-(Difluormethyl)-N-[2-(3-hydroxy-3-methylbutyl)-5-methoxy-l-methyl-l//-benzimidazol-6- yl]pyridin-2-carboxamid Example 11 6- (Difluoromethyl) -N- [2- (3-hydroxy-3-methylbutyl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] pyridine-2-carboxamide
Figure imgf000056_0002
Figure imgf000056_0002
97 mg (368 μιηοΐ) 4-(6-Amino-5-methoxy-l-methyl-lii-benzimidazol-2-yl)-2-methylbutan-2-ol und 76.5 mg (442 μιηοΐ) 6-(Difluormethyl)pyridin-2-carbonsäure wurden mit 168 mg (442 μιηοΐ) HATU in Gegenwart von 260 μΐ (1.8 mmol) Triethylamin in 3.2 mL DMF bei Raumtemperatur über Nacht gerührt. Das Reaktionsgemisch wurde auf gesättigte Natriumhydrogencarbonatlösung gegeben und mit Ethylacetat extrahiert. Die organische Phase wurde mit gesättigter Kochsalzlösung gewaschen, über wasserabweisendes Papier filtriert und eingeengt. Dabei wurden 279 mg Rohprodukt erhalten, welches mit Flash-Chromatographie gereinigt wurde. So wurden 84 mg der Titelverbindung erhalten. Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 1.18 (s, 6H), 1.85 (m, 2H), 2.89 (m, 2H), 3.72 (s, 3H), 3.97 (s, 3H), 7.16 (t, 1H), 7.29 (s, 1H), 8.00 (dd, 1H), 8.32 (dd, 2H), 8.35 (dd, 1H), 10.55 (s, 1H). 97 mg (368 μιηοΐ) of 4- (6-amino-5-methoxy-1-methyl-1-benzimidazol-2-yl) -2-methylbutan-2-ol and 76.5 mg (442 μιηοΐ) 6- (difluoromethyl) pyridine 2-carboxylic acid were treated with 168 mg (442 μιηοΐ) of HATU in the presence of 260 μΐ (1.8 mmol) of triethylamine in 3.2 mL of DMF at room temperature overnight touched. The reaction mixture was added to saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, filtered over water-repellent paper and concentrated. This gave 279 mg of crude product, which was purified by flash chromatography. Thus, 84 mg of the title compound was obtained. Ή NMR (400MHz, DMSO-d 6 ): δ [ppm] = 1.18 (s, 6H), 1.85 (m, 2H), 2.89 (m, 2H), 3.72 (s, 3H), 3.97 (s, 3H ), 7.16 (t, 1H), 7.29 (s, 1H), 8.00 (dd, 1H), 8.32 (dd, 2H), 8.35 (dd, 1H), 10.55 (s, 1H).
UPLC-MS (ESI+): [M + H]+ = 419; Rt = 0.81 min (Methode E). UPLC MS (ESI +): [M + H] + = 419; R t = 0.81 min (method E).
Bewertung der physiologischen Wirksamkeit Evaluation of physiological activity
Inhibition der IKAK4 Kinaseaktivtät und Selektivität gegenüber TrkA und Flt3 Inhibition of IKAK4 Kinase Activity and Selectivity to TrkA and Flt3
IRAK4-Kinaseassay IRAK4 kinase assay
Die iRAK4-inhibitorische Aktivität der erfindungsgemäßen Substanzen wurde in dem nachfolgend beschriebenen Irak4-TR-FRET-Assay gemessen (TR-FRET = Time Resolved Fluorescence Resonance Energy Transfer).  The iRAK4 inhibitory activity of the substances according to the invention was measured in the subsequently described Iraq4-TR-FRET assay (TR-FRET = time-resolved fluorescence resonance energy transfer).
Rekombinantes Fusionsprotein aus N-terminalem GST (Glutathion-S-Transferase) und humanem IRAK4 (IRAK4 Accession Number NP_057207.2 (Uniport No Q9NWZ3)), exprimiert in Bakulovirus-infizierten Insektenzellen (Hi5, BTI-TN-5B1-4, Zelllinie gekauft von Invitrogen, Katalog-Nr. B 855-02) und gereinigt via Affinitätschromatographie, wurde als Enzym verwendet. Als Substrat für die Kinasereaktion wurde das biotinylierte Peptid Biotin-Ahx- KKARFSRFAGSSPSQASFAEPG (C-Terminus in Amid-Form) verwendet, das z.B. bei der Firma Biosyntan GmbH (Berlin-Buch) gekauft werden kann.  Recombinant fusion protein from N-terminal GST (glutathione S-transferase) and human IRAK4 (IRAK4 accession number NP_057207.2 (Uniport No Q9NWZ3)) expressed in baculovirus-infected insect cells (Hi5, BTI-TN-5B1-4, cell line purchased by Invitrogen, catalog No. B 855-02) and purified via affinity chromatography was used as the enzyme. As a substrate for the kinase reaction, the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in amide form) was used, e.g. can be bought at the company Biosyntan GmbH (Berlin-Buch).
Für den Assay wurden 11 verschiedene Konzentrationen im Bereich von 20 μΜ bis 0,073 nM aus einer 2 mM Lösung der Testsubstanz in DMSO hergestellt. 50 nl der jeweiligen Lösung wurden in eine schwarze low-volume 384well-Mikrotiterplatte (Greiner Bio-One, Frickenhausen, Deutschland) pipettiert, 2 μΐ einer Lösung von Irak4 in Assaypuffer [50 mM HEPES pH 7.5, 5 mM MgC12, 1.0 mM Dithiothreitol, 30 μΜ aktiviertes Natriumorthovanadat, 0,1 % (w/v) bovines gamma-Globulin (BGG) 0,04% (v/v) Nonidet-P40 (Sigma)] hinzugegeben und die Mischung für 15 min inkubiert, um eine Vorbindung der Substanzen an das Enzym vor der Kinasereaktion zu ermöglichen. Dann wurde die Kinasereaktion gestartet durch Zugabe von 3 μΐ einer Lösung von Adenosine-tri-phosphat (ATP, 1,67 mM =Endkonzentration in 5 μΐ Assayvolumen ist 1 mM) und Peptidsubstrat (0,83 μΜ =Endkonzentration in 5 μΐ Assayvolumen ist 0,5 μΜ) in Assaypuffer und die resultierende Mischung für die Reaktionszeit von 45 min bei 22°C inkubiert. Die Konzentration des Irak4 wurde an die jeweilige Aktivität des Enzyms angepasst und so eingestellt, dass der Assay im linearen Bereich arbeitete. Typische Konzentrationen lagen in der Größenordnung von etwa 0,2 nM. Die Reaktion wurde gestoppt durch Zugabe von 5 μΐ einer Lösung von TR-FRET-Detektionsreagentien [0,1 μΜ Streptavidin-XL665 (Cisbio Bioassays; Frankreich, Katalog-Nr. 610SAXLG) und 1,5 nM Anti- phosho-Serin Antikörper [Merck Millipore, „STK Antibody", Katalog-Nr. 35-002] und 0,6 nM LANCE EU-W1024-markierter anti-Maus-IgG-Antikörper (Perkin-Elmer, Produkt-Nr. AD0077, alternativ kann ein Terbium-Kryptat-markierter anti-Maus-IgG-Antikörper von Cisbio Bioassays verwendet werden) in wässriger EDTA-Lösung (100 mM EDTA, 0.4 % [w/v] bovines Serumalbumin [BSA] in 25 mM HEPES pH 7,5]. For the assay, 11 different concentrations ranging from 20 μΜ to 0.073 nM were prepared from a 2 mM solution of the test substance in DMSO. 50 μl of the respective solution were pipetted into a black low-volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of Iraq 4 in assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl 2, 1.0 mM dithiothreitol. Added 30 μΜ activated sodium orthovanadate, 0.1% (w / v) bovine gamma-globulin (BGG) 0.04% (v / v) Nonidet-P40 (Sigma)] and incubated the mixture for 15 min Allow substances to the enzyme before the kinase reaction. Then, the kinase reaction was started by adding 3 μΐ of a solution of adenosine tri-phosphate (ATP, 1.67 mM = final concentration in 5 μΐ assay volume is 1 mM) and peptide substrate (0.83 μΜ = final concentration in 5 μΐ assay volume is 0 , 5 μΜ) in assay buffer and the resulting mixture for the reaction time of 45 min at 22 ° C incubated. 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 μM of a solution of TR-FRET detection reagents [0.1 μL 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].
Die resultierende Mischung wurde 1 h bei 22°C inkubiert, um die Bildung eines Komplexes aus dem biotinylierten phosphorylierten Substrat und den Detektionsreagentien zu ermöglichen. Anschließend wurde die Menge des phosphorylierten Substrates ausgewertet durch eine Messung des Resonanz- Energietransfers vom Europium-Chelat markierten anti-Maus-IgG-Antikörper zum Streptavidin- XL665. Hierzu wurden in einem TR-FRET-Meßgerät, z.B. einem Rubystar (BMG Labtechnologies, Offenburg, Germany) oder einem Viewlux (Perkin-Elmer), die Fluoreszenz-Emissionen bei 620 nm and 665 nm nach Anregung bei 350 nm gemessen. Das Verhältnis der Emissionen bei 665 nm und 622 nm wurde als Maß für die Menge des phosphorylierten Substrates genommen. Die Daten wurden normalisiert (Enzymreaktion ohne Testsubstanz = 0 % Inhibition, alle anderen Assaykomponenten aber kein Enzym = 100 % Inhibition). Üblicherweise wurden die Testsubstanzen auf derselben Mikrotiterplatten bei 11 verschiedenen Konzentrationen im Bereich von 20 μΜ bis 0,073 nM getestet (20 μΜ, 5,7 μΜ, 1,6 μΜ, 0,47 μΜ, 0,13 μΜ, 38 nM, 11 nM, 3,1 nM, 0,89 nM, 0,25 nM und 0,073 nM). Die Verdünnungsreihen wurden vor dem Assay hergestellt (2 mM bis 7,3 nM in 100 % DMSO) durch serielle Verdünnungen. Die ICso-Werte wurden kalkuliert mit einem 4-Parameter-Fit. Die Beispielverbindungen zeigen eine Inhibition der IRAK4 Kinaseaktivität (siehe Tabelle 1). 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. The ratio of emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. The data were normalized (enzyme reaction without test substance = 0% inhibition, all other assay components but no enzyme = 100% inhibition). Typically, the test substances were tested on the same microtiter plates at 11 different concentrations ranging from 20 μΜ to 0.073 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 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).
Tabelle 1 : ICso-Werte der Beispielverbindungen im IRAK4, Flt3 und TrkA Kinase Assay Table 1: IC 50 values of the example compounds in the IRAK4, Flt3 and TrkA kinase assay
Beispiel IRAK4 Flt3 TrkA  Example IRAK4 Flt3 TrkA
IC50 [mol/1] IC50 [mol/1] IC50 [mol/1]  IC50 [mol / l] IC50 [mol / l] IC50 [mol / l]
1 3.97 E-8 4.43 E-7 1.99 E-5  1 3.97 E-8 4.43 E-7 1.99 E-5
6.17 E-8 1.60 E-5  6.17 E-8 1.60 E-5
2 5.28 E-8 2.46 E-7 > 2.00 E-5  2 5.28 E-8 2.46 E-7> 2.00 E-5
8.40 E-8 > 2.00 E-5  8.40 E-8> 2.00 E-5
3 7.91 E-9 2.81 E-7 1.68 E-5  3 7.91 E-9 2.81 E-7 1.68 E-5
6.52 E-9 > 5.71 E-6  6.52 E-9> 5.71 E-6
4 1.88 E-9 2.90 E-8 5.21 E-7  4 1.88 E-9 2.90 E-8 5.21 E-7
2.29 E-9 6.13 E-7  2.29 E-9 6.13 E-7
5 2.08 E-8 3.82 E-7 > 5.71 E-6  5 2.08 E-8 3.82 E-7> 5.71 E-6
4.47 E-7 > 5.71 E-6  4.47 E-7> 5.71 E-6
6 1.50 E-8 5.69 E-8 1.31 E-6  6 1.50 E-8 5.69 E-8 1.31 E-6
8.57 E-8 8.65 E-7  8.57 E-8 8.65 E-7
7 4.13 E-9 4.81 E-6 1.08 E-5  7 4.13 E-9 4.81 E-6 1.08 E-5
2.34 E-9 2.93 E-6 8.49 E-6 Beispiel IRAK4 Flt3 TrkA 2.34 E-9 2.93 E-6 8.49 E-6 Example IRAK4 Flt3 TrkA
IC50 [mol/1] IC50 [mol/1] IC50 [mol/1]  IC50 [mol / l] IC50 [mol / l] IC50 [mol / l]
8 3.29 E-9 3.19 E-6 6.53 E-6  8 3.29 E-9 3.19 E-6 6.53 E-6
2.39 E-9 2.04 E-6 3.84 E-6  2.39 E-9 2.04 E-6 3.84 E-6
9 1.77 E-8 5.62 E-7 > 2.00 E-5  9 1.77 E-8 5.62 E-7> 2.00 E-5
1.94 E- 8 6.45 E-7 > 2.00 E-5  1.94 E- 8 6.45 E-7> 2.00 E-5
10 4.85 E-9 8.72 E-8 > 2.00 E-5  10 4.85 E-9 8.72 E-8> 2.00 E-5
5.06 E-9 8.93 E-8 > 2.00 E-5  5.06 E-9 8.93 E-8> 2.00 E-5
11 1.50 E-9 4.49 E-8 2.93 E-7  11 1.50 E-9 4.49 E-8 2.93 E-7
2.08 E-9 6.35 E-8 3.68 E-7  2.08 E-9 6.35 E-8 3.68 E-7
