WO2018060072A1 - New substituted benzimidazoles, methods for the production of same, pharmaceutical preparations containing same, and use of same to produce drugs - Google Patents

Abstract

The invention relates to new substituted benzimidazoles, to methods for the production thereof, to the use thereof alone or in combinations to treat and/or prevent diseases, and to the use thereof to produce 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 diseases, tumor diseases, and psoriasis.

Description

 Novel substituted benzimidazoles, processes for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments

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.

The present invention relates to novel substituted benzimidazoles of general formula (I) which inhibit interleukin-1 receptor-associated kinase 4 (IRAK4).

 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).

 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).

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 kinases IRAK1 or IRAK2 (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. For example, there is an increased expression of different inflammatory signaling 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).

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). Also in 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 show an association 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).

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).

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).

 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).

 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 Vasc 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; 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).

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). 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, Ovarialka rzinom, 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 (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 associated with myocardial infarction, various pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS), making prophylactic and / or therapeutic action in said indications by the inhibition of IRAK4 is expected (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-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).

A variety of IRAK4 inhibitors are known in the art (see, for example, Expert Opinion on Therapeutic Patents (2016) 26: 8, 917-932).

 WO2015091426 describes indazoles, such as example WO2015091426-64, which are substituted at position 2 with a carboxamide side chain and inhibit IRAK-4. WO2016083433 describes further indazole derivatives having an alkyl group at the 2-position. However, both WO2015091426 and WO2016083433 do not disclose benzimidazoles.

 The unpublished application EP16172162.6 (filing date May 31, 2016) describes benzimidazoles which are substituted at position 5 with 2-hydroxypropan-2yl.

 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 the generic structure WO 13042137) as IRAK4 inhibitors substituted at position 2 with morpholine, wherein the morpholine is linked via the ring nitrogen with 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, -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-lll-benzo [cf] imidazol-6-yl) - [2,3'-bipyridines] -6-carboxamides) becomes explicit as the sole benzimidazole derivative disclosed. <R ¹ ) n (R ² ) p

Generic structure WO 13042137

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 benzimidazolylcarboxamides as vanilloid receptor (VRI) antagionists for the treatment of pain, 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- (IH-benzimidazol-6-yl) -6- (4-fluorophenyl) -2-methyl-nicotinamide) and WO2004072069-12 (6- (4-fluorophenyl) - 2-methyl- / V- (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,

Ci-Cs-OR ¹⁰ , where R ¹⁰ can be H,

wobei R¹⁰ H oder Methyl sein kann •

where R ^{10 can be} H or methyl

No alkyl substituents at position 2 substituted with a sulfone group are described.

 WO2010042785 describes the use of benzimidazoles for negative chemotaxis. The benzimidazoles described may be substituted at position 5 with alkoxy.

WO2013186229 describes TNF-alpha modulating benzimidazoles. However, 1-methyl-substituted benzimidazoles are not disclosed.

 WO2007076092 describes benzimidazoles as Raf kinase modulator, which are substituted at position 5 but not with alkoxy.

In WO2007020050 insecticides are reported, wherein the benzimidazoles described have two carboxamide structures. 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.

The object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (IRAK4).

The present invention relates to compounds of the general formula (I)

für eine Gru e der allgemeinen Formel (II) steht

is a group of the general formula (II)

d l)

dl)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

 m stands for 0 or 1 and

n is 1 or 2; for cyclopropylmethyl, 2-cyclopropylethyl, methyl or C 2 -C 6 -alkyl, which may be substituted in trisubstituted by fluorine or simply by C 1 -C 6 -alkoxy, and R is a group selected from the following general formulas (III) to (X):

 (IV) (V) (VI)

 (VII) (VIII) (ix) (X)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 is} hydrogen, cyclopropyl or C 1 -C 6 -alkyl which may be mono- or polysubstituted by identical or different substituents with fluoro, cyclopropyl or hydroxy;

R ^{5 is} hydrogen, methyl or fluorine and

R ^{6 is} Cs-Cö-cycloalkyl, cyclopropyl-Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, or Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, is;

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.

Furthermore, 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,

• metabolic diseases, especially liver diseases such as fatty liver and · kidney disease, especially chronic kidney disease, nephropathy and

• gynecological diseases, especially endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia. 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.

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. 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), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds 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.

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, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine. 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.

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 processes known to the person skilled in the art, for example by the methods described below and the instructions given for the exemplary embodiments, by corresponding isotopic modifications of the respective reagents and / or starting compounds can be used.

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.

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).

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 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.

 In the context of the invention, alkoxy represents a linear or branched alkoxy radical with the number of carbon atoms indicated in each case. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, 1-ethyl-propoxy, 1-methylbutoxy, 2-methylbutoxy , 3-methylbutoxy and n-hexoxy called.

 Cyclopropyl-C i -C 6 -alkyl in the context of the invention is a linear or branched alkyl radical having one to 6 carbon atoms which is substituted by a cyclopropyl group. The link to the rest of the molecule is via a carbon atom of the alkyl radical. Examples are cyclopropylmethyl, 2-cyclopropylethyl and 1-cyclopropylethyl.

 Hydroxy is OH in the context of the invention.

A symbol * on a bond means the point of attachment in the molecule. 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. Another embodiment for R is a group of the general formula (II)

 (I i)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

 m stands for 0 and

 n stands for 1 or 2.

Another embodiment of R ¹ is a group of general formula (II)

 (I i)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

 m stands for 1 and

 n stands for 1.

Another embodiment of R ² is cyclopropylmethyl, methyl or C ² -C 6 -alkyl, which may be mono- to trisubstituted by fluorine.

A likewise further embodiment of R ² is cyclopropylmethyl, methyl, isopropyl, ethyl, 2,2,2-trifluoroethyl or 2,2-Difluorefhyl.

Another embodiment of R ² is methyl. Another embodiment of R ³ is a group selected from the following general formulas (III) and (V) to (X

 (III) (V) (VI)

 (VII) (VIII) (IX) (X)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ⁴ represents hydrogen, cyclopropyl, or Ci-COE-alkyl which may be mono- or polysubstituted by identical or different substituents selected from fluoro, cyclopropyl or hydroxy group;

R ^{5 is} hydrogen, methyl or fluorine and

R ^{6 is} C 3 -C ⁶ -cycloalkyl, cyclopropyl-C 1 -C ⁶ -alkyl which may be mono- to trisubstituted by fluorine, or C 1 -C 6 -alkyl which may be mono- to trisubstituted by fluorine.

Another embodiment of R ³ is a group selected from the following general formulas III), (VII), (IX) and (X)

 (III) (VII) (IX) (X) where

 * represents the point of attachment of the group to the rest of the molecule;

R ⁴ represents hydrogen, cyclopropyl, or Ci-COE-alkyl which may be mono- or polysubstituted by identical or different substituents selected from fluoro, cyclopropyl or hydroxy group;

R ^{5 is} hydrogen, methyl or fluorine and

R ^{6 is} Cs-Cö-cycloalkyl, cyclopropyl-Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, or Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, is. Another embodiment of R ³ is a group selected from the following general formulas (III) and (X)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 is} hydrogen, cyclopropyl or C 1 -C 6 -alkyl which may be mono- or polysubstituted by identical or different substituents with fluoro, cyclopropyl or hydroxy;

R ^{5 is} hydrogen, methyl or fluorine and

R ^{6 is} C 3 -C ⁶ -cycloalkyl, cyclopropyl-C 1 -C ⁶ -alkyl which may be mono- to trisubstituted by fluorine, or C 1 -C 6 -alkyl which may be mono- to trisubstituted by fluorine.

Another embodiment of R ³ is a group of the following general formula (III)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 represents} hydrogen, cyclopropyl or C 1 -C 6 -alkyl which may be monosubstituted or polysubstituted by identical or different substituents with fluoro, cyclopropyl or hydroxy, and

R ^{5 is} hydrogen, methyl or fluorine.

A further embodiment of R ⁴ is C 1 -C ⁶ -alkyl which may be mono- to trisubstituted by fluorine.

Another embodiment of R ⁴ is C 1 -C ⁴ -alkyl, which is monosubstituted to trisubstituted by fluorine.

Another embodiment of R ⁴ is trifluoromethyl or 1,1-difluoroethyl.

Another embodiment of R ⁴ is 1,1-difluoroethyl.

Another embodiment of R ⁵ is hydrogen. Another embodiment of R ⁶ is Ci-COE-alkyl, which may be mono- to trisubstituted by fluorine.

A further embodiment of R ⁶ is C ₁ -C ₂ -alkyl which may be mono- to trisubstituted by fluorine.

Another embodiment of R ⁶ is methyl or trifluoromethyl.

Another object of the present invention are compounds of the general formula (I), in which:

R ^{1 stands} for a group of the general formula (II)

 (Ii)

 in which

 * represents the point of attachment of the group to the rest of the molecule and m is 0 or 1 when n is 1 or

 m is 0 when n is 2;

R ^{2 is} cyclopropylmethyl, methyl, ethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl, and R ^{3 is} a group selected from the following general formulas (III) and (V) to

(X)

 (Iii) (V) (vi)

 (VII) (VIII) (ix) (X)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 is} a mono- to trisubstituted fluoro-substituted C ₁ -C 4 alkyl;

R ^{5 is} hydrogen and

R ^{6 is} C ₁ -C ₂ -alkyl which may be monosubstituted to trisubstituted by fluorine as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.