Bindungskinetik der Beispielverbindungen an IRAK4 Binding kinetics of the example compounds at IRAK4
Dieses Experiment stellt direkt die Interaktion zwischen den Testsubstanzen und dem IRAK4 Protein dar. Bindungskinetikmessungen können Testsubstanzen mit langen Dissoziationsraten ermitteln, welche zu einer längeren Target-Bindung und damit Aktivität am Target in den Zellen führen kann.  This experiment directly illustrates the interaction between the test substances and the IRAK4 protein. Binding kinetics measurements can identify test substances with long dissociation rates, which can lead to longer target binding and thus activity at the target in the cells.
Für die Surface Plasmon Resonance (SPR) Messungen wurde ein rekombinantes, biotinyliertes Volllängen- Protein IRAK4 (Aminosäure 1-460 von IRAK4 Accession Number NP_057207.2 (Uniport No Q9NWZ3)) verwendet, welches von von Carna Biosciences, Japan (Produkt Nummer: 09-445-20N) gekauft wurde. Das biotinylierte IRAK4 Protein wurde mit Hilfe der Streptavidin-Biotin Interaktion auf einem SA-Biacore Chip (GE Healthcare, Produkt Nummer 29104992) immobilisiert. Dafür wurde das biotinylierte IRAK4 Protein in lx HBS-EP+ (hergestellt aus lOx HBS-EP+ Puffer (GE Healthcare, Produkt Nummer BR100669)) auf 5μg/ml verdünnt und anschließend auf der Streptavidin Oberfläche des SA-Biacore Chips im gleichen Puffer eingefangen. Dabei ergab sich ein Signal von ungefähr 1000 response units. Die Referenzzelle bestand aus nicht abgesättigtem Streptavidin. Die Testsubstanzen wurden in 100% Dimethylsulfoxid (DMSO, Sigma-Aldrich, Deutschland) auf 10 mM verdünnt und anschließend in Laufpuffer weiterverdünnt (lx HBS-EP+ pH 7.4 [hergestellt aus HBS-EP+ Puffer lOx (GE Healthcare): 0.1 M HEPES, 1.5 M NaCl, 30 mM EDTA und 0.5% v/v Detergenz P20], 1% v/v DMSO). Für die kinetischen Messungen wurden serielle Verdünnungen (0.235 nM bis 0.15μΜ) der Testsubstanzen hergestellt, die dann über die Oberfläche injiziert wurden. Die Bindungskinetik wurde bei 25°C und einer Flußrate von ΙΟΟμΙ/min in Laufpuffer gemessen. Die Testsubstanzen werden dafür für 80s injiziert und dann für 1000s die Dissoziation aufgenommen. Die erhaltenen Sensogramme werden gegen einen Leerwert und die Referenzoberfläche doppelt referenziert und mit der Biacore T200 Evaluation Software mit der in der Software hinterlegten Formel nach einem 1 : 1 Bindungsmodell gefittet. For surface plasmon resonance (SPR) measurements, a recombinant biotinylated full-length protein 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). For this, the biotinylated IRAK4 protein in lx HBS-EP + (prepared from 10x HBS-EP + buffer (GE Healthcare, product number BR100669)) was diluted to 5 μg / 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. The 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). For the kinetic measurements serial dilutions (0.235 nM to 0.15μΜ) of the test substances were prepared, which were then injected over the surface. The binding kinetics were measured at 25 ° C and a flow rate of ΙΟΟμΙ / min in running buffer. The 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.
Die Target residence time ist der reziproke Wert des koff Wertes, target residence time = 1/koff.  The target residence time is the reciprocal value of the koff value, target residence time = 1 / koff.
Die Beispiel Verbindungen zeigen eine lange Verweildauer an IRAK4 (siehe Tabelle 2). Tabelle 2: Bindungskinetik der Beispielverbindungen
Figure imgf000060_0001
The example compounds show a long residence time on IRAK4 (see Table 2). Table 2: Binding kinetics of the example compounds
Figure imgf000060_0001
TrkA-Kinaseassay TrkA kinase assay
Trk (tropomyosin-related kinase)-A wird durch die Bindung von NGF (Nerve growth factor) aktiviert. Es ist beispielsweise in der malignen Transformation, der Chemotaxis und Metastasis von Tumoren involviert. Insbesondere ist TrkA mit nociceptiven and neuropathischen Schmerz bei Erwachsenen inklusive chronischem Schmerz und Krebsschmerzen assoziiert (Hirose, Kuroda, et al., Pain Practice, 2016).  Trk (tropomyosin-related kinase) -A is activated by the binding of NGF (nerve growth factor). It is involved, for example, in the malignant transformation, chemotaxis and metastasis of tumors. In particular, TrkA is associated with nociceptive and neuropathic pain in adults, including chronic pain and cancer pain (Hirose, Kuroda, et al., Pain Practice, 2016).
Es ist jedoch zu beachten, dass Trk- A wichtig für die Entwicklung von sympathischen Nerven ist. Patienten mit einer Loss-of-Function Mutation in TrkA entwicklen hereditären sensorischen und autonomen Neuropathie Typ IV (CIPA, congenital insensitivity to pain and anhidrosis), welcher mit einer erheblichen Störung des Schmerz- und Temperatursinns einhergeht (Indo, Clinical Genetics, 2012). Des Weiteren scheint TrkA eine Rolle bei der Reifung von cholinergen Neuronen, bei der Entwicklung des Thymus, der frühen Ovarialentwicklung und bei der Entwicklung von bestimmen Immunzellen zu spielen (Tessarollo, L., Cytokine & Growth Factor Reviews, 1998; Garcia-Suärez, Germanä, et al., Journal of Neuroimmunology, 2000; Coppola, Barrick, et al., Development, 2004; Dissen, Garcia-Rudaz, et al., Seminars in reproductive medicine, 2009). Aufgrund der genannten potentiellen Funktionen wurde die Selektivität bezüglich TrkA bestimmt.  It should be noted, however, that 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). Furthermore, 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.
Die TrkA-inhibitorische Aktivität der Substanzen dieser Erfindung wurde in dem nachfolgend beschriebenen TrkA-HTRF-Assay (HTRF = Homogeneous Time Resolved Fluorescence) gemessen. Als Kinase wurde ein rekombinantes Fusionsprotein aus N-terminalem His6-getaggten GST und einem C-terminalen Fragment des humanen TrkA (Aminosäuren 443-796 von TrkA Accession- Number NP_002520.2), exprimiert in Bakulovirus-infizierten Insektenzellen (Sf9) und gereinigt durch Affinitätschromatographie, verwendet, das von der ProQinase GmbH, Freiburg (Product No.: 0311- 0000-2) gekauft wurde. Als Substrat für die Kinasereaktion wurde biotinyliertes poly-Glu,Tyr (4: 1)- Kopolymer von CisBio Bioassays (# 61GT0BLA) verwendet. The TrkA inhibitory activity of the substances of this invention was measured in the TrkA-HTRF Assay (HTRF = Homogeneous Time Resolved Fluorescence) described below. As 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). As a substrate for the kinase reaction, biotinylated poly-Glu, Tyr (4: 1) copolymer from CisBio Bioassays (# 61GT0BLA) was used.
Für den Assay wurden 50 nl einer lOOfach konzentrierten Lösung der Testsubstanz in DMSO in eine schwarze low-volume 384well-Mikrotiterplatte (Greiner Bio-One, Frickenhausen, Deutschland) pipettiert, 2 μΐ einer Lösung von TrkA in Assaypuffer [8 mM MOPS/HCl pH 7,0, 10 mM MgCl2, 1,0 mM Dithiothreitol, 0,2 mM EDTA, 0,01% (v/v) Nonidet-P40 (Sigma)] hinzugegeben und die Mischung für 15 min inkubiert, um eine Vorbindung der Substanzen an das Enzym vor der Kinasereaktion zu ermöglichen. Dann wurde die Kinasereaktion gestartet durch Zugabe von 3 μΐ einer Lösung von Adenosine-tri-phosphat (ATP, 16,7 μΜ => Endkonzentration in 5 μΐ Assayvolumen ist 10 μΜ) und Substrat (2,27 μg/ml μΜ => Endkonzentration in 5 μΐ Assayvolumen ist 1,36 μg/ml) in Assaypuffer und die resultierende Mischung für die Reaktionszeit von 60 min bei 22°C inkubiert. Die Konzentration des TrkA wurde an die jeweilige Aktivität des Enzyms angepasst und so eingestellt, dass der Assay im linearen Bereich arbeitete (typische TrkA-Endkonzentrationen im 5-μ1- Assayvolumen lagen in der Größenordnung von etwa 20 pg/μΐ). Die Reaktion wurde gestoppt durch Zugabe von 5 μΐ einer Lösung von HTRF-Detektionsreagentien (30 nM Streptavidin-XL665 (Cisbio Bioassays, Frankreich) und 1,4 nM PT66-Eu-Chelat, ein Europiumchelat-markierter anti-Phospho- Tyrosin Antikörper von Perkin Elmer (statt des PT66-Eu-Chelat kann auch PT66-Tb-Kryptat von Cisbio Bioassays verwendet werden) in wässriger EDTA-Lösung (100 mM EDTA, 0.2 % (w/v) Bovines Serumalbumin (BSA) in 50 mM HEPES/HC1 pH 7.0). Die resultierende Mischung wurde 1 h bei 22°C inkubiert, um die Bildung eines Komplexes aus dem biotinylierten phosphorylierten Substrat und den Detektionsreagentien zu ermöglichen. Anschließend wurde die Menge des phosphorylierten Substrates ausgewertet durch eine Messung des Resonanz -Energietransfers vom PT66-Eu-Chelat zum Streptavidin-XL665. Hierzu wurden in einem HTRF-Meßgerät, z.B. einem Pherastar (BMG Labtechnologies, Offenburg, Deutschland) oder einem Viewlux (Perkin-Elmer), die Fluoreszenz- Emissionen bei 620 nm und 665 nm nach Anregung bei 350 nm gemessen. Das Verhältnis der Emissionen bei 665 nm und at 622 nm wurde als Maß für die Menge des phosphorylierten Substrates genommen. Die Daten wurden normalisiert (Enzymreaktion ohne Inhibitor = 0 % Inhibition, alle anderen Assaykomponenten aber kein Enzym = 100 % Inhibition). Üblicherweise wurden die Testsubstanzen auf derselben Mikrotiterplatten bei 11 verschiedenen Konzentrationen im Bereich von 20 μΜ bis 0,072 nM (20 μΜ, 5,7 μΜ, 1,6 μΜ, 0,47 μΜ, 0,13 μΜ, 38 nM, 11 nM, 3,1 nM, 0,89 nM, 0,25 nM and 0,072 nM) getestet , die Verdünnungsreihen wurden vor dem Assay hergestellt auf der Ebene der lOOfach konzentrierten Lösung [d.h. 2 mM bis 7,2 nM in 100 % DMSO] durch serielle Verdünnungen, die exakten Konzentrationen können verschieden sein in Abhängigkeit von den jeweils verwendeten Pipettoren) in Doppelwerten für jede Konzentration getestet und IC50-Werte wurden kalkuliert mit einem 4-Parameter-Fit. For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of TrkA in assay buffer [8 mM MOPS / HCl pH 7.0, 10mM MgCl 2 , 1.0mM dithiothreitol, 0.2mM EDTA, 0.01% (v / v) Nonidet-P40 (Sigma)], and the mixture incubated for 15 min Allow substances to the enzyme before the kinase reaction. Then the kinase reaction was started by adding 3 μΐ of a solution of adenosine tri-phosphate (ATP, 16.7 μΜ => final concentration in 5 μΐ assay volume is 10 μΜ) and substrate (2.27 μg / ml μΜ => final concentration in 5 μΐ assay volume is 1.36 μg / ml) in Assay buffer and the resulting mixture for the reaction time of 60 min at 22 ° C incubated. 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 μL assay volume were on the order of about 20 pg / μΐ). The reaction was stopped by adding 5 μl 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. to allow the formation of a complex of the biotinylated phosphorylated substrate and the detection reagents, then 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. The data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components but no enzyme = 100% inhibition). Usually, the test substances were incubated on the same microtiter plates at 11 different concentrations ranging from 20 μΜ to 0.072 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 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.
Die Beispielverbindungen zeigen eine hohe Selektivität gegenüber TrkA (siehe Tabelle 1).  The example compounds show a high selectivity towards TrkA (see Table 1).
Flt3-Kinaseassay Flt3 kinase assay
Flt3 (Fms-like tyrosine kinase 3) wird vor allem von hematopoietischen Vorläuferzellen exprimiert und ist in der Entwicklung von hematopoietischen Stammzellen inbesondere von Dendritischen Zellen 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) involviert. Akute myeloische Leukämie ist mit Gain-of-Function Mutationen in Flt3 assoziiert.(DCs) involved. Acute myeloid leukemia is associated with gain-of-function mutations in Flt3.
Des Weiteren ist die Funktion von Flt3 in die Pathogenese von unterschiedlichen entzündlichenFurthermore, the function of Flt3 in the pathogenesis of different inflammatory
Erkrankungen involviert (Ramos, Tak, et al., Autoimmunity Reviews, 2014). Diseases involved (Ramos, Tak, et al., Autoimmunity Reviews, 2014).
Andererseits weisen Mäuse, die nicht Flt3 exprimieren, eine erhöhte Empfindlichkeit gegenüber Infektionen mit Zytomegalovirus und Toxoplasma gondii auf (Eidenschenk, Crozat, et al., PNAS, On the other hand, mice that do not express Flt3 exhibit increased sensitivity to cytomegalovirus and Toxoplasma gondii infections (Eidenschenk, Crozat, et al., PNAS,
2010; Dupont, Harms Pritchard, et al., The Journal of Immunology, 2015). Der Flt3 Signalweg ist essentiell für die Mobilisierung von DCs und für die T-Zell Antwort gegen Plasmodium Infektionen (Guermonprez, Helft, et al., Nature Medicine, 2013). Somit ist die Funktion von Flt3 für die 2010; Dupont, Harms Pritchard, et al., The Journal of Immunology, 2015). 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). Thus, the function of Flt3 is for the
Immunantwort gegen bestimmte Infektionen wichtig. Aufgrund dessen wurde eine potentielle Inhibierung der Flt3 Aktivität untersucht. Immune response against certain infections important. Because of this, a potential inhibition of Flt3 activity was investigated.
Die Flt3 -inhibitorische Aktivität der Substanzen dieser Erfindung wurde in dem in dem nachfolgend beschriebenen Flt3-HTRF-Assay gemessen (HTRF = Homogeneous Time Resolved Fluorescence). The Flt3 inhibitory activity of the substances of this invention was measured in the Flt3-HTRF assay described below (HTRF = Homogeneous Time Resolved Fluorescence).
Als Kinase wurde ein rekombinantes Fusionsprotein aus N-terminalem GST und einem C-terminalen Fragment des humanen Flt3 (Aminosäuren 564-Ende von Flt3 GenBank NM_004119), exprimiert in Bakulovirus-infizierten Insektenzellen (Sf21) und gereinigt durch Affinitätschromatographie, verwendet, das von Merck Millipore (Katalog-Nr. 14-500) gekauft wurde. Als Substrat für die Kinasereaktion wurde das biotinylierte Peptid Biotin-Ahx- GGEEEEYFELVKKKK (C-Terminus in Amidform) verwendet, das z.B. bei der Firma Biosynthan GmbH (Berlin-Buch, Germany) gekauft werden kann. As the kinase, 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. As a substrate for the kinase reaction, 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).
Für den Assay wurden 50 nl einer lOOfach konzentrierten Lösung der Testsubstanz in DMSO in eine schwarze low-volume 384well-Mikrotiterplatte (Greiner Bio-One, Frickenhausen, Deutschland) pipettiert, 2 μΐ einer Lösung von Flt3 in Assaypuffer [25 mM HEPES pH 7,5, 10 mM MgCl2, 5 mM Glycerol-2-phosphat, 2 mM Dithiothreitol (DTT), 0,5 mM EDTA, 0,01% (v/v) Triton X-100 (Sigma)] hinzugegeben und die Mischung für 15 min inkubiert, um eine Vorbindung der Substanzen an das Enzym vor der Kinasereaktion zu ermöglichen. Dann wurde die Kinasereaktion gestartet durch Zugabe von 3 μΐ einer Lösung von Adenosine-tri-phosphat (ATP, 16,7 μΜ =>Endkonzentration in 5 μΐ Assayvolumen ist 10 μΜ) und Substrat (1,67 μΜ => Endkonzentration in 5 μΐ Assayvolumen ist 1 μΜ) in Assaypuffer und die resultierende Mischung für die Reaktionszeit von 45 min bei 22°C inkubiert. Die Konzentration des Flt3 wurde an die jeweilige Aktivität des Enzyms angepasst und so eingestellt, dass der Assay im linearen Bereich arbeitete (typische Flt3 -Endkonzentrationen im 5-μ1- Assayvolumen lagen in der Größenordnung von etwa 0,2 nM) . Die Reaktion wurde gestoppt durch Zugabe von 5 μΐ einer Lösung von HTRF-Detektionsreagentien (0,2 μΜ Streptavidin-XL665 (Cisbio Bioassays, Frankreich) und 3 nM PT66-Eu-Chelat, ein Europiumchelat-markierter anti-Phospho- Tyrosin Antikörper von Perkin Elmer [statt des PT66-Eu-Chelat kann auch PT66-Tb-Kryptat von Cisbio Bioassays verwendet werden) in wässriger EDTA-Lösung (50 mM EDTA, 0.1 % (w/v) Bovines Serumalbumin (BSA) in 50 mM HEPES pH 7.5). For the assay, 50 μl of a 100 × concentrated solution of the test substance in DMSO were pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of Flt3 in assay buffer [25 mM HEPES pH 7, 5, 10mM MgCl 2 , 5mM glycerol-2-phosphate, 2mM dithiothreitol (DTT), 0.5mM EDTA, 0.01% (v / v) Triton X-100 (Sigma)] was added and the mixture was incubated Incubated for 15 min to allow a Vorbindung the substances to the enzyme before the kinase reaction. Then, the kinase reaction was started by adding 3 μΐ of a solution of adenosine tri-phosphate (ATP, 16.7 μΜ => final concentration in 5 μΐ assay volume is 10 μΜ) and substrate (1.67 μΜ => final concentration in 5 μΐ assay volume 1 μΜ) in assay buffer and the resulting mixture for the reaction time of 45 min at 22 ° C incubated. The 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 μL assay volume were on the order of about 0.2 nM). The reaction was stopped by adding 5 μΐ of a solution of HTRF detection reagents (0.2 μΜ 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 ).
Die resultierende Mischung wurde 1 h bei 22°C inkubiert, um die Bildung eines Komplexes aus dem biotinylierten phosphorylierten Substrat und den Detektionsreagentien zu ermöglichen. Anschließend wurde die Menge des phosphorylierten Substrates ausgewertet durch eine Messung des Resonanz- Energietransfers vom PT66-Eu-Chelat zum Streptavidin-XL665. Hierzu wurden in einem HTRF- Meßgerät, z.B. einem Pherastar (BMG Labtechnologies, Offenburg, Deutschland) oder einem 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
Viewlux (Perkin-Elmer), die Fluoreszenz-Emissionen bei 620 nm and 665 nm nach Anregung bei 350 nm gemessen. Das Verhältnis der Emissionen bei 665 nm und at 622 nm wurde als Maß für die Menge des phosphorylierten Substrates genommen. Die Daten wurden normalisiert (Enzymreaktion ohne Inhibitor = 0 % Inhibition, alle anderen Assaykomponenten aber kein Enzym = 100 % Inhibition). Üblicherweise wurden die Testsubstanzen auf derselben Mikrotiterpl arten bei 11 verschiedenen Konzentrationen im Bereich von 20 μΜ bis 0,072 nM (20 μΜ, 5,7 μΜ, 1,6 μΜ, 0,47 μΜ, 0,13 μΜ, 38 nM, 11 ηΜ, 3,1 ηΜ, 0,89 ηΜ, 0,25 nM and 0,072 nM) getestet , die Verdünnungsreihen wurden vor dem Assay hergestellt auf der Ebene der lOOfach konzentrierten Lösung [d.h. 2 mM bis 7,2 nM in 100 % DMSO] durch serielle Verdünnungen, die exakten Konzentrationen können verschieden sein in Abhängigkeit von den jeweils verwendeten Pipettoren) in Doppelwerten für jede Konzentration getestet und IC50-Werte wurden kalkuliert mit einem 4-Parameter-Fit. 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 at 622 nm was taken as a measure of the amount of phosphorylated substrate. The data were normalized (enzyme reaction without Inhibitor = 0% inhibition, all other assay components but no enzyme = 100% inhibition). Usually, the test substances were incubated on the same microtiter plate at 11 different concentrations ranging from 20 μΜ to 0.072 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 nM, 11 ηΜ, 3.1 ηΜ, 0.89 ηΜ, 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.
Die Beispielverbindungen zeigen eine hohe Selektivität gegenüber Flt3 (siehe Tabelle 1). The example compounds show a high selectivity towards Flt3 (see Table 1).
TNF-α Ausschüttung in THP-1 Zellen TNF-α release into THP-1 cells
Mithilfe dieses Tests können Substanzen auf ihre Fähigkeit hin getestet werden, TNF-a (Tumornekrosefaktor-alpha) Ausschüttung in THP-1 Zellen (humane monozytische akute Leukämie-Zellinie) zu inhibieren. TNF-α ist ein Zytokin, welches in inflammatorischen Prozessen beteiligt ist. Die TNF-α Ausschüttung wird in diesem Test ausgelöst durch Inkubation mit bakteriellem Lipopolysaccharid (LPS). The assay will test for the ability to inhibit TNF-a (tumor necrosis factor-alpha) release in THP-1 cells (human monocytic acute leukemia cell line). TNF-α is a cytokine involved in inflammatory processes. The TNF-α release is triggered in this assay by incubation with bacterial lipopolysaccharide (LPS).
THP-1 Zellen werden in kontinuierlicher Suspensions-Zellkultur [RPMI 1460 Medium ohne L-Glutamax (GE Healthcare, Kat.-Nr. El 5-039) supplementiert mit foetalem Kälberserum (FCS) 10% (Invitrogen, Kat-Nr. 10082-147), 1% L-Glutamine (Sigma, Kat.-Nr. G7513), 1% Penicillin/Streptomycin (PAA, Kat.-Nr. PI 1-010) und 50 μΜ 2-Mercaptoethanol (Gibco, Kat.-Nr. 31350-010)] gehalten und sollten eine Zellkonzentration von lxlO6 Zellen/ml nicht überschreiten. Der Assay erfolgte im Zellkulturmedium (RPMI 1460 Medium supplementiert mit L-Glutamine, Penicillin, Streptomycin und 2-Mercaptoethanol). 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 50μl 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).