Another object of the present invention are compounds of the general formula (I), in which

R ^{1 stands} for a group of the general formula (II)

 dl) represents the point of attachment of the group to the rest of the molecule and is 0 or 1, when n is 1 or

 is 0 when n is 2; is cyclopropylmethyl, methyl, ethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl and is a group selected from the following general formulas (III) and (X)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 represents} a mono- to trisubstituted fluorine-substituted C1-C4 alkyl

R ^{5 is} hydrogen and

R ^{6 is} C ₁ -C ₂ -alkyl which may be mono- to trisubstituted by fluorine;

as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. Another object of the present invention are compounds of the general formula (I), in which

R ^{1 stands} for a group of the general formula (II)

 (Ii)

 in which

 * represents the point of attachment of the group to the rest of the molecule and m is 0 or 1 when n is 1 or

 m is 0 when n is 2;

R ^{2 is} cyclopropylmethyl, methyl, ethyl, 2,2,2-trifluorofhyl or 2,2-difluoroethyl and R ^{3 is} a group of the general formula (III)

 (III)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 is} a mono- to trisubstituted fluorine-substituted C 1 -C ⁴ alkyl and

R ^{5 is} hydrogen;

as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.

Another object of the present invention are compounds of the general formula (I), in which

R ^{1 represents} a group of the general formula (II)

 (Ii)

 in which

* represents the point of attachment of the group to the rest of the molecule and m is 0 or 1 when n is 1 or m is 0 when n is 2;

R ^{2 is} methyl and

R ^{3 represents} a group of the general formula (III)

 (III)

 in which

 * represents the point of attachment of the group to the rest of the molecule;

R ^{4 is} a mono- to trisubstituted fluorine-substituted C 1 -C ⁴ alkyl and

R ^{5 is} hydrogen;

as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.

Another object of the present invention are compounds of the general formula (I), in which

R ^{1 stands} for a group of the general formula (II)

 dl) represents the point of attachment of the group to the rest of the molecule and is 0 or 1, when n is 1 or

 is 0 when n is 2; stands for methyl and

wobei represents a group of the general formula (III)

in which

 * represents the point of attachment of the group to the rest of the molecule;

R ⁴ is trifluoromethyl or 1,1-difluoroethyl and

R ^{5 is} hydrogen.

as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.

A further subject of the present invention are in particular the following compounds:

 1 (±) - N - [2- (1,1-dioxotetrahydro-2-i-thiopyran-3-yl) -5-methoxy-1-methyl-1-i-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide

 1-1 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -6-

(trifluoromethyl) pyridine-2-carboxamide (enantiomer A)

 1 -2 N- [2- (1,1-dioxo-tetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1'-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 carboxamide (enantiomer B)

 2 (±) -6- (1,1-difluorofhyl) - / V- [2- (1,1-dioxotetrahydro-2 / i-thiopyran-3-yl) -5-methoxy-1-methyl-1-yl] benzimidazol-6-yl] pyridine-2-carboxamide

 2-1 (+) - 6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2 / f-thiopyran-3-yl) -5-mehoxy-1-methyl-1-i benzimidazol-6-yl] pyridine-2-carboxamide (enantiomer A)

 2- 2 (-) - 6- (1,1-Difluorofhenyl) - N - [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-i-benzimidazole -6-yl] pyridine-2-carboxamide (enantiomer B)

 3 (±) - N - [2- (1,1-dioxotetrahydro-2-i-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -4- (trifluoromethyl) -l, 3-thiazol-2-carboxamide

 3-1 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -4-

(trifluoromethyl) -1,3-thiazole-2-carboxamide (enantiomer A)

 3- 2 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -4-

(trifluoromethyl) -1,3-thiazole-2-carboxamide (enantiomer B)

 4 (+) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl) -pyridine-2-carboxamide

 4-1 / V- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6-

(trifluoromethyl) pyridine-2-carboxamide (enantiomer A)

 4- 2 / V- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6-

(trifluoromethyl) pyridine-2-carboxamide (enantiomer B)

 5 (±) -6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] pyridine -2-carboxamide

 5-1 6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -pyridine-2 carboxamide (enantiomer A)

 5-2 6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-IH-benzimidazol-6-yl] pyridine-2 carboxamide (enantiomer B)

 6 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-1 -7-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide

7 6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -5-methoxy-1-methyl-IH-benzimidazol-6-yl] pyridine-2-carboxamide 8 N - [2- (1,1-dioxo-tetrahydro-2-i-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -4- (trifluoromethyl) -1,3 -thiazol-2-carboxamide

 9 ^ 2- (1-Dioxide-tetrahydro-2-i-hiopyran-yl) -methyl-5,2,2,2-trifluoroethoxy) -1-benzimidazol-6-yl] -6- (trifluoromethyl) -pyridine-2-carboxamide

10 A ⁱ 5 ^ 2,2-difluoroethoxy) -2- (1-dioxotetrahydro-2ii-thiopyrari-4-yl) -1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 -carboxamide

 11 / V- [5- (2,2-difluoroethoxy) -2- (1,1-dioxotetrahydro-2 # -fiopyran-4-yl) -1-methyl-1 H-benzimidazol-6-yl] -6- (1,1-difluoroethyl) pyridine-2-carboxamide

12A ^r - [5- (Cyclopropylmethoxy) -2- (1,1-dioxotetrahydro-2ii-thiopyrari-4-yl) -1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 -carboxamide

13 / V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5- (2-methoxyethoxy) -l -methyl-IH-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine -2-carboxamide

14 7V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -1-ethyl-1-pyrazole-3-carboxamide

15 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -5-fluoro-6-methylpyridine-2-one carboxamide

16 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -2- (trifluoromethyl) pyrimidine-4-carboxamide

17 7V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -6-ethylpyridine-2-carboxamide

 A further subject of the present invention is in particular the list of the following compounds:

 2 (±) -6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydro-2 / f-thiopyran-3-yl) -5-mehoxy-1-methyl-1-yl] benzimidazol-6-yl] pyridine-2-carboxamide

 2-1 (+) - 6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazole -6-yl] pyridine-2-carboxamide (enantiomer A)

 2-2 (-) - 6- (1,1-Difluoroethyl) - / V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-yl] benzimidazol-6-yl] pyridine-2-carboxamide (enantiomer B)

The compounds of general formula (I) according to 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 kinase Trk (tropomyosin-related kinase) -A, a kinase whose inhibition can be associated with possible side effects (compare section "Inhibition of IKAK4 Kinase Activity and Selectivity to TrkA") No evidence 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 of the formula (I) according to the invention for the treatment and / or prophylaxis of diseases in humans and animals.

 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 particularly preferred.

The compounds of the formula (I) 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 family-mediated diseases or diseases, the 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 formula (I) according to the invention can furthermore 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.

Due to the mechanism of action of the compounds of formula (I) according to the invention they are 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 suitable. Furthermore, the compounds of the formula (I) according to the invention are suitable for the prophylaxis and / or treatment of transplant rejection, lupus erythematosus, Adult Still's disease and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.

In addition to the diseases already mentioned, the use of the compounds of the formula (I) 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. The mechanism of action of the compounds of the formula (I) according to 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 liver cirrhosis.

Furthermore, the compounds of the formula (I) 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 renal disease and nephropathies.

Furthermore, the prophylaxis and / or treatment of itching and pain, in particular of acute, chronic, inflammatory and neuropathic pain by the compounds of formula (I) according to the invention is given.

Due to the mechanism of action of the compounds of formula (I) according to 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 Rasabhängige tumors.

 In addition, the compounds of the formula (I) according to the invention are suitable for the treatment and / or prevention of diseases which are 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 dysmenorrhoea, dyspareunia, dysuria and dyscheza, chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are associated with a Dysregulation of the IL-1 receptor family associated and suitable for the therapeutic and / or prophylactic use of the compounds of formula (I) according to the invention.

The compounds of the formula (I) according to the invention can furthermore 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. Furthermore, the compounds of the formula (I) 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, postoperative 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.

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 of the formula (I) according to the invention. 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".

 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.

 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 formula (I) according to the invention can be used alone or as needed in combination with other active substances. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the formula (I) and one or more further active compounds, 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:

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), yak / 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.

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, after termination of the non- Medicamentous tumor therapy such as chemotherapy, radiotherapy or phototherapy can be supplemented by a drug treatment with the IRAK4 inhibitors according to the invention.

The 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 the 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 inflammatory bowel disease. 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.

Also mentioned are drugs which contain at least one of the compounds of the formula (I) 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 AKRlC3 inhibitors (Aldo-keto reductase family 1 member C3 inhibitors), for the treatment and / or prevention of the aforementioned diseases.

The compounds of the formula (I) 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. For the oral administration are according to the prior art functioning, the compounds of formula (I) according to the invention rapidly and / or modified donating application forms, which contain the compounds of the formula (I) according to the invention in crystalline and / or amorphized and / or dissolved form, for example tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which release the compound according to the invention of the formula (I)), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

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.

Preference is given to oral or parenteral administration, in particular oral administration. The compounds of the formula (I) 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, polyoxysorbitol oleate), 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.

Another object of the present invention are pharmaceutical compositions containing at least one inventive compound of formula (I), usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above. 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. Thus, in some cases it may be sufficient to manage 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.

The following embodiments illustrate the invention. The invention is not limited to the examples.

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.

Preparation of the compounds of the invention

 The invention further provides a process for the preparation of the compounds of the general formula (I) according to the invention, which comprises reacting a compound of the general formula (XII)

 (XII)

 in which

R represents a group of the general formula (II)

 (Ii)

 in which

* represents the point of attachment of the group to the rest of the molecule; m stands for 0 or 1 and n is 1 or 2;

R ^{2 is} cyclopropylmethyl, 2-cyclopropylethyl, methyl or C 1 -C 6 -alkyl which may be monosubstituted to trisubstituted by fluorine or simply by C 1 -C 6 -alkoxy, or a compound of general formula (XIII)

R ³ C (= 0) R ⁷

 (XII I),

in which

R ^{7 is} OH or chlorine and

represents a group selected from the following general formulas (III) to (X:

 in which

* represents the point of attachment of the group to the rest of the molecule; R ^{4 is} hydrogen, cyclopropyl or C 1 -C 6 -alkyl which may be mono- or polysubstituted by identical or different substituents with fluoro, cyclopropyl or hydroxy;

R ^{5 is} hydrogen, methyl or fluorine and

R ^{6 is} Cs-Cö-cycloalkyl, cyclopropyl-Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, or Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, is;

As illustrated in S ntheseschema 1 illustrated.