Die THP-1 Zellen wurden in 96-well Platten mit einer Zelldichte von 2.5xl05 Zellen/well ausgesät. Die erfindungsgemäßen Verbindungen wurden in einem konstanten Volumen von 100% DMSO seriell verdünnt und in dem Assay mit 8 verschiedenen Konzentrationen im Bereich von 10 μΜ bis 3 nM so eingesetzt, so dass die finale DMSO Konzentration 0.4% DMSO betrug. Die Zellen wurden damit für 30 min vor der eigentlichen Stimulation vorinkubiert. Zur Induktion der Zytokinsekretion erfolgte eine Stimulation mit 1 μg/ml LPS (Sigma, Escherichia coli 0127:B8, Kat.-Nr. L4516) für 6 Stunden. Als Neutralkontrolle wurden Zellen mit 1 μg/ml LPS und 0.04 % DMSO und als Inhibitorkontrolle nur mit 0.04 % DMSO behandelt. Die Bestimmung der Zellviabilität erfolgte unter Verwendung des CellTiter-Glo Luminescent Assay (Promega, Kat.-Nr. G7571 (G755/G756A)) nach Anweisung des Herstellers. Die Bestimmung der Menge an sekretiertem TNF-α im Zellkulturüberstand erfolgte mittels Human Prolnflammatory 9-Plex Tissue Culture Kit (MSD, Kat.-Nr. K15007B) nach Anweisung des Herstellers. 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 μΜ to 3 nM so that the final DMSO concentration was 0.4% DMSO. The cells were preincubated for 30 min before the actual stimulation. For the induction of cytokine secretion, stimulation was carried out with 1 μg / ml LPS (Sigma, Escherichia coli 0127: B8, Cat. No. L4516) for 6 hours. As a neutral control, cells were treated with 1 μg / ml LPS and 0.04% DMSO and as inhibitor control only with 0.04% DMSO. Determination of cell viability was performed using the CellTiter-Glo Luminescent Assay (Promega, Cat # G7571 (G755 / G756A)) as directed by the manufacturer. The determination of the amount of secreted TNF-α in the Cell culture supernatant was prepared using the Human Prolifflammatory 9-Plex Tissue Culture Kit (MSD, Cat # K15007B) as directed by the manufacturer.
Die Wirkung der Substanzen wird als Verhältnis zwischen Neutral- und Inhibitorkontrolle in Prozent ausgedrückt. Die ICso-Werte wurden mit einem 4-Parameter-Fit kalkuliert. 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.
Tabelle 3: ICso-Werte der Beispielverbindungen bezüglich der TNF-α Ausschüttung in THP- 1 Zellen, die die Zellviabilität nicht beeinflusst haben.
Figure imgf000064_0001
Table 3: IC 50 values of the exemplary compounds for TNF-α release in THP-1 cells that did not affect cell viability.
Figure imgf000064_0001
In vitro Mikrokerntest  In vitro micronucleus test
Das Fehlen klastogener Eigenschaften, das heißt ein negatives Ergebnis im in vitro Mikrokerntest, ist bei einem Wirkstoffkandidaten für die Therapie nicht-lebensbedrohlicher Erkrankungen von großer Bedeutung, da Klastogenität mit einer mutagenen Wirkung verknüpft sein kann und folglich zu einem höheren Krebsrisiko des mit dem Wirkstoff behandelten Patienten führen kann. Es wurde mit einem in vitro Mikrokerntest (in vitro MNT, vgl. OECD Test Guideline 487, 2014; Bryce SM et al., Mutation Research, 2008) untersucht, ob die Beispielverbindung 7 Chromosomenbrüche (strukturelle Chromosomenaberrationen) oder eine Fehlverteilung der Chromosomen, die zu Aneuploidie führt, induziert. Der Test wurde in Abwesenheit und Gegenwart eines extrinsischen metabolisierenden Systems (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) durchgeführt. Es wurden V79 Zellen des Chinesischen Hamsters verwendet. Der in vitro MNT zeigte keinen Anstieg der Mikrokernrate in mit der Beispielverbindung 7 behandelten V79 Zellen, weder in Abwesenheit noch in Gegenwart von S9 Mix. Negativ- und Positivkontrollen mit bekannten Mutagenen (Mitomycin C, Cyclophosphamid, Vinblastin) zeigten die Eignung und Empfindlichkeit des Testsystems. Zusammenfassend zeigte Beispielverbindung 7 keinen Hinweis auf Mutagenität im in vitro MNT, wobei die Substanz bis zur Löslichkeitsgrenze (Präzipitation) getestet wurde. Zusätzlich zeigte Beispielverbindung 10 keinen Hinweis auf Mutagenität im in vitro MNT, wobei die Substanz bis zur Löslichkeitsgrenze (Präzipitation) getestet wurde. In vivo IL-lß-vermitteltes Inflammationsmodel The lack of clastogenic properties, that is a negative result in the in vitro micronucleus test, is of great importance for a drug candidate for the treatment of non-life-threatening diseases, since clastogenicity may be linked to a mutagenic effect and consequently to a higher cancer risk of the drug treated Patients can lead. An in vitro micronucleus test (in vitro MNT, see OECD Test Guideline 487, 2014, Bryce SM et al., Mutation Research, 2008) was used to investigate whether the example compound has 7 chromosomal breaks (structural chromosome aberrations) or a maldistribution of the chromosomes induces aneuploidy. 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 ™ 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. The in vitro MNT showed no increase in microkernel rate in V79 cells treated with Exemplified Compound 7, either in the absence or in the presence of S9 mix. Negative and positive controls with known mutagens (mitomycin C, cyclophosphamide, vinblastine) demonstrated the suitability and sensitivity of the test system. In summary, Example Compound 7 showed no evidence of mutagenicity in in vitro MNT, with the substance tested to solubility limit (precipitation). In addition, Example Compound 10 showed no evidence of mutagenicity in the in vitro MNT, with the substance being tested to the solubility limit (precipitation). In vivo IL-lß-mediated inflammation model
Zur Erfassung der potentiellen Wirksamkeit der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) in IL-l ß-vermittelten Erkrankungen, werden weiblichen Balb/c Mäusen (ca. 8 Wochen, Charles River Laboratories, Deutschland) IL- l ß i.p. appliziert und die Wirkung der erfindungsgemäßen Verbindungen auf die IL- l ß -vermittelte Zytokinsekretion untersucht. Die Gruppengröße beträgt jeweils 5 Tiere. Die Kontrollgruppe wird mit den Vehikeln, welche zur Lösung der Substanz und des IL-l ß eingesetzt werden, behandelt. Den Substanz-behandlungsgruppen und der Positivkontrollgruppe wird jeweils 90 μg IL-l ß kg Körpergewicht (R&D, Kat.-Nr. 401-ML/CF) i.p verabreicht. Die Substanz bzw. dessen Vehikel in der Positivkontrollgruppe wird 6 Stunden vor der IL-l ß Verabreichung appliziert. Die Bestimmung von TNF-α im Plasma nach finaler Blutentnahme erfolgt 2 Stunden nach Verabreichung des IL-l ß mittels des Mouse Prolnflammatory 7-Plex Tissue Culture Kit (MSD, Kat.-Nr. K15012B) nach Anweisung des Herstellers. In vivo Adjuvanz-induziertes Arthritismodell To measure the potential effectiveness of the compounds of the general formula (I) according to the invention in IL-1β-mediated diseases, female Balb / c mice (about 8 weeks, Charles River Laboratories, Germany) are injected with IL-1β.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-1β. Each of the substance treatment groups and the positive control group is administered with 90 μg IL-1β 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. The determination of TNF-α 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. In vivo adjuvant-induced arthritis model
Zur Ermittlung der anti-inflammatorischen Aktivität der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) wird diese in einem Arthritismodel hinsichtlich ihrer in vivo Wirksamkeit untersucht. Hierzu werden männlichen Lewis-Ratten (ca. 100- 125g, Charles River Laboratories, Deutschland) je ΙΟΟμΙ einer Complete- Freund 'sehen Adjuvanz (CFA)-Lösung (M. tuberculosis H37Ra [Difo Lab, Kat.-Nr. -231141] gelöst in Incomplete Freund'schen Adjuvanz [Difco Lab, Kat.- Nr. -263910]) subkutan in die Schwanzwurzel an Tag 0 appliziert. Die Gruppengröße beträgt jeweils n= 8 Ratten. Es wird sowohl eine gesunde Kontrollgruppe als auch eine Erkrankungs-Kontrollgruppe im Experiment mitgeführt. Beide Kontrollgruppen werden jeweils nur mit dem Vehikel der Prüfsubstanz p.o. behandelt. Die Behandlung mit unterschiedlichen Dosierungen der Prüfsubstanz wird präventiv, d.h. ab Tag 0, per oraler Gabe durchgeführt. An Tag 0 wird zudem die Ausgangssituation der Tiere bezüglich des Disease Activity Scores (Bewertung des Schweregrads der Arthritis anhand eines Punktesystems) bestimmt. In diesem Punktesystem (Score) werden je nach Ausmaß der Gelenkentzündung Punkte von 0 bis 4 für das Vorhandensein eines Erythems inklusive einer Gelenkschwellung (0= keine; l=leicht; 2= moderat; 3=deutlich; 4=massiv) für beide Hinterpfoten vergeben und addiert. Zur Ermittlung der anti-entzündlichen Wirksamkeit der Verbindungen wird ab Tag 8, an dem die Tiere erstmals Zeichen einer Arthritis zeigen, und weiterfolgend 3 Mal in der Woche der Erkrankungsstatus der Tiere mittels Disease Activity Score bis zum Ende (Tag 20) bewertet. Die statistische Analyse erfolgt unter Verwendung der einfaktoriellen Varianzanalyse (ANOVA; Analysis of Variance) und dem Vergleich zur Kontrollgruppe mittels multipler Vergleichsanalyse (Dunnett-Test). To determine the anti-inflammatory activity of the compounds of the general formula (I) according to the invention, this is examined in an arthritis model with regard to their in vivo effectiveness. For this purpose, male Lewis rats (about 100-125 g, Charles River Laboratories, Germany) are each given ΙμΙ of a Complete Freunds Adjuvanz (CFA) solution (M. tuberculosis H37Ra [Difo Lab, cat. dissolved in Incomplete Freund's adjuvant [Difco Lab, Cat. No. 263910]) applied subcutaneously to the tail root on day 0. The group size is in each case n = 8 rats. Both a healthy control group and a disease control group are included in the experiment. Both control groups are in each case only with the vehicle of the test substance p.o. treated. The treatment with different dosages of the test substance is preventive, i. from day 0, carried out by oral administration. On day 0, the starting situation of the animals with regard to the disease activity score (evaluation of the severity of the arthritis using a scoring system) is also determined. Depending on the degree of arthritis, this scoring system assigns points from 0 to 4 for the presence of erythema including joint swelling (0 = none, l = easy, 2 = moderate, 3 = clear, 4 = massive) for both hind paws and added. To determine the anti-inflammatory activity of the compounds from Day 8, on which the animals show signs of arthritis for the first time, and subsequently 3 times a week 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).