 Synthetic Scheme 1

The compounds (I) according to the invention are obtained by acylation of the compounds of the general formula (XII) with suitable compounds of the general formula (XIII). When using carboxylic acids (R ⁷ in formula (XIII) OH), 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 (in combination with 1-hydroxybenzotriazole hydrate (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, p. 2093)), (1-i-benzotriazol-1-yloxy) (dimethylamino)

 (TB TU, CAS-RN 125700-67-6), (dimethylamino) - ^ - dimethyl (3,1- [1,2,3] triazolo [4,5-fc] pyridiri-3-yloxy) methaneiminium hexafluoro-phosphate ( HATU, CAS-RN 148893-10-1),

Propanphosphonsäureanhydrid (as a solution in ethyl acetate or DMF, CAS-RN 68957-94-8) or diimid-imidazol-1-ylmethanone (CDI) can be used as coupling reagents, in each case to the reaction mixture, a base such as triethylamine or / V-ethyl - / V-isopropylpropan-2-amine is given. 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. If appropriate, compounds of the formula (XII) can also be reacted with carboxylic acid chlorides (R ⁷ in formula (XIII) has the meaning chloro) to give the compounds (I) according to the invention. Suitable methods for this purpose are those suitable for the person skilled in the art (compare, for example, Journal of Medicinal Chemistry, 1984, Vol. 27, # 2 p., 125-128 for the use of triethylamine and DMF).

In one embodiment of the process according to the invention, compounds of the formula (XII) with compounds of the general formula (XIII), where R ^{7 is} OH, are converted into compounds of the formula (I) in the context of an amide synthesis. In this case, in a further embodiment of the method HATU is used in combination with the base triethylamine.

Compounds of the general formula (XIII) are commercially available or can be prepared by methods known from the literature or analogously to the literature (see, for example, synthesis scheme 1 in WO2016083433).

Another object of the invention are compounds of general formula (XII),

 (XII)

in the

 R represents a group of the general formula (II)

 (I i)

 in which

 * represents the point of attachment of the group to the rest of the molecule; m stands for 0 or 1 and

 n is 1 or 2;

R ^{2 is} cyclopropylmethyl, 2-cyclopropylethyl, methyl or C 2 -C 6 -alkyl which may be monosubstituted to trisubstituted by fluorine or simply by C 1 -C 6 -alkoxy

as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.

A further subject of the present invention are in particular the following compounds:

(XII) -1 (±) -2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) - 1-1 (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-amine

 (XII) - 1-2 (-) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -2 (±) -2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -2- 1 (+) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -2-2 (-) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -3 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

(XII) -4 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -l-methyl-5- (2,2,2-trifluoroethoxy) -H- benzimidazol-6-amine

 (XII) -5- 5- (2,2-Difluoroethoxy) -2- (1,1-dioxotetrahydro-2H-t -opyran-4-yl) -m ^

 benzimidazol-6-amine

 (XII) -6- (Cyclopropylmethoxy) -2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-1H-benzimidazole-6-amine

 (XII) -7 2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5- (2-methoxyethoxy) -1-methyl-IH-benzimidazol-6-amine

A further subject of the present invention are in particular the following compounds:

(XII) -2 (±) -2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -2A (+) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

 (XII) -2B (-) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine

The compounds of the general formula (XII) are suitable for the preparation of the compounds of the general formula (I).

The compounds of the formula (XII) according to the invention can be prepared according to synthesis scheme 2 or 3.

 Synthesis Scheme 2:

 Intermediate 1 can be prepared by alkylation of the phenol group of 2-amino-4-chloro-5-nitrophenol (CAS-RN 6358-07-2) 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 (see also Bioorganic & Medicinal Chemistry Letters 16 (2006) 2293-2298).

Intermediate 2 are obtained from intermediates 1 by introducing a "Boc" (ieri-butoxycarbonyl group) amino-protecting group The ieri-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, the introduction of the ieri-butoxycarbonyl group is accomplished by treatment with di-ieri-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).

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 iron and ammonium chloride in water and ethanol or methanol (Journal of the Chemical Society, 1955, 2412-2419), or preferably by the use of palladium on carbon and ammonium formate in methanol or ethanol, respectively.

The intermediates 5 are obtained in two stages starting from the intermediates 4. First, an acylation is carried out with a carboxylic acid HOOC-R ¹ (wherein R ^{1 has} the definition given in the general formula (I)). The carboxylic acids HOOC-R ¹ are commercially available, known from the literature or can be prepared by the methods known to those skilled in the art. Various coupling reagents known in the literature can be used for the acylation (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 (in combination with 1-hydroxy-li7-benzotriazole hydrate (HOBt, WO2012107475, Bioorg. Med. Chem. Lett., 2008, 18, 2093)), (relative benzotriazol-1-yloxy) (dimethylamino) - / V, / V-dimethylmethaniminiumtetrafluoroborat (TB TU, CAS RN 125700-67-6), (dimethylamino) -A ^r, A ^r dimethyl (3 i- [l, 2 , 3] triazolo [4,5-fc] 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-1-imidazol-1-ylmethanone (CDI) can be used as coupling reagents, in each case to the reaction mixture, a base such as triethylamine or N-ethyl / V-isopropylpropan-2-amine is added. Preferably, the coupling reagent is HATU in combination with triethylamine in DMF.

 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.

By cleavage of the feri-butoxycarbonyl group is obtained from the intermediates 5, the compounds of general formula (XII). For this purpose, methods known to the person skilled in the art (compare also PGM Wuts, TW Greene, Greene's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) are considered. Preferably, the cleavage can be effected by treatment with trifluoroacetic acid in dichloromethane.

Intermediate 1 Intermediate 2 Intermediate 3

 Intermediate 4

 Synthesis Scheme 2

The substituents R ¹ and R ² have the definitions given in the general formula (I). Synthesis Scheme 3:

 Alternatively, the compounds of the formula (XII) according to the invention can be prepared according to synthesis scheme 3:

The intermediates 8 are obtained in two stages starting from the intermediates 7. The intermediates 7 are commercially available or known in the literature. First, an acylation with a carboxylic acid HOOC-R ^{3 takes place} . 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 (in combination with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, 2093)), (1H- Benzotriazol-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 (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. Preferably, the coupling reagent is HATU in combination with triethylamine in DMF. 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. The intermediates 9 can be obtained by nitration of the intermediates 8. For this purpose, nitration methods known to the person skilled in the art, for example the use of nitric acid in combination with concentrated sulfuric acid, of concentrated sulfuric acid and potassium nitrate or preferably nitric acid in acetic acid, are suitable. In this case, mixtures of nitrated compounds are obtained (see also European Journal of Medicinal Chemistry 45 (2010) 1873-1879, Org. Biomol. Chem., 2007, 5, 3665-3673). Starting from the mixtures, the intermediates 9 can be obtained by the methods known to the person skilled in the art, for example chromatography. A further processing of the mixture of the nitrated compounds and a purification after a later stage of synthesis is also possible. The compounds of the formula (XII) according to the invention are obtained by reduction of the nitro group from the intermediates 9. 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 may be replaced by the use of iron and ammonium chloride in water and ethanol or methanol (Journal of the Chemical Society, 1955, 2412-2419), palladium on carbon and ammonium formate in methanol or ethanol, or preferably by use be reduced by palladium on carbon under a hydrogen atmosphere. If intermediate 9 is reduced as a mixture with one or more nitro compounds, the compounds of the formula (XII) according to the invention can be separated by the methods known to the person skilled in the art, for example by chromatography.

 Intermediate 7 Intermediate e Intermediate 9 (XII)

 Synthesis Scheme 3

The substituents R ¹ and R ² have the definitions given in the general formula (I).

Description of the picture

Figure 1: Inhibition of IL-1-induced IL-6 secretion by administration of Exemplary Compound 2-2 in peritoneal lavage. Synthesis of the example compounds

definitions:

Methoden

methods

The compounds according to the invention and their precursors and / or intermediates were analyzed by LC-MS:

LC-MS methods (analytical): UPLC-MS method A

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; 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 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 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 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; 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 some cases, the purification of substance mixtures by column chromatography on silica gel.

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.

Preparation of Starting Materials and Intermediate Methyl 6- (1,1-difluoroethyl) pyridine-2-carboxylate

2-Bromo-6- (1,1-difluoroethyl) pyridine (5 g, 21.4 mmol, CAS No 1211535-69-1) was dissolved in a mixture of 15.2 mL methanol and 23.7 mL DMSO in the presence of triethylamine (7 mL, 50 mmol), propan-l, 3-diylbis (diphenylphosphine) (573 mg, 1.35 mmol) and palladium (II) acetate (302 mg, 1.35 mmol) in an autoclave. It was then stirred in a carbon monoxide atmosphere (20.8 bar for 0.5 h) at room temperature. It was then evacuated and stirred under a carbon monoxide atmosphere (20.3 bar) at 100 ° C for 22 h.

After cooling, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried and concentrated. The residue was purified by chromatography.

There were obtained 3.45 g (80%) of the title compound.

^X H NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.02 (t, 3H), 3.91 (s, 3H), 7.94-7.98 (m, 1H), 8.17 - 8.22 (m, 2H).

6- (1,1-Difluoroethyl) pyridine-2-carboxylic acid

3.45 g of methyl 6- (1,1-difluoroethyl) pyridine-2-carboxylate (17 mmol) in 75 ml of THF, 2.5 ml of methanol and 30 ml of water were mixed with 5.4 g of lithium hydroxide and the mixture was stirred at room temperature for 6 h. It was then diluted with water, the pH was adjusted to pH 4 with 10% citric acid and extracted 5 times with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. There were obtained 3.65 g of a crude product, which was used without further purification.