Claims

Patentansprüche claims
1 Verbindun en der allgemeinen Formel (I) 1 compound of general formula (I)
Figure imgf000066_0001
Formel (I) worin
Figure imgf000066_0001
Formula (I) wherein
R1 für -C(=0)0(Ci-C3-Alkyl), R6S(=0)2-, R6S(=0)- oder für eine Gruppe steht, ausgewählt aus: R 1 is -C (= O) O (C 1 -C 3 -alkyl), R 6 is S (= O) 2 -, R 6 is S (= O) - or is a group selected from:
Figure imgf000066_0002
Figure imgf000066_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff, Ci-C3-Alkyl steht und R 5 is hydrogen, C 1 -C 3 -alkyl and
R6 für Ci-C4-Alkyl, Cyclopropyl, Cylopropylmethyl oder 2,2,2-Trifluorethyl steht; R 6 is C 1 -C 4 alkyl, cyclopropyl, cyclopropylmethyl or 2,2,2-trifluoroethyl;
R2 für Cyclopropylmethyl oder Ci-Cö-Alkyl, welches ein- bis dreifach mit Fluor substituiert sein kann, steht; R 2 is cyclopropylmethyl or C 1 -C 6 -alkyl which may be substituted one to three times by fluorine;
R3 für C3-C6-Cycloalkyl oder Ci-Cö-Alkyl, welches ein- bis fünffach mit Fluor substituiert sein kann, steht; R 3 is C 3 -C 6 -cycloalkyl or C 1 -C 6 -alkyl which may be substituted one to five times by fluorine;
R4 für Wasserstoff oder Fluor steht; R 4 is hydrogen or fluorine;
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze.  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
2. Verbindungen der allgemeinen Formel (I) nach Anspruch 1, worin 2. Compounds of general formula (I) according to claim 1, wherein
R1 für -C(=0)OMe,
Figure imgf000066_0003
oder für eine Gruppe steht, ausgewählt aus: R 1 is -C (= O) OMe,
Figure imgf000066_0003
or stands for a group selected from:
Figure imgf000066_0004
Figure imgf000066_0004
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht; R5 für Wasserstoff oder Methyl steht und * represents the point of attachment of the group to the rest of the molecule; R 5 is hydrogen or methyl and
R6 für Methyl oder Ethyl steht; R 6 is methyl or ethyl;
R2 für Ci-C4-Alkyl, 2,2,2-Trifluorethyl oder 2,2-Difluorethyl steht; R 2 is C 1 -C 4 alkyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl;
R3 für Cyclopropyl oder Ci-Ct-Alkyl, welcher ein- bis dreifach mit Fluor substituiert sein kann, steht; und R 3 is cyclopropyl or C t -alkyl, which may be substituted with fluorine mono- to trisubstituted group; and
R4 für Wasserstoff steht. R 4 is hydrogen.
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze.  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
3. Verbindungen der allgemeinen Formel (I) nach Anspruch 2, worin 3. Compounds of general formula (I) according to claim 2, wherein
R1 für -C(=0)OMe,
Figure imgf000067_0001
oder für eine Gruppe steht, ausgewählt aus: R 1 is -C (= O) OMe,
Figure imgf000067_0001
or stands for a group selected from:
Figure imgf000067_0002
Figure imgf000067_0002
wobei  in which
* für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  * represents the point of attachment of the group to the rest of the molecule;
R5 für Wasserstoff oder Methyl steht und R 5 is hydrogen or methyl and
R6 für Methyl steht; R 6 is methyl;
R2 für Methyl, Ethyl oder wo-Propyl steht; R 2 is methyl, ethyl or where-propyl;
R3 für Methyl, Ethyl, 2,2,2-Trifluorethyl, 1 , 1 -Difluorethyl oder Trifluormethyl steht; und R4 für Wasserstoff steht; R 3 is methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl or trifluoromethyl; and R 4 is hydrogen;
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze.  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
4. Verbindungen der allgemeinen Formel (I) nach Anspruch 3, worin 4. Compounds of general formula (I) according to claim 3, wherein
R1 f , ausgewählt aus: R 1 f, selected from:
Figure imgf000067_0003
Figure imgf000067_0003
wobei  in which
für die Verknüpfungsstelle der Gruppe mit dem Rest des Moleküls steht;  represents the point of attachment of the group to the remainder of the molecule;
für Wasserstoff oder Methyl steht und  is hydrogen or methyl and
für Methyl steht; R2 für Methyl oder Ethyl steht; is methyl; R 2 is methyl or ethyl;
R3 1,1-Difluorethyl oder Trifluormethyl steht; und R 3 is 1,1-difluoroethyl or trifluoromethyl; and
R4 für Wasserstoff steht; R 4 is hydrogen;
sowie ihre Diastereomere, Enantiomere, ihre Metabolite, ihre Salze, ihre Solvate oder die Solvate ihrer Salze.  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
5. Verbindungen der allgemeinen Formel (I) nach Anspruch 4, nämlich 5. Compounds of general formula (I) according to claim 4, namely
1 Methyl-3-[5-methoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2- yfjcarbonyl } amino)- lH-benzimidazol-2-yl]propanoat  1 Methyl 3- [5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-ylcarbonyl} amino) -1H-benzimidazol-2-yl] propanoate
2 Methyl-3-[5-ethoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2-yl]carbonyl}amino)- lH-benzimidazol-2-yl]propanoat  2 Methyl 3- [5-ethoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1H-benzimidazol-2-yl] propanoate
3 Methyl-4-[5-methoxy-l-methyl-6-({ [6-(trifluormethyl)pyridin-2- yfjcarbonyl } amino)- lH-benzimidazol-2-yl] -2,2-dimethylbutanoat  3 Methyl 4- [5-methoxy-1-methyl-6 - ({[6- (trifluoromethyl) pyridin-2-ylcarbonyl} amino) -1H-benzimidazol-2-yl] -2,2-dimethylbutanoate
4 Methyl-4- [6-( { [6-( 1 , 1 -difluorethyl)pyridin-2-yl]carbonyl } amino)-5-methoxy- 1 - methyl-lH-benzimidazol-2-yl] -2,2-dimethylbutanoat  4 methyl 4- [6- ({[6- (1,1-difluoroethyl) pyridin-2-yl] carbonyl} amino) -5-methoxy-1-methyl-1H-benzimidazol-2-yl] -2, 2-dimethylbutanoate
5 4- [5-Methoxy- 1 -methyl-6-( { [6-(trifluormethyl)pyridin-2-yl] carbonyl } amino)- 1 H- benzimidazol-2-yl]-2,2-dimethylbutansäure  5 4- [5-methoxy-1-methyl-6- ({[6- (trifluoromethyl) pyridin-2-yl] carbonyl} amino) -1 H -benzimidazol-2-yl] -2,2-dimethylbutanoic acid
6 4- [6-( { [6-( 1 , 1 -Difluorethyl)pyridin-2-yl] carbonyl } amino)-5-methoxy- 1 -methyl- 1 H- benzimidazol-2-yl]-2,2-dimethylbutansäure  6 4- [6- ({[6- (1,1-Difluoroethyl) pyridin-2-yl] carbonyl} amino) -5-methoxy-1-methyl-1H-benzimidazol-2-yl] -2,2 -dimethylbutansäure
7 N-[2-(3-Hydroxy-3-methylbutyl)-5-methoxy-l -methyl- lH-benzimidazol-6-yl]-6- (trifluormethyl)pyridin-2-carboxamid  7 N - [2- (3-Hydroxy-3-methylbutyl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
8 N- [5-Ethoxy-2-(3-hydroxy-3-methylbutyl)- 1 -methyl- 1 H-benzimidazol-6-yl] -6- (trifluormethyl)pyridin-2-carboxamid  8 N - [5-Ethoxy-2- (3-hydroxy-3-methylbutyl) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide
9 N- { 5-Methoxy- 1 -methyl-2- [2-(methylsulfonyl)ethyl] - 1 H-benzimidazol-6-yl } -6- (trifluormethyl)pyridin-2-carboxamid  9 N- {5-Methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1 H -benzimidazol-6-yl} -6- (trifluoromethyl) pyridine-2-carboxamide
10 6-( 1 , 1 -Difluorethyl)-N- { 5-methoxy- 1 -methyl-2- [2-(methylsulfonyl)ethyl] - 1H- benzimidazol-6-yl}pyridin-2-carboxamid  10 6- (1,1-Difluoroethyl) -N- {5-methoxy-1-methyl-2- [2- (methylsulfonyl) ethyl] -1H-benzimidazol-6-yl} pyridine-2-carboxamide
11 6-(Difluormethyl)-N-[2-(3-hydroxy-3-methylbutyl)-5-methoxy-l -methyl- 1H- benzimidazol-6-yl]pyridin-2-carboxamid.  11 6- (Difluoromethyl) - N - [2- (3-hydroxy-3-methylbutyl) -5-methoxy-1-methyl-1 H -benzimidazol-6-yl] pyridine-2-carboxamide.
6. Verbindung der allgemeinen Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Krankheiten. 6. A compound of the general formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of diseases.
7. Verbindung der allgemeinen Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Tumorerkrankungen, dermatologischen Erkrankungen, gynäkologischen Erkrankungen, kardiovaskulären Erkrankungen, pulmonalen Erkrankungen, ophthalmologischen Erkrankungen, neurologischen Erkrankungen,7. A compound of the general formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of tumor diseases, dermatological diseases, gynecological diseases, cardiovascular diseases, pulmonary diseases, ophthalmological diseases, neurological diseases
Stoffwechselerkrankungen, Lebererkrankungen, Nierenerkrankungen, inflammatorischen Erkrankungen, Autoimmunerkrankungen und Schmerz. Metabolic diseases, liver diseases, kidney diseases, inflammatory diseases, autoimmune diseases and pain.
8. Verbindung der allgemeinen Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Lymphomen, Makuladegeneration, Psoriasis, Lupus erythematodes, Multipler Sklerosis, COPD, Gicht, NASH, Leberfibrose, Insulinresistenz, des metabolischen Syndroms, von Spondyloarthritiden und rheumatoider Arthritis, chronische Nierenkrankheit, Nephropathien, Endometriose sowie Endometriose-assoziierten Schmerzen und anderen Endometriose-assoziierten Symptomen wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie. A compound of the general formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of lymphomas, Macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, the metabolic syndrome, spondyloarthritis and rheumatoid arthritis, chronic renal disease, nephropathies, endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, Dyspareunia, dysuria and dyschez.
9. Verbindung der allgemeinen Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Schmerz inklusive akutem, chronischem, entzündlichem und neuropathischem Schmerz, vorzugsweise von Hyperalgesie, Allodynie, Schmerz bei Arthritis (wie Osteoarthritis, rheumatoider Arthritis undA compound of general formula (I) as defined in any one of claims 1 to 5 for use in a method for the treatment and / or prophylaxis of pain including acute, chronic, inflammatory and neuropathic pain, preferably hyperalgesia, allodynia, pain in arthritis (such as osteoarthritis, rheumatoid arthritis and
Spondylarthritis), prämenstruellem Schmerz, Endometriose-assoziiertem Schmerz, postoperativem Schmerz, Schmerz bei interstitieller Zystitis, CRPS (komplexes regionales Schmerzsyndrom), Trigeminusneuralgie, Schmerz bei Prostatitis, Schmerzen verursacht durch Rückenmarksverletzungen, entzündungsinduziertem Schmerz, Kreuzschmerzen, Krebsschmerzen, Chemotherapie-assoziiertem Schmerz, HIV behandlungsinduzierter Neuropathie, Verbrennungs- induziertem Schmerz und chronischem Schmerz. Spondylarthritis), premenstrual pain, endometriosis-associated pain, postoperative pain, interstitial cystitis pain, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain in 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.
10. Verwendung einer Verbindung der allgemeinen Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, zur Herstellung eines Arzneimittels. Use of a compound of general formula (I) as defined in any one of claims 1 to 5 for the manufacture of a medicament.
11. Verwendung gemäß Anspruch 10, wobei das Arzneimittel zur Behandlung und/oder Prophylaxe von Tumorerkrankungen, dermatologischen Erkrankungen, gynäkologischen Erkrankungen, kardiovaskulären Erkrankungen, pulmonalen Erkrankungen, ophthalmologischen Erkrankungen, neurologischen Erkrankungen, Stoffwechselerkrankungen, Lebererkrankungen, Nierenerkrankungen, inflammatorischen Erkrankungen, Autoimmunerkrankungen und Schmerz verwendet wird. 11. Use according to claim 10, wherein the medicament is used for the treatment and / or prophylaxis of tumor diseases, dermatological diseases, gynecological diseases, cardiovascular diseases, pulmonary diseases, ophthalmological diseases, neurological diseases, metabolic diseases, liver diseases, kidney diseases, inflammatory diseases, autoimmune diseases and pain becomes.
12. Verwendung gemäß der Ansprüche 10 oder 11 zur Behandlung und/oder Prophylaxe von Lymphomen, Makuladegeneration, Psoriasis, Lupus erythematodes, Multipler Sklerosis, COPD, Gicht, NASH, Leberfibrose, Insulinresistenz, metabolisches Syndrom, Spondyloarthritiden und rheumatoider Arthritis, chronische Nierenkrankheit, Nephropathien, Endometriose sowie Endometriose-assoziierten Schmerzen und anderen Endometriose-assoziierten Symptomen wie Dysmenorrhoe, Dyspareunie, Dysurie und Dyschezie. 12. Use according to claims 10 or 11 for the treatment and / or prophylaxis of lymphomas, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome, spondyloarthritis and rheumatoid arthritis, chronic renal disease, nephropathies , Endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia.
13. Verwendung gemäß der Ansprüche 10 oder 11 zur Behandlung und/oder Prophylaxe von Schmerz inklusive akutem, chronischem, entzündlichem und neuropathischem Schmerz, vorzugsweise von Hyperalgesie, Allodynie, Schmerz bei Arthritis (wie Osteoarthritis, rheumatoider Arthritis und Spondylarthritis), prämenstruellem Schmerz, Endometriose-assoziiertem Schmerz, postoperativem Schmerz, Schmerz bei interstitieller Zystitis, CRPS (komplexes regionales Schmerzsyndrom), Trigeminusneuralgie, Schmerz bei Prostatitis, Schmerzen verursacht durch Rückenmarksverletzungen, entzündungsinduziertem Schmerz, Kreuzschmerzen, Krebsschmerzen, Chemotherapie-assoziiertem Schmerz, HIV behandlungsinduzierter Neuropathie, Verbrennungs- induziertem Schmerz und chronischem Schmerz. Use according to claims 10 or 11 for the treatment and / or prophylaxis of pain including acute, chronic, inflammatory and neuropathic pain, preferably hyperalgesia, allodynia, pain in arthritis (such as osteoarthritis, rheumatoid arthritis and the like) Spondylarthritis), premenstrual pain, endometriosis-associated pain, postoperative pain, interstitial cystitis pain, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain in 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.
14. Arzneimittel enthaltend eine Verbindung der Formel (I), wie in einem der Ansprüche 1 bis 5 definiert, in Kombination mit einem inerten, nicht-toxischen, pharmazeutisch geeigneten Hilfsstoff. 14. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 5, in combination with an inert, non-toxic, pharmaceutically suitable excipient.
PCT/EP2017/074320 2016-09-29 2017-09-26 Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs WO2018060174A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16191319 2016-09-29
EP16191319.9 2016-09-29

Publications (1)

Publication Number Publication Date
WO2018060174A1 true WO2018060174A1 (en) 2018-04-05

Family

ID=57042720

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/074320 WO2018060174A1 (en) 2016-09-29 2017-09-26 Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs

Country Status (1)

Country Link
WO (1) WO2018060174A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021158498A1 (en) * 2020-02-03 2021-08-12 Bristol-Myers Squibb Company Tricyclic heteroaryl compounds useful as irak4 inhibitors
WO2022156788A1 (en) * 2021-01-22 2022-07-28 武汉人福创新药物研发中心有限公司 Benzimidazole compound and use thereof
WO2022267673A1 (en) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 Sulfoximide substituted indazole irak4 kinase inhibitor, preparation method therefor, and use thereof

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001057020A1 (en) 2000-02-01 2001-08-09 Cor Therapeutics, Inc. INDOLE AND BENZIMIDAZOLE INHIBITORS OF FACTOR Xa
WO2003030902A1 (en) 2001-10-09 2003-04-17 Tularik Inc. Imidazole derivates as anti-inflammatory agents
WO2004072069A1 (en) 2003-02-14 2004-08-26 Glaxo Group Limited Carboxamide derivatives
WO2004113281A1 (en) 2003-06-25 2004-12-29 Je Il Pharmaceutical Co., Ltd. Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them
WO2005082866A2 (en) 2004-02-20 2005-09-09 Pfizer Limited Substituted 1, 2, 4- triazole derivatives as oxytocin antagonists
WO2006030031A1 (en) 2004-09-17 2006-03-23 Janssen Pharmaceutica N.V. Novel thieno-pyridine and thieno-pyrimidine derivatives and their use as positive allosteric modulators of mglur2-receptors
WO2006061715A2 (en) 2004-12-08 2006-06-15 Warner-Lambert Company Llc Methylene inhibitors of matrix metalloproteinase
WO2007076092A2 (en) 2005-12-23 2007-07-05 Amgen Inc. Nitrogen- containing bicyclic hetroaryl compounds for the treatment of raf protein kinase-mediated diseases
US20070185058A1 (en) 2006-02-07 2007-08-09 Aurelia Conte Heteroaryl and benzyl amide compounds
WO2008005457A2 (en) 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Pyridinonyl pdk1 inhibitors
WO2009117421A2 (en) 2008-03-17 2009-09-24 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
WO2010042785A1 (en) 2008-10-10 2010-04-15 Celtaxsys, Inc. Method of inducing negative chemotaxis
WO2012061926A1 (en) 2010-11-08 2012-05-18 Zalicus Pharmaceuticals Ltd. Bisarylsulfone and dialkylarylsulfone compounds as calcium channel blockers
WO2012107475A1 (en) 2011-02-10 2012-08-16 Syngenta Participations Ag Microbiocidal pyrazole derivatives
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
WO2013186229A1 (en) 2012-06-11 2013-12-19 Ucb Pharma S.A. Tnf -alpha modulating benzimidazoles
WO2015091426A1 (en) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Novel carboxamides, method for the production thereof, pharmaceutical preparations comprising them, and use thereof for producing medicaments
WO2017108744A1 (en) * 2015-12-22 2017-06-29 Bayer Pharma Aktiengesellschaft Novel substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001057020A1 (en) 2000-02-01 2001-08-09 Cor Therapeutics, Inc. INDOLE AND BENZIMIDAZOLE INHIBITORS OF FACTOR Xa
WO2003030902A1 (en) 2001-10-09 2003-04-17 Tularik Inc. Imidazole derivates as anti-inflammatory agents
WO2004072069A1 (en) 2003-02-14 2004-08-26 Glaxo Group Limited Carboxamide derivatives
WO2004113281A1 (en) 2003-06-25 2004-12-29 Je Il Pharmaceutical Co., Ltd. Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them
WO2005082866A2 (en) 2004-02-20 2005-09-09 Pfizer Limited Substituted 1, 2, 4- triazole derivatives as oxytocin antagonists
WO2006030031A1 (en) 2004-09-17 2006-03-23 Janssen Pharmaceutica N.V. Novel thieno-pyridine and thieno-pyrimidine derivatives and their use as positive allosteric modulators of mglur2-receptors
WO2006061715A2 (en) 2004-12-08 2006-06-15 Warner-Lambert Company Llc Methylene inhibitors of matrix metalloproteinase
WO2007076092A2 (en) 2005-12-23 2007-07-05 Amgen Inc. Nitrogen- containing bicyclic hetroaryl compounds for the treatment of raf protein kinase-mediated diseases
US20070185058A1 (en) 2006-02-07 2007-08-09 Aurelia Conte Heteroaryl and benzyl amide compounds
WO2008005457A2 (en) 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Pyridinonyl pdk1 inhibitors
WO2009117421A2 (en) 2008-03-17 2009-09-24 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
WO2010042785A1 (en) 2008-10-10 2010-04-15 Celtaxsys, Inc. Method of inducing negative chemotaxis
WO2012061926A1 (en) 2010-11-08 2012-05-18 Zalicus Pharmaceuticals Ltd. Bisarylsulfone and dialkylarylsulfone compounds as calcium channel blockers
WO2012107475A1 (en) 2011-02-10 2012-08-16 Syngenta Participations Ag Microbiocidal pyrazole derivatives
WO2012112743A1 (en) 2011-02-18 2012-08-23 Vertex Pharmaceuticals Incorporated Chroman - spirocyclic piperidine amides as modulators of ion channels
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
WO2013186229A1 (en) 2012-06-11 2013-12-19 Ucb Pharma S.A. Tnf -alpha modulating benzimidazoles
WO2015091426A1 (en) 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Novel carboxamides, method for the production thereof, pharmaceutical preparations comprising them, and use thereof for producing medicaments
WO2017108744A1 (en) * 2015-12-22 2017-06-29 Bayer Pharma Aktiengesellschaft Novel substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs

Non-Patent Citations (267)