^X H NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.03 (t, 3H), 7.91-7.95 (m, 1H), 8.14-8.20 (m, 2H), 13.45 (sbr, 1H). Intermediate 1-1

5-chloro-2-methoxy-4-nitroaniline

10 g (53 mmol) of 2-amino-4-chloro-5-nitrophenol (CAS-RN 6358-07-2) were dissolved in 200 ml of DMF and 3.3 ml (53 mmol) of iodomethane and 11 g (79 mmol) of potassium carbonate added 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 of the title compound were obtained. ^X H 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).

Intermediate 1-2

aniline 5-Chloro-4-nitro-2- (2,2,2-trifluoroethoxy)

500 mg (2.65 mmol) of 2-amino-4-chloro-5-nitrophenol (CAS-RN 6358-07-2) were dissolved in 10 ml of DMF and treated with 612 μΐ (4.24 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate ( CAS-RN 6226-25-1) and 733 mg (5.30 mmol) of potassium carbonate and 1.47 g (3.98 mmol) of tetrabutylammonium iodide were added and stirred at room temperature overnight. The reaction mixture was concentrated, the residue was diluted with water and saturated aqueous sodium bicarbonate solution and added with ethyl acetate. The organic phase was separated and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. 657 mg of the title compound were obtained. Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 4.89 (q, 2H), 6.55 (sbr, 2H), 6.80 (s, 1H), 7.79 (s, 1H).

UPLC MS (ESI +): [M + H] ⁺ = 271; R _t = 1.10 min (method A).

The following intermediates were prepared according to the procedure described for Intermediate 1-2 using the indicated alkylating agents from 2-amino-4-chloro-5-nitrophenol.

 nitroaniline

Intermediate 2-1 terf-butyl (5-chloro-2-methoxy-4-nitrophenyl) carbamate

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-ieri-butyl dicarbonate, 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-d ₆ ): δ [ppm] = 1.48 (s, 9H), 3.91 (s, 3H), 7.73 (s, IH), 8.15 (s, IH), 8.78 (s, IH ).

UPLC MS (ESI +): [M + H] ⁺ = 302; R _t = 1.44 min (method D). The following intermediates were prepared according to the procedure described for Intermediate 2-1 Intermediate 1.

nitrophenyl] carbamate

Intermediate 3-1

ter ^ butyl [2-methoxy-5- (methylamino) -4-nitrophenyl] carbamate

16 g ieri-Butyl-(5-chlor-2-methoxy-4-nitrophenyl)carbamat (Intermediat 2-1) wurden in 160 ml Methylaminlösung (33% in Ethanol) gelöst und im verschlossenen 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 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 of ieri-butyl (5-chloro-2-methoxy-4-nitrophenyl) carbamate (Intermediate 2-1) 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 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; R _t = 1.35 min (method B).

The following intermediates were prepared from the indicated Intermediate 2 according to the procedure described for Intermediate 3-1.

(Methylamino) -4-nitrophenyl] carbamate Intermediate 4-1i-butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate

4.9 g (16 mmol) of feri-butyl [2-methoxy-5- (methylamino) -4-nitrophenyl] carbamate (Intermediate 3-1) were mixed with 3.34 g of Pd-carbon (10% Pd), 5.2 g (82 mmol ) Ammonium formate in 120 ml of methanol for one hour at 60 ° C stirred. 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 of the title compound were obtained.

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; R _t = 0.72 min (method A).

The following intermediates were prepared according to Intermediate 3 given for Intermediate 4-1.

Intermediat 5-1

Intermediate 5-1

(+) - ieri-butyl- [2- (1,1-dioxotetrahydro-2-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] carbamate

1 g of butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate (Intermediate 4-1) and 0.56 g (3.1 mmol) of (+) - tetrahydro-2H-thiopyran-3-carboxylic acid 1, l-dioxide was 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. It was then concentrated and the residue was stirred in 8 ml of acetic acid overnight at 40 ° C. It was concentrated and a crude product (3.7 g) was obtained, which was used without further purification in the subsequent stage.

UPLC MS (ESI +): [M + H] ⁺ = 410; R _t = 1.09 min (method B)

Intermediate 5-2

(+) - ieri-butyl [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] carbamate

l g ieri-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat und 0.56 g (3.1 mmol) (+)- Tetrahydrothiophen-3-carbonsäure-l,l-dioxid 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. Dann wurde eingeengt und der Rückstand wurde in 8 ml Essigsäure über Nacht bei 40 °C gerührt. Es wurde eingeengt und ein Rohprodukt (3.4 g) erhalten, welches ohne weitere Reinigung in der Folgestufe eingesetzt wurde.

1,2-Butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate and 0.56 g (3.1 mmol) of (+) - tetrahydrothiophene-3-carboxylic acid 1,1-dioxide were mixed with 1.8 g (4.7 mmol) HATU in the presence of 0.65 ml (4.7 mmol) of triethylamine in 20 ml of DMF at room temperature overnight. It was then concentrated and the residue was stirred in 8 ml of acetic acid overnight at 40 ° C. It was concentrated and a crude product (3.4 g), which was used without further purification in the next step.

UPLC-MS (ESI +): [M + H] ⁺ = 396; R _t = 1.08 min (Method B) Intermediate 5-3 ethylbutyl 2- (1,1-dioxotetrahydro-2-thiopyran-4-yl) -5-methoxy-1-methyl-1-benzimidazole 6-yl] carbamate

l g ieri-Butyl-[4-amino-2-methoxy-5-(methylamino)phenyl]carbamat und 0.56 g (3.1 mmol) Tetrahydro-2ii-thiopyran-4-carbonsäure-l,l-dioxid 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. Dann wurde eingeengt und der Rückstand wurde in 8 ml Essigsäure über Nacht bei 40 °C gerührt. Es wurde eingeengt und ein Rohprodukt (3.5 g) erhalten, welches ohne weitere Reinigung in der Folgestufe eingesetzt wurde.

1,2-Butyl [4-amino-2-methoxy-5- (methylamino) phenyl] carbamate and 0.56 g (3.1 mmol) of tetrahydro-2ii-thiopyran-4-carboxylic acid 1,1-dioxide were mixed with 1.8 g (4.7 mmol) HATU in the presence of 0.65 ml (4.7 mmol) of triethylamine in 20 ml of DMF at room temperature overnight. It was then concentrated and the residue was stirred in 8 ml of acetic acid overnight at 40 ° C. It was concentrated and a crude product (3.5 g) was obtained, which was used without further purification in the subsequent stage.

UPLC MS (ESI +): [M + H] ⁺ = 410; R _t = 1.06 min (method B)

The following intermediates were prepared according to the procedure described for Intermediate 5-3 Intermediate 4.

Preparation of the compounds of the formula (XII): Compound (XII) - 1

(+) - 2- (l, l-dioxidotetrahydro-2 // - thiopyran-3-yl) -5-methoxy-l-methyl-l // - benzimidazol-6-amine

3.7 g (+) - ieri-butyl- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] carbamate (used as crude product , Intermediate 5-1) were stirred in 18 ml of dichloromethane with 1.76 ml (23 mmol) of trifluoroacetic acid overnight at room temperature. An additional 1.76 ml (23 mmol) of trifluoroacetic acid was added and stirred at room temperature for 3 hours. Then, 10 ml of water was added and a pH of 8-9 was adjusted by adding saturated sodium bicarbonate solution. The dichloromethane was distilled off in vacuo. The aqueous residue was extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, over Dried magnesium sulfate and concentrated. There were obtained 0.8 g of the title compound as a crude product.

'H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1.63 - 1.77 (m, 1H), 1.95 - 2.16 (m, 3H), 3:06 to 3:15 (m, 1H), 3:20 to 3:32 (m , 2H), 3.39- 3.55 (m, 2H), 3.61 (m, 3H), 3.78 (s, 3H), 4.67 (s, 2H), 6.65 (s, 1H,) 6.98 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 310; R, = 0.65 min (Method B).

Compound (XII) -2

(+) - 2- (l, l-Dioxidotetrahydrothiophen-3-yl) -5-methoxy-l-methyl-l // - benzimidazol-6-am

3.4 g (+) - ieri-butyl- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1-i7-benzimidazol-6-yl] carbamate (used as crude product, intermediate 5 -2) were stirred in 18 ml of dichloromethane with 1.83 ml (24 mmol) of trifluoroacetic acid overnight at room temperature. An additional 1.83 ml (24 mmol) of trifluoroacetic acid was added and the mixture was stirred at room temperature for 3 hours. 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 in vacuo. The aqueous residue was extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There were obtained 0.7 g of the title compound as a crude product.

UPLC-MS (ESI +): [M + H] ⁺ = 296; R _t = 0.60 min (method B).

Compound (XII) -3 2- (1,1-dioxotetrahydro-2 // hiopyran-4-yl) -5-methoxy-1-methyl-1-benzimidazol-6-amine

3.5 g of ieri-butyl [2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] carbamate (used as crude product, intermediate 5 -3) were stirred in 18 ml of dichloromethane with 1.76 ml (23 mmol) of trifluoroacetic acid overnight at room temperature. An additional 1.76 ml (23 mmol) of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated and stored for 2 days in the refrigerator (5 ° C). 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 in vacuo. The aqueous residue was extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated. There were obtained 0.74 g of the title compound as a crude product. UPLC-MS (ESI +): [M + H] ⁺ = 310; R _t = 0.63 min (method B). Compound (XII) -4

2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-5- (2,2,2-trifluoroethoxy) -li-benzimidazole-6-amine

388 mg of ieri-butyl [2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -l-methyl-5- (2,2,2-trifluoroethoxy) -1,1-benzimidazol-6-yl] carbamate (used as crude product, intermediate 5-4) were stirred in 5.6 ml of dichloromethane with 0.88 ml (11 mmol) of trifluoroacetic acid for 4 h at room temperature. The reaction mixture was concentrated in vacuo, treated with toluene, and again concentrated in vacuo. The crude product was immediately reacted further.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.34 (m, 4H), 3.29 (m, 2H), 3.40 (m, 2H), 3.72 (m, 1H), 3.85 (s, 3H ), 4.90 (q, 2H), 7.02 (s, 1H), 7.26 (s, 1H).

UPLC MS (ESI +): [M + H] ⁺ = 478; R _t = 0.80 min (method B).

The following compounds were prepared according to the procedure described for compound (XII) -4 the indicated Intermediate 5.

Intermediate 8-1

(+) - 2- (l, l-dioxidotetrahydro-2H-thiopyran-3-yl) -5-methoxy-l-methyl-lH-benzimidazole

0.5 g (3.3 mmol) 4-Methoxy-N¹-methylbenzol-l,2-diamin (CAS Nr. 3360-78-9) und 0.58 g (3.3 mmol) (+)-Tetrahydro-2H-thiopyran-3-carbonsäure-l,l-dioxid wurden mit 1.9 g (4.9 mmol) HATU in der Gegenwart von 0.69 ml (4.9 mmol) Triethylamin in 21 ml DMF bei Raumtemperatur über Nacht gerührt. Es wurde auf 200 ml eines Eiswasser-Gemisches gegeben und der pH Wert mittels gesättigter Natriumhydrogencarbonatlösung auf 9 gestellt. Dann wurde mit dreimal 150 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden mit 50 ml Wasser sowie gesättigter Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde in 10 ml Essigsäure über Nacht bei RT gerührt. Es wurde eingeengt und ein Rohprodukt (1.31 g) erhalten, welches ohne weitere Reinigung in der Folgestufe eingesetzt wurde.

0.5 g (3.3 mmol) of 4-methoxy-N- ^1- methylbenzene-1,2-diamine (CAS No. 3360-78-9) and 0.58 g (3.3 mmol) of (+) - tetrahydro-2H-thiopyran-3-carboxylic acid -l, l-dioxide was stirred with 1.9 g (4.9 mmol) of HATU in the presence of 0.69 ml (4.9 mmol) of triethylamine in 21 ml of DMF at room temperature overnight. It was added to 200 ml of an ice-water mixture and the pH was adjusted to 9 by means of saturated sodium bicarbonate solution. Then, it was extracted with three times 150 ml of ethyl acetate. The combined organic phases were washed with 50 ml of water and saturated brine, dried over magnesium sulfate and concentrated. The residue was in 10 ml of acetic acid stirred overnight at RT. It was concentrated and a crude product (1.31 g) was obtained, which was used without further purification in the subsequent stage.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.68-1.82 (m, 1H), 1.96-2.11 (m, 3H), 3.06-3.17 (m, 1H), 3.22-3.3 (m , 1H), 3.44 - 3.53 (m, 1H), 3.53 - 3.62 (m, 1H), 3.76 (m, 6H), 6.83 - 6.88 (m, 1H), 7.09 - 7.12 (m, 1H), 7.39 - 7.44 (m, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 295; R _t = 0.78 min (method B)

Intermediate 9-1

(+) - 2- (l, l-dioxidotetrahydro-2H-thiopyran-3-yl) -5-meth ^

1.21 g of (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy was dissolved in 15 ml of acetic acid and treated slowly with 5.1 ml of nitric acid (fuming) and stirred at RT overnight , Then another 1.9 ml of nitric acid (smoking) was added and stirred for a further hour at RT. Thereafter, the reaction mixture was added slowly to 100 ml of ice and 500 ml of saturated sodium hydrogen carbonate solution. The pH was adjusted to 10 with saturated sodium bicarbonate solution and the precipitated solid was filtered off. 0.78 g of a mixture of (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-6-nitro-1H-benzimidazole and (±) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-4-nitro-1H-benzimidazole.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.69-1.87 (m, 2H), 1.95-2.18 (m, 6H), 3.04-3.18 (m, 2H), 3.45-3.54 (m, 2H), 3.57- 3.69 (m, 2H), 3.83 (m, 6H), 3.91 (s, 6H), 7.26 (d, 1H, 4-nitro compound), 7.46 (s, 1H, 6-nitro compound) 7.81 (d, 1H, 4-nitro compound), 8.28 (s, 1H, 6-nitro compound).

UPLC MS (ESI +): [M + H] ⁺ = 340; R _t = 0.81 min (method A)

Alternative Preparation of Compound (XII) - 1:

0.63 g of the mixture of (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-6-nitro-1H-benzimidazole obtained in the precursor and (± ) -2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-4-nitro-1H-benzimidazole were dissolved in 37 ml of THF and 12 ml of ethanol containing 327 mg Pd / Charcoal (10%) hydrogenated under a hydrogen atmosphere for 1.5 hours. Thereafter, the catalyst was filtered off and concentrated. There was obtained 595 mg of a residue, which was purified by chromatography. 178 mg of the title compound (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine, 168 mg (±) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-4-amine and 122 mg mixed fraction.

Compound (XII) -l: ^X H-NMR (400MHz, DMSO-d _6): δ [ppm] = 1.63 - 1.77 (m, 1H), 1.95 - 2.16 (m, 3H), 3:06 to 3:15 (m, 1H ), 3.20-3.32 (m, 2H), 3.39-3.55 (m, 2H), 3.61 (m, 3H), 3.78 (s, 3H), 4.67 (s, 2H), 6.65 (s, 1H,) 6.98 ( s, 1H). Preparation of Exemplified Compounds Example 1

(±) -N 2 → 1, 1-dioxotetrahydro-2 // hiopyran-3-yl) -5-methoxy-1-methyl-1: -benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 -carboxamide

0.27 g (+) - 2- (1 -dioxide-tetrahydro-2-i-hiopyran-3-yl) -5-methoxy-m

amine (Intermediate (XII) - 1) and 115 mg (0.6 mmol) of 6- (trifluoromethyl) pyridine-2-carboxylic acid were treated with 344 mg (0.9 mmol) of HATU in the presence of 126 μΐ (0.9 mmol) of triethylamine in 3 ml of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 156 mg of the title compound.

Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.68-1.84 (m, 1H), 1.99-2.29 (m, 3H), 3.09

1H), 3.45 - 3.55 (m, 1H), 3.56 - 3.67 (m, 1H), 3.78 (s, 3H), 3.96 (s, 3H), 7.35 (s, 1H), 8.20

1H), 8.38-8.50 (m, 2H), 8.57 (s, 1H), 10.53 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 483; R _t = 1.13 min (method B).

Example 1-1

N- [2- (l, l-dioxidotetrahydro-2/7-thiopyran-3-yl) -5-methoxy-l-methyl-

(trifluoromethyl) pyridine-2-carboxamide (enantiomer A)

Example 1-2 N- [2- (1,1-dioxotetrahydro-2-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl ) pyridine-2-carboxamide (enantiomer B)

The racemic compound (+) - / V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6- ( trifluoromethyl) pyridine-2-carboxamide was separated into the enantiomers by means of chiral HPLC. There were obtained 59 mg of the title compound (Enantiomer A, Example 1-1) and 63 mg (Enantiomer B, Example 1-2).

analytics:

 Instrument: Agilent HPLC 1260; Column: Chiralpak LB 3μ 100x4.6mm;

Eluent A: acetonitrile + 0.1% by volume diethylamine (99%); Eluent B: methanol; isocratic:

50% A + 50% B;

Flow 1.4 ml / min; Temperature: 25 ° C; DAD 254 nm

Enantiomer AR _t = 1.16 min

Enantiomer BR _t = 1.67 min

Preparation:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000,

 Column: Chiralpak IB 5μ 250x30mm; Eluent A: acetonitrile + 0.1% by volume diethylamine (99%);

Eluent B: methanol + 0.1% by volume diethylamine (99%); Isocratic: 50% A + 50% B; Flow 40.0 ml / min; UV 254 nm

Enantiomer AR _t = 4.0 - 4.7 min

Enantiomer BR _t = 5.7 - 6.6 min

Example 2

(+) - 6- (l, l-difluoroethyl) -N- [2- (l, l-dioxidotetrahydr ^^

l / 7-benzimidazol-6-yl] pyridine-2-carboxamide

0.27 g of (+) - 2- (1 -dioxide-tetrahydro-2-i-thiopyran-3-yl) -5-methoxy ^^

amine (Intermediate (XII) - 1) and 113 mg (0.6 mmol) of 6- (1,1-difluoroethyl) pyridine-2-carboxylic acid were treated with 345 mg (0.9 mmol) HA TU in the presence of 126 μΐ (0.9 mmol). Triethylamine in 3 mL of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 178 mg of the title compound.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.68-1.84 (m, 1H), 1.98-2.24 (m, 6H), 3.08-3.19 (m, 1H), 3.45- 3.56 (m, 1H), 3.58 - 3.68 (m, 1H), 3.80 (s, 3H), 3.98 (s, 3H), 7.36 (s, 1H), 7.99 - 8.07 (m, 1H), 8.27 - 8.36 (m, 2H) , 8.57 (s, 1H), 10.71 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 479; R _t = 1.10 min (method B). Example 2-1

(+) - 6- (1,1-Difluoroethyl) -N 2- (1-dioxotetrahydro-2-thiopyran-3-yl) -5-methoxy-1-methyl-l / 7-benzimidazol-6-yl ] pyridine-2-carboxamide (enantiomer A)

Example 2-2

(-) - 6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazole -6-yl] pyridine-2-carboxamide (enantiomer B)