* Cited by examiner, † Cited by third party
Title
"Chem. Soc. Rev.", vol. 38, 2009, pages: 606
"Science of Synthesis", GEORG THIEME VERLAG
ABBATE; KONTOS ET AL., THE AMERICAN JOURNAL OF CARDIOLOGY, 2010
ABBATE; VAN TASSELL ET AL., THE AMERICAN JOURNAL OF CARDIOLOGY, 2013
AHMAD, R.; P. SHIHAB ET AL., DIABETOLOGY & METABOLIC SYNDROME, 2015
AKASH; SHEN ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, 2012
AKCAY; NGUYEN ET AL., JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2011
AKOUM; LAWSON ET AL., HUMAN REPRODUCTION, 2007
ALEXANDER-BRETT ET AL., THE JOURNAL OF CLINICAL INVESTIGATION, 2013
ALLHORN; BOING ET AL., REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY, 2008
AMINO ACIDS; ANDREW B. HUGHES: "Building Blocks, Catalysis and Coupling Chemistry", vol. 3, WILEY, article "Peptides and Proteins in Organic Chemistry", pages: 407 - 442
ANDREW B. HUGHES: "Building Blocks, Catalysis and Coupling Chemistry", vol. 3, WILEY, article "Amino Acids, Peptides and Proteins in Organic Chemistry", pages: 407 - 442
ANNUAL REPORTS IN MEDICINAL CHEMISTRY, vol. 49, 2014, pages 117 - 133
BALLAK; STIENSTRA ET AL., CYTOKINE, 2015
BAO; NA ET AL., JOURNAL OF CLINICAL IMMUNOLOGY, 2011
BATAL ET AL., TRANSPLANTATION, 2014
BAUER; SHAPIRO ET AL., MOL MED, 2012
BENIAS; GOPAL ET AL., CLIN RES HEPATOL GASTROENTEROL, 2012
BERAUD; MAGUIRE-ZEISS, PARKINSONISM & RELATED DISORDERS, 2012
BIJANI, INTERNATIONAL REVIEWS OF IMMUNOLOGY, 2012
BIOORG. MED. CHEM. LETT., vol. 16, 2006, pages 2842 - 2845
BIOORG. MED. CHEM. LETT., vol. 18, 2008, pages 2093
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 16, 2014, pages 4039 - 4043
BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 19, no. 17, 2011, pages 5093 - 5102
BOMFIM; DOS SANTOS ET AL., CLIN SCI (LONDON), 2012
BOMFIM; ECHEM ET AL., LIFE SCIENCES, 2015
BRENNER; RUZICKA ET AL., BRITISH JOURNAL OF DERMATOLOGY, 2009
BROUGH; TYRRELL ET AL., TRENDS IN PHARMACOLOGICAL SCIENCES, 2011
BRYCE SM ET AL., MUTATION RESEARCH, 2008
BUNTING; SHADIE ET AL., BIOMED RESEARCH INTERNATIONAL, 2013
BYERS; ALEXANDER-BRETT ET AL., THE JOURNAL OF CLINICAL INVESTIGATION, 2013
CAMERON; TSE ET AL., THE JOURNAL OF NEUROSCIENCE, 2012
CANDIA; MARQUEZ ET AL., THE JOURNAL OF RHEUMATOLOGY, 2007
CARIO, INFLAMMATORY BOWEL DISEASES, 2010
CARRASCO ET AL., CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2011
CARTY; BOWIE, BIOCHEMICAL PHARMACOLOGY, 2011
CASO; COSTA ET AL., MEDIATORS OF INFLAMMATION, 2014
CECCARELLI, S.; V. NOBILI ET AL., WORLD J GASTROENTEROL, 2014
CEVIKBAS; STEINHOFF, J INVEST DERMATOL, 2012
CHANG; MCCLUSKEY ET AL., CLINICAL & EXPERIMENTAL OPHTHALMOLOGY, 2012
CHEM. REV., vol. 48, no. 3, 1951, pages 397 - 541
CHEM. SOC. REV., vol. 38, 2009, pages 606
CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 38, no. 9, 1990, pages 2446 - 2458
CHEMICAL COMMUNICATIONS (CAMBRIDGE, ENGLAND, vol. 15, 2003, pages 1948 - 1949
CHEN ET AL., ARTHRITIS RESEARCH & THERAPY, 2013
CHEN; LIN ET AL., ARTHRITIS RES THER, 2013
CHEN; ZHAO ET AL., INT J CLIN EXP PATHOL, 2015
CHIANG ET AL., THE JOURNAL OF IMMUNOLOGY, 2010
CHOI; KIM ET AL., HUMAN PATHOLOGY, 2013
CHOPRA; COOPER, J NEUROIMMUNE PHARMACOL, 2013
CHRISTENSEN; SHUPE ET AL., IMMUNITY, 2006
CHRISTIA; FRANGOGIANNIS, EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2013
CICCIA ET AL., RHEUMATOLOGY, 2015
CONTI; SPINELLI ET AL., CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY, 2010
COPPOLA; BARRICK ET AL., DEVELOPMENT, 2004
CORDIGLIERI; MAROLDA ET AL., J AUTOIMMUN, 2014
COUILLIN; VASSEUR ET AL., THE JOURNAL OF IMMUNOLOGY, 2009
CSAK, T.; A. VELAYUDHAM ET AL., AM J PHYSIOL GASTROINTEST LIVER PHYSIOL, 2011
DALTON TRANSACTIONS, vol. 43, no. 19, 2014, pages 7176 - 7190
DASU; RAMIREZ ET AL., CLINICAL SCIENCE, 2012
DATTA; NOVOTNY ET AL., THE JOURNAL OF IMMUNOLOGY, 2004
DAVID; RATNAYAKE ET AL., NEUROBIOLOGY OF DISEASE, 2013
DAVIDSON; CURRIE ET AL., THE JOURNAL OF IMMUNOLOGY, 2006
DE KONING, CLIN TRANSL ALLERGY, 2014
DEL REY; APKARIAN ET AL., ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 2012
D'ELIA; BRUCATO ET AL., CLIN EXP RHEUMATOL, 2015
DENES; KITAZAWA; CHENG ET AL., THE JOURNAL OF IMMUNOLOGY, 2011
DENES; WILKINSON ET AL., DISEASE MODELS & MECHANISMS, 2013
DENG; MA-KRUPA ET AL., CIRC RES, 2009
DENG; YANG ET AL., PLOS ONE, 2013
DEVARAJ; TOBIAS ET AL., ARTERIOSCLER THROMB VASC BIOL, 2011
DINARELLO, ANNU. REV. IMMUNOL., 2009
DINARELLO, EUROPEAN JOURNAL OF IMMUNOLOGY, 2011
DISPENZA; WOLPERT ET AL., J INVEST DERMATOL, 2012
DISSEN; GARCIA-RUDAZ ET AL., SEMINARS IN REPRODUCTIVE MEDICINE, 2009
DUBANIEWICZ, A., HUMAN IMMUNOLOGY, 2013
DUPONT; HARMS PRITCHARD ET AL., THE JOURNAL OF IMMUNOLOGY, 2015
EIDENSCHENK; CROZAT ET AL., PNAS, 2010
ELSHERBINY; AL-GAYYAR, CYTOKINE, 2016
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2, 2002, pages 327 - 330
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 8, 2003, pages 1559 - 1568
FALCK-HANSEN; KASSITERIDI ET AL., INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2013
FANG; HU, MED SCI MONIT, 2011
FLANNERY; BOWIE, BIOCHEMICAL PHARMACOLOGY, 2010
FOSTER; BALIWAG ET AL., THE JOURNAL OF IMMUNOLOGY, 2014
FRANGOGIANNIS, CURR OPIN CARDIOL, 2015
FREEMAN; MARTINEZ ET AL., RESPIRATORY RESEARCH, 2013
FRESNO, ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY, 2011
GAMBUZZA; LICATA ET AL., JOURNAL OF NEUROIMMUNOLOGY, 2011
GARCIA-SUAREZ; GERMANÄ ET AL., JOURNAL OF NEUROIMMUNOLOGY, 2000
GILLIET; CONRAD ET AL., ARCHIVES OF DERMATOLOGY, 2004
GOH; MIDWOOD, RHEUMATOLOGY, 2012
GRESNIGT; VAN DE VEERDONK, SEMINARS IN IMMUNOLOGY, 2013
GUERMONPREZ; HELFT ET AL., NATURE MEDICINE, 2013
GUERRERO; CUNHA ET AL., EUROPEAN JOURNAL OF PHARMACOLOGY, 2012
GUL; TUGAL-TUTKUN ET AL., ANN RHEUM DIS, 2012
GUO; GAO ET AL., IMMUNOL CELL BIOL, 2012
HAENUKI; MATSUSHITA ET AL., JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2012
HAHN; CHO ET AL., PEDIATRIC NEPHROLOGY, 2009
HAN; ZHAO ET AL., NEUROSCIENCE, 2013
HAO; LIU ET AL., CURR OPIN GASTROENTEROL, 2013
HEIMESAAT; FISCHER ET AL., PLOS ONE, 2007
HEIMESAAT; NOGAI ET AL., GUT, 2010
HENDERSON; GOLDBACH-MANSKY, CLINICAL IMMUNOLOGY, 2010
HERNANZ; MARTINEZ-REVELLES ET AL., BRITISH JOURNAL OF PHARMACOLOGY, 2015
HILBERATH; CARLO ET AL., THE FASEB JOURNAL, 2011
HIROSE; KURODA ET AL., PAIN PRACTICE, 2016
HOFFMANN, J INVESTIG DERMATOL SYMP PROC, 1999
HOLLE; WINDMOLLER ET AL., RHEUMATOLOGY, 2013
HOLTMANN; ENNINGA ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, 2001
IMAOKA; HOSHINO ET AL., EUROPEAN RESPIRATORY JOURNAL, 2008
INDO, CLINICAL GENETICS, 2012
J. ORG. CHEM., vol. 66, no. 23, 2001, pages 7832 - 7840
JAIN; THONGPRAYOON ET AL., AM J CARDIOL., 2015
JANEWAY; MEDZHITOV, ANNU. REV. IMMUNOL., 2002
JEYASEELAN; CHU ET AL., INFECTION AND IMMUNITY, 2005
JIALAL; MAJOR ET AL., J DIABETES COMPLICATIONS, 2014
JO ET AL., WORLD J SURG ONCOL, 2012
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 135, no. 32, 2013, pages 12122 - 12134
JOURNAL OF THE CHEMICAL SOCIETY, 1955, pages 2412 - 2419
KAARNIRANTA; SALMINEN, J MOL MED (BERL, 2009
KAMARI; SHAISH ET AL., J HEPATOL, 2011
KANG; HOMER ET AL., THE JOURNAL OF IMMUNOLOGY, 2007
KAPLAN; YAZGAN ET AL., SCAND J GASTROENTEROL, 2014
KAWAYAMA; OKAMOTO ET AL., J INTERFERON CYTOKINE RES, 2013
KEZIC; TAYLOR ET AL., J LEUKOC BIOL, 2011
KFOURY, A.; K. L. CORF ET AL., JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2013
KHAN; KITAJIMA ET AL., JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH, 2013
KIM; CHO ET AL., CLIN RHEUMATOL, 2010
KIM; FEBBRAIO ET AL., THE JOURNAL OF IMMUNOLOGY, 2011
KIM; LEE ET AL., TOLL-LIKE RECEPTORS: ROLES IN INFECTION AND NEUROPATHOLOGY, 2009
KIM; STASCHKE ET AL., JEM, 2007
KOBORI; YAGI ET AL., J GASTROENTEROL, 2010
KOLLEWE; MACKENSEN ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY, 2004
KOVACH; STANDIFORD, INTERNATIONAL IMMUNOPHARMACOLOGY, 2011
KREISEL; GOLDSTEIN, TRANSPLANT INTERNATIONAL, 2013
KU; VON BERNUTH ET AL., JEM, 2007
KWOK; HUTCHINSON ET AL., PLOS ONE, 2012
LAWSON; BOURCIER ET AL., JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 2008
LEE; HATTORI ET AL., INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2012
LEE; LEE ET AL., J NEUROINFLAMMATION, 2015
LEVENTHAL; SCHROPPEL, KIDNEY INT, 2012
LI; GUABIRABA ET AL., JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2014
LI; WANG ET AL., PHARMACOLOGY & THERAPEUTICS, 2013
LI; ZHANG ET AL., ONCOL REP., 2015
LIANG; CHEN ET AL., CLINICAL CANCER RESEARCH, 2013
LIM; KOU ET AL., THE AMERICAN JOURNAL OF PATHOLOGY, 2011
LIN; TANG, NEPHROLOGY DIALYSIS TRANSPLANTATION, 2014
LIU; HU ET AL., BIOCHIM BIOPHYS ACTA., 2015
LIU; JI, PFLUGERS ARCH., 2013
LIU; ZHANG ET AL., CELL RESEARCH, 2014
LIU-BRYAN; SCOTT ET AL., ARTHRITIS & RHEUMATISM, 2005
LLOYD, CURRENT OPINION IN IMMUNOLOGY, 2010
LUGRIN; PARAPANOV ET AL., THE JOURNAL OF IMMUNOLOGY, 2015
MAEKAWA; MIZUE ET AL., CIRCULATION, 2009
MARGARITOPOULOS; ANTONIOU ET AL., FIBROGENESIS & TISSUE REPAIR, 2010
MARON DM; AMES BN.: "Revised methods for the Salmonella mutagenicity test", MUTATION RESEARCH, vol. 113/3-4, 1983, pages 173 - 215, XP023455372, DOI: doi:10.1016/0165-1161(83)90010-9
MARQUEZ ET AL., ANN RHEUM DIS, 2014
MARTINEZ-GONZÄLEZ; ROCA ET AL., AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2013
MCGETTRICK; J. O'NEILL, BRITISH JOURNAL OF HAEMATOLOGY, 2007
MILLER, ADV DERMATOL, 2008
MIN; AHMAD ET AL., PHOTOCHEM PHOTOBIOL., 2015
MINKIS; AKSENTIJEVICH ET AL., ARCHIVES OF DERMATOLOGY, 2012
MIURA; KODAMA ET AL., GASTROENTEROLOGY, 2010
MIURA; OHNISHI, WORLD J GASTROENTEROL, 2014
NADIGEL; PREFONTAINE ET AL., RESPIRATORY RESEARCH, 2011
NAKANISHI; YAMAGUCHI ET AL., PLOS ONE, 2013
NARAYANAN; CORRALES ET AL., CORNEA, 2008
NGO; YOUNG ET AL., NATURE, 2011
NICKERSON; CHRISTENSEN ET AL., THE JOURNAL OF IMMUNOLOGY, 2010
NICOTRA; LORAM ET AL., EXPERIMENTAL NEUROLOGY, 2012
NIEBUHR; LANGNICKEL ET AL., ALLERGY, 2008
NOELKER; MOREL ET AL., SCI. REP., 2013
NORDSTRÖM; KNIGHT ET AL., THE JOURNAL OF RHEUMATOLOGY, 2012
NOZAKI; SAIBARA ET AL., ALCOHOL CLIN EXP RES, 2004
OCHI; NGUYEN ET AL., J EXP MED, 2012
OECD TEST GUIDELINE, vol. 487, 2014
OKIYAMA ET AL., ARTHRITIS RHEUM, 2012
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, vol. 4, no. 1, August 1980 (1980-08-01), pages 55 - 65
OUZIEL; GUSTOT ET AL., AM J PATHO, 2012
OYAMA; BLAIS ET AL., CIRCULATION, 2004
P. G. M. WUTS; T. W. GREENE: "Greene's Protective Groups in Organic Synthesis. 4th ed.", 2006
PARK; STOKES ET AL., CANCER CHEMOTHER PHARMACOL, 2014
PAUWELS; BRACKE ET AL., EUROPEAN RESPIRATORY JOURNAL, 2011
PETTERSSON, ANNALS OF MEDICINEPETTERSON, 2012
PIGGOTT; EISENBARTH ET AL., J CLIN INVES, 2005
PRECIOUS ET AL., J. BIOL. CHEM., 2009
PUENTE; PINYOL ET AL., NATURE, 2011
QI; ZHAO ET AL., INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2014
QIU; LI ET AL., IMMUNOLOGY, 2013
RAKOFF-NAHOUM; HAO ET AL., IMMUNITY, 2006
RAMIREZ CRUZ; MALDONADO BERNAL ET AL., REV ALERG MEX, 2004
RAMIREZ; DASU, CURR DIABETES REV, 2012
RAMOS; TAK ET AL., AUTOIMMUNITY REVIEWS, 2014
REDFERN; MCDERMOTT, EXPERIMENTAL EYE RESEARCH, 2010
REKHTER; STASCHKE ET AL., BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATION, 2008
ROGER; FROIDEVAUX ET AL., PNAS, 2009
ROH; SEKI, J GASTROENTEROL HEPATOL, 2013
ROSA; RAMIREZ; RAVI KRISHNA DASU, CURR DIABETES REV, 2012
RUPERTO; BRUNNER ET AL., NEW ENGLAND JOURNAL OF MEDICINE, 2012
SALUJA; KETELAAR ET AL., MOLECULAR IMMUNOLOGY, 2014
SANTULLI; BORGHESE ET AL., HUMAN REPRODUCTION, 2013
SCANZELLO; PLAAS ET AL., CURR OPIN RHEUMATOL, 2008
SCHMIDT; MITTNACHT ET AL., J DERMATOL SCI, 1996
SCHMIDT; RAGHAVAN ET AL., NAT IMMUNOL, 2010
SCHREPF; BRADLEY ET AL., BRAIN BEHAV IMMUN, 2015
SEDIMBI; HAGGLOF ET AL., CELL MOL LIFE SCI, 2013
SEGANISH, W.M.: "Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015)", EXPERT OPINION ON THERAPEUTIC PATENTS., vol. 26, no. 8, 29 June 2016 (2016-06-29), pages 917 - 932, XP055308579, ISSN: 1354-3776, DOI: 10.1080/13543776.2016.1202926 *
SEKI; TASAKA ET AL., INFLAMMATION RESEARCH, 2010
SELWAY; KURCZAB ET AL., BMC DERMATOLOGY, 2013
SENEVIRATNE; SIVAGURUNATHAN ET AL., CLINICA CHIMICA ACTA, 2012
SHI; MUCSI ET AL., IMMUNOLOGICAL REVIEWS, 2010
SIKORA; MIELCZAREK-PALACZ ET AL., AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 2012
SRIVASTAVA; GENG ET AL., CANCER RESEARCH, 2012
STASCHKE ET AL., THE JOURNAL OF IMMUNOLOGY, 2009
STASCHKE; DONG ET AL., THE JOURNAL OF IMMUNOLOGY, 2009
STOJSAVLJEVIC; PALCIC ET AL., WORLD J GASTROENTEROL, 2014
STOKES; CHEUNG ET AL., JOURNAL OF NEUROINFLAMMATION, 2013
SUN; PEARLMAN, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2009
SUN; YANG ET AL., PLOS ONE, 2014
SUZUKI; SUZUKI ET AL., JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2008
SUZUKI; SUZUKI ET AL., NATURE, 2002
SYNTHESIS, vol. 10, 2004, pages 1619 - 1624
SYNTHETIC COMMUNICATIONS, vol. 42, 2012, pages 658 - 666
SZCZEPANSKI; CZYSTOWSKA ET AL., CANCER RES, 2009
TALABOT-AYE ET AL., CYTOKINE, 2014
TERHORST; KALALI ET AL., AM J CLIN DERMATOL, 2010
TESSAROLLO, L., CYTOKINE & GROWTH FACTOR REVIEWS, 1998
TETRAHEDRON, vol. 60, no. 51, 2004, pages 11869 - 11874
THOMPSON; WEBB, CLIN SCI (LONDON), 2013
TIMMERS; SLUIJTER ET AL., CIRCULATION RESEARCH, 2008
TIMPER; SEELIG ET AL., J DIABETES COMPLICATIONS, 2015
TREON; XU ET AL., NEW ENGLAND JOURNAL OF MEDICINE, 2012
URBONAVICIUTE; STARKE ET AL., ARTHRITIS & RHEUMATISM, 2013
VALAPERTI; NISHII ET AL., CIRCULATION, 2013
VAN DER WATT; WILKINSON ET AL., BMC INFECT DIS, 2014
VENNEGAARD; DYRING-ANDERSEN ET AL., CONTACT DERMATITIS, 2014
VIGUIER; GUIGUE ET AL., ANNALS OF INTERNAL MEDICINE, 2010
VIJMASI; CHEN ET AL., MOL VIS, 2013
VOLIN; KOCH, J INTERFERON CYTOKINE RES, 2011
WALSH; CARTHY ET AL., CYTOKINE & GROWTH FACTOR REVIEWS, 2013
WAN; CHI ET AL., NAT IMMUNOL, 2006
WANG ET AL., EXPERIMENTAL AND THERAPEUTIC MEDICINE, 2015
WANG; DENG ET AL., NATURE, 2001
WANG; QIAN ET AL., BR J CANCER KIM, 2010
WANG; WANG ET AL., STROKE, 2013
WOLF; LIVSHITS ET AL., BRAIN, BEHAVIOR, AND IMMUNITY, 2008
WOLLINA; KOCH ET AL., INDIAN DERMATOL ONLINE, 2013
WON, K. A.; M. J. KIM ET AL., J PAIN, 2014
WONG, L.; J. D. DONE ET AL., PROSTATE, 2015
XIANG; CHAO ET AL., REV NEUROSCI, 2015
XIANG; FAN ET AL., MEDIATORS OF INFLAMMATION, 2010
YAMADA; ARAKAKI ET AL., OPINION ON THERAPEUTIC TARGETS, 2013
YANG ET AL., MOL MED REP, 2016
YANG, L.; E. SEKI, FRONT PHYSIOL, 2012
YANG; TUZUN ET AL., J IMMUNOL, 2005
YAP; LAI, NEPHROLOGY, 2013
YE, LI ET AL., GUT, 2012
YIN; LI ET AL., CLINICAL & EXPERIMENTAL IMMUNOLOGY, 2012
ZAMBRANO-ZARAGOZA ET AL., INTERNATIONAL JOURNAL OF INFLAMMATION, 2014
ZAWADA; ROGACEV ET AL., EPIGENETIC, 2014
ZHANG; HE ET AL., MOL BIOL REP, 2009
ZHAO; ZHANG ET AL., FRONT IMMUNOL, 2014
ZHAO; ZHANG ET AL., NEUROSCIENCE, 2013
ZHAO; ZHAO ET AL., SCAND J GASTROENTEROL, 2011
ZHU; JIANG ET AL., AUTOIMMUNITY, 2013
ZONG; DORPH ET AL., ANN RHEUM DI, 2014