The racemic compound (±) -6- (1,1-difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2,7-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazole] 6-yl] pyridine-2-carboxamide was separated into the enantiomers by means of chiral HPLC. Enantiomer A (Example 2-1) and Enantiomer B (Example 2-2) were obtained. Chiral HPLC analysis:

 Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3μ 100x4.6mm;

 Eluent A: acetonitrile + 0.1% by volume diethylamine (99%); Eluent B: ethanol; Isocratic: 90% A + 10% B; Flow 1.4 ml / min; Temperature: 25 ° C; DAD 254 nm

Enantiomer AR _t = 1.25 min

Enantiomer BR _t = 1.83 min

Preparation:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000,

 Column: Chiralpak IB 5μ 250x30mm; Eluent A: acetonitrile + 0.1% by volume diethylamine (99%);

 Eluent B: ethanol + 0.1% by volume diethylamine (99%); Isocratic: 90% A + 10% B; Flow 40.0 ml / min; UV

254 nm

Enantiomer AR _t = 4.0 - 4.7 min

Enantiomer BR _t = 5.7 - 6.6 min

Alternative method chiral HPLC analysis:

Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100x4.6 mm; Eluent A: methanol;

Isocratic: 100% A; Flow 1.0 ml / min; Temperature: 25 ° C; DAD 325 nm

Enantiomer AR _t = 5.78 min

Enantiomer BR _t = 15.62 min

Preparation:

Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Chiralpak IC 5μ 250x50mm No.024; Eluent A: methanol; Isocratic: 100% A; Flow 150.0 ml / min; UV 325 nm

Enantiomer AR _t = 7.1 - 11.2 min

Enantiomer BR _t = 20.8 - 26.5 min

For example 2-1 (enantiomer A) a rotation of [a] _D ²⁰ = + 9.41 ° +/- 0.45 ° (C = 0.73, chloroform) was found.

For example 2-2 (enantiomer B), a rotation of [a] _D ²⁰ = -8.98 ° +/- 0.42 ° (C = 0.60, chloroform) was found.

Example 3 (+) - N- [2- (l, l-dioxidotetrahydro-2/7-thiopyran-3-yl) -5-methoxy-l- ^

 l] -4- (trifluoromethyl) -l, 3-thiazol-2-carboxamide

 0.27 g of (+) - 2- (1,1-dioxotetrahydro-2 / i-thiopyran-3-yl) -5-metto

amine (Intermediate (XII) -l) and 119 mg (0.6 mmol) of 4- (trifluoromethyl) -1,3-thiazole-2-carboxylic acid were treated with 345 mg (0.9 mmol) of HATU in the presence of 126 μΐ (0.9 mmol). Triethylamine in 3 mL of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There was obtained 106 mg of the title compound.

Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.69-1.83 (m, 1H), 1.97-2.29 (m, 3H), 3.06-3.18 (m, 1H), 3.45- 3.56 (m, 1H), 3.57 - 3.65 (m, 1H), 3.76 (s, 3H), 3.93 (s, 3H), 7.35 (s, 1H), 8.24 (s, 1H), 8.89 (s, 1H), 9.86 (s , 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 489; R _t = 1.13 min (method B). Example 3-1

N- [2- (l, l-dioxidotetrahydro-2/7-thiopyran-3-yl) -5-methoxy-l-meth ^

(trifluoromethyl) -1,3-thiazole-2-carboxamide (enantiomer A)

Example 3-2

N- [2- (1,1-dioxotetrahydro-2-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -4- (trifluoromethyl) -1, 3-thiazole-2-carboxamide (enantiomer B)

The racemic compound (+) - / V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -4- ( trifluoromethyl) -l, 3-thiazole-2-carboxamide was separated into the enantiomers by means of chiral HPLC. There were obtained 35 mg Enantiomer A (Example 3-1) and 40 mg Enantiomer B (Example 3-2).

analytics:

 Instrument: Agilent: 1260, Aurora SFC Module; Column: Chiralpak LB 5μιη 100x4.6mm;

Eluent A: C02, eluent B: ethanol; Isocratic: 17% B;

 Flow 4.0 ml / min; Temperature: 37.5 ° C; BPR: lOObar; MWD @ 254nm

Enantiomer AR _t = 2.34 min

Enantiomer BR _t = 3.31 min

Preparation: Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IB 5μιη 250x30mm;

 Eluent A: C02, eluent B: ethanol; Isocratic: 17% B;

Flow 100.0 ml / min temperature: 40 ° C; BPR: 150bar; MWD @ 254nm enantiomer AR _t = 6.5 - 9.0 min

Enantiomer BR _t = 10.5 - 14.5 min

Example 4

(±) -N 2 → 1, 1-dioxotetrahydrothiophen-3-yl) -5-meth

(Trifluoromethyl) pyridine-2-carboxamide

0.385 g of (±) -2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1-i-benzimidazol-6-amine (intermediate (XII) -2) and 174 mg (0.9 mmol ) 6- (Trifluoromethyl) pyridine-2-carboxylic acid were stirred with 520 mg (1.37 mmol) of HATU in the presence of 190 μΐ (1.37 mmol) of triethylamine in 3 ml of DMF at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 216 mg of the title compound.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.30-2.41 (m, 1H), 2.54-2.65 (m, 3H), 3.18-3.29 (m, 1H), 3.35-3.49 (m, 2H), 3.59 - 3.70 (m, 1H), 3.78 (s, 3H), 3.96 (s, 3H), 4.09 - 4.20 (m, 1H), 7.40 (s, 1H), 8.20 - 8.26 (m, 1H) , 8.38 - 8.49 (m, 2H), 8.59 (s, 1H), 10.53 (s, 1H). UPLC-MS (ESI +): [M + H] ⁺ = 469; R _t = 1.12 min (method B). Example 4-1

N- [2- (l, l-Dioxidotetrahydrothiophen-3-yl) -5-methoxy-l-methyl-l / ^

(trifluoromethyl) pyridine-2-carboxamide (enantiomer A)

Example 4-2 N- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide (Enantiomer B)

The racemic compound was (+) - N- [2- (1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide separated by chiral HPLC into the enantiomers. There were obtained 90 mg enantiomer A (Example 4-1) and 80 mg enantiomer B (Example 4-2).

analytics:

 Instrument: Agilent HPLC 1260; Column: Chiralpak lA 3μ 100x4.6mm;

Eluent A: acetonitrile + 0.1% by volume diethylamine (99%); Eluent B: methanol; isocratic:

50% A + 50% B;

Flow 1.4 ml / min; Temperature: 25 ° C; DAD 254 nm

Enantiomer A Rt = 1.29 min

Enantiomer B Rt = 1.98 min

Preparation:

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000,

 Column: Chiralpak IA 5μ 250x30mm; Eluent A: acetonitrile + 0.1% by volume diethylamine (99%);

 Eluent B: methanol + 0.1% by volume diethylamine (99%); Isocratic: 50% A + 50% B; Flow 40.0 ml / min;

UV 254 nm

Enantiomer AR _t = 4.1 - 4.7 min

Enantiomer BR _t = 5.0 - 6.01 min

Example 5

(+) - 6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotrothothiophene-3-yl) -5-methoxy-1-methyl-1/7-benzimidazol-6-yl] pyridine-2-carboxamide

0.385 g (+)-2-(1 -Dioxidotetrahydrothiophen-3-yl)-5-methoxy-l^

0.385 g of (+) - 2- (1 -dioxidotetrahydrothiophene-3-yl) -5-methoxy-1H

and 170 mg (0.9 mmol) of 6- (1,1-difluoroethyl) pyridine-2-carboxylic acid (intermediate (XII) -2) were mixed with 520 mg (1.37 mmol) of HATU in the presence of 190 μΐ (1.37 mmol) of triethylamine 3 ml of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 199 mg of the title compound. Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.17 (t, 3H), 2.30-2.42 (m, 1H), 2.54-2.65 (m, 1H), 3.19-3.29 (m, 1H) , 3.36 - 3.48 (m, 2H), 3.60 - 3.70 (m, 1H), 3.79 (s, 3H), 3.98 (s, 3H), 4.09 - 4.20 (m, 1H), 7.40 (s, 1H), 7.99 - 8.06 (m, 1H), 8.28 - 8.35 (m, 2H), 8.57 (s, 1H), 10.70 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 465; R _t = 1.1 1 min (method B).

Example 5-1 6- (1,1-Difluoroethyl) -N 2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] pyridine-2 carboxamide (enantiomer A)

Example 5-2

6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] pyridine-2-carboxamide (Enantiomer B) The racemic compound (+) - 6- (1,1-difluoroethyl) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazole -6-yl] pyridine-2-carboxamide was resolved by chiral HPLC into the enantiomers. There were obtained 75 mg Enantiomer A (Example 5-1) and 78 mg Enantiomer B (Example 5-2). analytics:

 Instrument: Agilent HPLC 1260; Column: Chiralpak lA 3μ 100x4.6mm;

Eluent A: acetonitrile + 0.1% by volume diethylamine (99%); Eluent B: methanol; isocratic:

50% A + 50% B;

Flow 1.4 ml / min; Temperature: 25 ° C; DAD 254 nm

Enantiomer A Rt = 1.28 min

Enantiomer B Rt = 1.92 min

preparation

Instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000,

 Column: Chiralpak IA 5μ 250x30mm; Eluent A: acetonitrile + 0.1% by volume diethylamine (99%);

 Eluent B: methanol + 0.1% by volume diethylamine (99%); Isocratic: 50% A + 50% B; Flow 40.0 ml / min;

UV 254 nm

Enantiomer AR _t = 3.9 - 4.6 min

Enantiomer BR _t = 5.0 - 6.0 min

Example 6

 N 2 ^ 1 -dioxide tetrahydro-2 // hiopyran-4-yl) -5-methoxy-1-methyl-1 // benzimidazole

(Trifluoromethyl) pyridine-2-carboxamide

0.25 g of 2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-amine (used as crude product) and 106 mg (0.56 mmol) 6 (Trifluoromethyl) pyridine-2-carboxylic acid were stirred with 319 mg (0.84 mmol) of HATU in the presence of 117 μΐ (0.84 mmol) of triethylamine in 3 ml of DMF at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 68 mg of the title compound.

^X H NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.20-2.32 (m, 4H), 3.42- 3.53 (m, 1H), 3.77 (s, 3H), 3.96 (s, 3H), 7.39 (s, 1H), 8.19 - 8.26 (m, 1H), 8.37 - 8.49 (m, 2H), 8.57 (s, 1H), 10.52 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 483; R _t = 1.10 min (method B). Example 7

6- (1,1-Difluoroethyl) -N 2 → 1, 1-dioxotetrahyl ^^

benzimidazol-6-yl] pyridine-2-carboxamide

0.25 g 2-(1 -Dioxidotetrahydro-2/i hiopyran-4-yl)-5-methoxy -mem^

0.25 g of 2- (1 -dioxide-tetrahydro-2-i-hiopyran-4-yl) -5-methoxy-methyl

(used as the crude product) and 6-10 mg (0.56 mmol) of 6- (l, l-difluoroethyl) pyridine-2-carboxylic acid were reacted with 318 mg (0.84 mmol) of HATU in the presence of 117 μΐ (0.84 mmol) of triethylamine in 3 mL of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 54 mg of the title compound. Ή NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.17 (t, 3H), 2.23-2.31 (m, 4H), 3.41- 3.51 (m, 1H), 3.78 (s, 3H), 3.97 (s, 3H), 7.38 (s, 1H), 8.00-8.05 (m, 1H), 8.29-8.34 (m, 2H), 8.56 (s, 1H), 10.70 (s, 1H).

UPLC-MS (ESI +): [M + H] ⁺ = 479; R _t = 1.10 min (method B). Example 8 N 2 ^ 1 -dioxide-tetrahydro-2 // hiopyran-4-yl) -5-methoxy-1-methyl-1: -benzimidazol-6-yl] -4- (trifluoromethyl) -l, 3-thiazole 2-carboxamide

0.25 g of 2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-amine (used as crude product) and 110 mg (0.56 mmol) of (Trifluoromethyl) -1,3-thiazole-2-carboxylic acid were treated with 319 mg (0.84 mmol) of HATU in the presence of 117 .mu.l (0.84 mmol) of triethylamine in 3 mL of DMF stirred at room temperature overnight. The reaction mixture was purified by HPLC. There were obtained 81 mg of the title compound.

Ή-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.23-2.31 (m, 4H), 3.42- 3.51 (m, 1H), 3.77 (s, 3H), 3.93 (s, 3H), 7.38 (s, 1H), 8.24 (s, 1H), 8.89 (s, 1H), 9.85 (s, 1H). UPLC-MS (ESI +): [M + H] ⁺ = 489; R _t = 1.10 min (method B).

The following examples were prepared according to the procedure described for Example 1 from Intermediate XII using the indicated carboxylic acids.

.

,

carboxamide

Evaluation of physiological activity

Inhibition of IKAK4 Kinase Activity and Selectivity to TrkA IRAK4 Kinase Assay

 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).

 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-5B 1-4, cell line purchased from 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).

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 MgCh, 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 IRAK4 concentration was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear regime. 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]. 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, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET measuring instrument, eg a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). 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). Usually, the test substances were tested on the same microtiter plates at 11 different concentrations in the range of 20 μΜ to 0.073 nM (20 μΜ, 5.7 μΜ, 1.6 μΜ, 0.47 μΜ, 0.13 μΜ, 38 ηΜ, 11 ηΜ, 3.1 ηΜ, 0.89 ηΜ, 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 and TrkA kinase assay

 Example IRAK4 TrkA

 IC50 [mol / l] IC50 [mol / l]

 1-1 4.49 E-9 8.90 E-7

 6.64 E-9 8.33 E-7

 5.61 E-9

 1-2 8.81 E-9 2.04 E-6

 1.50 E-6

 2-1 5.22 E-9 3.37 E-7

 5.44 E-9 3.60 E-7

 4.48 E-9 3.19 E-7

 2.14 E-9 3.34 E-7

 2.50 E-9

 2-2 1.37 E-9 4.35 E-7

 1.92 E-9 3.40 E-7

 2.51 E-9 4.16 E-7

 1.50 E-9 4.30 E-7

 1.53 E-9

 3-1 2.48 E-8 1.05 E-5

 3.47 E-8 7.75 E-6

 3-2 2.58 E-8 1.45 E-5

 2.05 E-8 1.24 E-5

 4-1 1.30 E-7 1.19 E-6

 1.11 E-6

 4-2 8.78 E-8 5.49 E-6

 3.72 E-6

 5-1 5.14 E-8 1.58 E-7

 1.83 E-7

5-2 1.89 E-8 5.63 E-7 Example IRAK4 TrkA

 IC50 [mol / l] IC50 [mol / l]

 6.68 E-7

 6 3.24 E-8 1.73 E-6

 3.59 E-8 1.20 E-6

 7 1.49 E-8 2.59 E-7

 1.36 E-8 1.79 E-7

 8 1.23 E-6> 2.00 E-5

 1.15 E-6> 2.00 E-5

 9 2.54 E-7 1.06 E-6

 2.22 E-7 1.88 E-6

 10 8.26 E-8 1.52 E-6

 1.00 E-7 1.34 E-6

 11 6.92 E-8 3.50 E-7

 8.15 E-8 3.79 E-7

 12 1.46 E-7 5.33 E-7

 1.29 E-7 6.86 E-7

 13 1.38 E-7 7.45 E-7

 7.39 E-8 9.54 E-7

 14 3.55 E-7 1.10 E-6

 3.64 E-7 1.45 E-6

 15 1.30 E-7> 2.00 E-5

 1.74 E-7> 2.00 E-5

 16 8.69 E-7 1.47 E-5

 6.67 E-7 1.23 E-5

 17 9.51 E-8 2.51 E-7

 8.85 E-8 1.88 E-7

TrkA kinase assay

 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).

 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.

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.

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 MgCh, 1.0mM dithiothreitol, 0.2mM EDTA, 0.01% (v / v) Nonidet-P40 (Sigma)] and the mixture incubated for 15 min to pre-contract the substances to allow for 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 is incubated for 60 min at 22 ° C for the reaction time. 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 each used pipettor) were tested in duplicate for each concentration and IC 50 values were calculated using a 4-parameter fit.

 The example compounds show a high selectivity towards TrkA (see Table 1).

Binding kinetics of the example compounds at IRAK4

 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.

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.

The target residence time is the reciprocal value of the koff value, target residence time = 1 / koff.

The example compounds show a long residence time on IRAK4 (see Table 2).

Table 2: Binding kinetics of the example compounds

In vitro micronucleus test

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 2-2 showed no evidence of mutagenicity in the in vitro MNT, testing the substance to the solubility limit (precipitation).

CYP inhibition

The determination of the in vitro inhibition potential of a substance to be tested against CYP P450 enzymes (eg CYP3A4, CYP1A2, CYP2C8, CYP2C9, etc.) is a basic component for the evaluation of interaction risks (DDIs) with co-administered drugs, which relevant substrates of the investigated CYP isoforms are described. The in vitro studies on CYP inhibition are recommended in agency guidelines for the evaluation of drug interaction risks (eg EMA, FDA). The inhibitory potential of test compounds for CYP P450 enzymes was investigated in human liver microsomes (HLM). For this purpose CYP isoform-selective standard substrates (phenacetin, coumarin, bupropion, amodiaquine, diclofenac, S-mephenytoin, dextromethorphan, chlorzoxazone, midazolam, testosterone) have been used as well as reference inhibitors as positive controls. Incubation conditions (protein and substrate concentration, incubation time) have been optimized for linear metabolite formation. The assay was performed in 96-well plates at 37 ° C using a Genesis workstation (Tecan, Crailsheim, Germany). After stopping the reactions by means of protein precipitation, the quantification of formed metabolites was carried out with LC-MS / MS, thus the evaluation of the inhibition in the test substance used concentration and respectively calculation of IC50 values.

The example compounds 1-1, 1-2 and 7 showed no inhibition of the enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C8, CYP2C9 up to the highest measured concentration of 5 μΜ.

Example compounds 2-2 and 5-2 showed no inhibition of the enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C8, CYP2C9 up to the highest measured concentration of 10 μΜ.

Example compound 5-1 did not show any inhibition of the enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C8, CYP2C9 up to the highest measured concentration of 20 μΜ.

CYP induction

Induction of CYP P450 enzymes may have clinical significance, for example leading to reduced systemic exposure of co-administered drugs. CYP3A4 is hepatically the most abundant CYP enzyme and metabolically relevant to a variety of approved drugs (Fahmi et al.). The evaluation of potential CYP induction in vitro, in particular CYP3A4, is therefore an important element in the evaluation of potential interaction risks with other medicinal products (EMA, FDA). To assess CYP induction potential in vitro, sandwich cultures of hepatocytes from three different liver donors were treated once a day for three consecutive days with vehicle control, eight different concentrations of a test substance and known positive controls (for example omeprazole, phenobarbiotal, rifampicin). After treatment, the cells were incubated in situ with appropriate standard substrates for CYP3A4 and CYP1A2, and their activity quantified over respective formed metabolites with LC-MS / MS. Following in situ incubation with standard substrates, the same hepatocytes from the different treatment groups were harvested, the RNA was isolated and the effect of the test substances on the CYP1 A2, CYP3A4 and CYP2B6 mRNA expression levels was determined by qRT-PCR. Example 2-2 showed no induction of CYP3A4 mRNA and CYP1A2 mRNA up to a concentration of 10,000 micrograms per liter.