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021158498A1 (en) * 2020-02-03 2021-08-12 Bristol-Myers Squibb Company Tricyclic heteroaryl compounds useful as irak4 inhibitors
CN115335380A (en) * 2020-02-03 2022-11-11 百时美施贵宝公司 Tricyclic heteroaryl compounds useful as IRAK4 inhibitors
WO2022156788A1 (en) * 2021-01-22 2022-07-28 武汉人福创新药物研发中心有限公司 Benzimidazole compound and use thereof
WO2022267673A1 (en) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 Sulfoximide substituted indazole irak4 kinase inhibitor, preparation method therefor, and use thereof

Similar Documents

Publication Publication Date Title
EP3674298B1 (en) Substituted indazoles, process for their preparation, pharmaceutical formulations containing them, and their use for the preparation of medicaments
WO2017207385A1 (en) Substituted 3-methylindazoles, methods for the production thereof, pharmaceutical preparations containing same, and use thereof for the production of medicaments
EP3423446B1 (en) New 2-substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs
WO2017108744A1 (en) Novel substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs
AU2017257208B2 (en) Crystalline forms of N-(2-(3-Hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide
AU2017257211A1 (en) Polymorphic form of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide
WO2018060174A1 (en) Substituted benzimidazoles, pharmaceutical preparations containing same, and use of same to produce drugs
WO2017207340A1 (en) Novel substituted benzimidazole, methods for the production thereof, pharmaceutical preparations containing same, and use thereof to produce medicaments
WO2018060072A1 (en) New substituted benzimidazoles, methods for the production of same, pharmaceutical preparations containing same, and use of same to produce drugs
NZ746526B2 (en) Polymorphic form of n-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulphonyl)ethyl]-2h-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17783763

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17783763

Country of ref document: EP

Kind code of ref document: A1