Characterization of the Permeationsverhaltens of the substances according to the invention in the bidirectional Caco-2 assay

To characterize the permeation properties of the substances according to the invention, the human intestinal Caco-2 cell line (ACC169, lot 9 of: German Collection of Microorganisms and Cell Cultures GmbH (DSMZ) Braunschweig, Germany) was used. These cells are derived from a human colon carcinoma and differentiated in culture to a polarized monolayer exhibiting enterocytic differentiation with formation of a brush border membrane and the expression of transport proteins. The cultivation of the cells on permeable filter inserts allows the separate study of transport processes at the apical and basolateral membrane. The bidirectional Caco-2 assay is the FDA-recommended in vitro method for evaluating the permeation properties of substances. (Elsby R, et al., Xenobiotics, 38 (7-8): 1140-1164, 2008.)

For the investigations, the cells were incubated at a density of 3 × 10 ⁵ / ml on Transwell filter inserts (polyester, pore size 0.4 μιη; Corning, Costar, Cat. 3378) in 24-well cell culture plates for at least 14 days in cell culture medium [Dulbelco's Modiefied Eagle medium ( DMEM) sub-cultured with 10% fetal calf serum (FCS), 1% GlutaMAX (100x, GIBCO), 100 U / ml penicillin, 100 μθ / ml streptomycin] at 37 ° C, 5% CO 2 and 95% humidity. Medium change took place every 2-3 days. Before starting the permeation experiment, the cell culture medium was replaced with FCS-free Hepes-carbonate buffer (pH 7.4, consisting of 25 mM Hepes and HBSS with CaCl ₂ and MgCl ₂ (Gibco, ref. 14025-050)) and the integrity of the cell monolayer checked by measuring the transepithelial resistance (TEER value). The substances according to the invention were predissolved in DMSO and as a rule added in a final concentration of 2 μΜ to the apical or basolateral compartment (donor compartment). Aliquots were taken from both compartments (donor and acceptor compartment) before and after the 2 hour incubation at 37 ° C. The quantification of the substance amount was carried out after precipitation of the samples with methanol (1: 1, overnight at -20 ° C) by LC / MS / MS.

To describe the permeability (permeability) of the cell monolayer for the substances according to the invention, the so-called "apparent permeability coefficient" (P _app ) was calculated by the following formula:

P _app = (V r / Po) (l / S) (P2 / t) where Vr Domiziano the buffer volume on the receptor side, Po of the substance concentration on the donor side at time 0, S of the filter area (0.3 cm ^2), P2 of the substance concentration in the Acceptor compartment after 2 hours of incubation and t of incubation time. The efflux ratio was calculated as the ratio of P _app (basolateral to apical) to Papp (apical to basolateral) In addition to the permeation coefficient, substance recovery was also determined Assay control served reference substances that were tested in parallel to the substances according to the invention.

A substance with a P _app value (apical to basolateral) below 10 nm / s is described as a weakly permeable substance, with a value between 10 nm / sec and 70 nm / sec as moderately permeable substance and with a value> 70 nm / sec defined as a highly permeable substance. An efflux above 2 is an indication of involvement of an efflux transporter, an efflux below 0.7 indicates the involvement of a receiving transporter.

The example compounds show high permeability from apical to basolateral as well as vice versa. Furthermore, the efflux ratios of the example substances 1-1, 1-2 and 2-2 indicate neither the involvement of an efflux transporter nor the involvement of a receiving transporter. For example compound 7, the efflux ratio indicates a mild efflux, but below 2 (see Table 3).

Table 3: Permeability and efflux ratio of the example compounds

In vitro LPS (lipopolysaccharide) -induced cytokine production in human PBMCs (peripheral blood mononuclear cells)

The effect of the compounds of the general formula (I) according to the invention on the induced cytokine production in human PBMCs was investigated. The induction of cytokine production by LPS, a TLR4 ligand, led to the activation of the IRAK4-mediated signaling pathway.

Recovery of human PBMCs was from anti-coagulated human whole blood from 5 donors (Example Compound 2-2) and 2 donors, respectively (Example Compound 1-1). For this purpose, 15 ml of Ficoll-Paque (Biochrom, cat. No. L6115) were placed in Leucosep tubes and 20 ml of human blood were added. After centrifugation of the blood at 800 g for 15 min at room temperature, plasma including the platelets was removed and discarded. The PBMCs were transferred to centrifuge tubes and filled with PBS (Phosphate Buffered Saline) (Gibco, Cat # 14190). The cell suspension was centrifuged at 250g for 10 min at room temperature and the supernatant discarded. The resuspension of the PBMCs was carried out in complete medium (RPMI 1640, without L-glutamine (PAA, cat # E15-039), 10% FCS; 50 U / ml penicillin, 50 μιηι streptomycin (PAA, cat.no. Pl l-010) and 1% L-glutamine (Sigma, cat.no. G7513)).

The assay was carried out in complete medium including FCS. The indicated IC 50 values were not corrected for protein binding. The PBMCs 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 0.4% DMSO was. The cells were allowed to stand for 30 min before the actual

Stimulation preincubated. To induce cytokine secretion, stimulation was carried out with 0.1 μg / ml LPS (Sigma, Escherichia coli 0128: B12, Cat. No. L2887) for 24 hours. The determination of

Cell viability was determined using the CellTiter-Glo Luminescent Assay (Promega, Cat # G7571 (G755 / G756A)) as directed by the manufacturer. The amount of secreted TNF-alpha in the cell culture supernatant was determined by means of the Human Prolifflammatory 9-Plex Tissue Culture Kit (MSD, Cat. No. K15007B) according to the manufacturer's instructions. 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 4: IC 50 values which were not corrected for protein binding of the exemplary compounds with respect to TNF-α release in PBMC cells,

In vivo IL-lß-mediated inflammation model

To assess the potential potency of the compounds of general formula (I) according to the invention in IL-1β-mediated diseases, female Balb / c mice (about 8 weeks, Charles River Laboratories, Germany) were IL-1β i.p. and investigated the effect of the compounds according to the invention on the IL-Lβ-mediated cytokine secretion in the peritoneal lavage. The group size was 5 animals each. The control group was treated with the vehicles used to dissolve the substance and IL-1β. Each of the substance treatment groups and the positive control group was administered with 90 μg IL-1 / kg body weight (R & D, Cat # 401-ML / CF) i.p. The substance or its vehicle in the

Positive control group was administered 3 hours before IL-lß administration. The determination of TNF-α and IL-6 in the peritoneal lavage and in the plasma after the final blood collection were performed 2 hours after the administration of the IL-Lß using the Mouse Prolnflammatory 7-Plex Tissue Culture Kit (MSD, Cat. # K15012B) according to the manufacturer's instructions ,

The administration of IL-1 ß leads to an increased concentration of IL-6 in the peritoneal lavage, which was inhibited by the treatment with the example substance 2-2 (see Figure 1).

Claims

claims  1. Compound of the general formula (I)

 wherein R ^{1 stands} for a group of the general formula (II)

 (Ii)  in which  * represents the point of attachment of the group to the rest of the molecule; m stands for 0 or 1 and  n is 1 or 2; R ^{2 is} cyclopropylmethyl, 2-cyclopropylethyl, methyl or C 2 -C 6 -alkyl, which may be monosubstituted to trisubstituted by fluorine or simply by C 1 -C 6 -alkoxy, and R ^{3 is} a group selected from the following general formulas (III) to (X):

 (IV) (V) (VI)

(VII) (VIII) (ix) ( ^χ ) in which  * represents the point of attachment of the group to the rest of the molecule; R ^{4 is} hydrogen, cyclopropyl or Ci-Gs-Aikyl, which may be monosubstituted or polysubstituted by identical or different fluorine, cyclopropyl or hydroxy, is; R ^{5 is} hydrogen, methyl or fluorine and R ^{6 is} Cs-Cö-cycloalkyl, cyclopropyl-Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, or Ci-Cö-alkyl, which may be mono- to trisubstituted by fluorine, is;  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the Solvates of their salts. 2. Compounds of general formula (I) according to claim 1, wherein: R ^{1 stands} for a group of the general formula (II)

 (I i)  in which  * represents the point of attachment of the group to the rest of the molecule and m is 0 or 1 when n is 1 or  m is 0 when n is 2; R ^{2 is} cyclopropylmethyl, methyl, ethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl, and R ^{3 is} a group selected from the following general formulas (III) and (V) to (X)

 (III) (V) (VI)

 (VII) (VIII) (IX) (X) in which * represents the point of attachment of the group to the rest of the molecule; R ^{4 is} a mono- to trisubstituted fluoro-substituted C ₁ -C 4 alkyl; R ^{5 is} hydrogen and R ^{6 is} C ₁ -C ₂ -alkyl which may be mono- to trisubstituted by fluorine; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. Compounds of general formula (I) according to claim 2, wherein R ¹ and R ^{2 have} the meaning given in claim 2 and R ^{3 is} a group of the general formula (III)

in which  * represents the point of attachment of the group to the rest of the molecule; R ^{4 is} a mono- to trisubstituted fluorine-substituted C ₁ -C 4 alkyl and R ^{5 is} hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. Compounds of general formula (I) according to claim 3, wherein R ^{1 has} the meaning given in claim 2; R ^{2 is} methyl and R ^{3 is} a group of the general formula (III)

in which  * represents the point of attachment of the group to the rest of the molecule; R ^{4 is} a mono- to trisubstituted fluorine-substituted C ₁ -C 4 alkyl and R ^{5 is} hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. 5. Compounds of general formula (I) according to claim 4, wherein R ^{1 has} the meaning given in claim 2; R ^{2 is} methyl and R ^{3 is} a group of the general formula (III)

 in which  * represents the point of attachment of the group to the rest of the molecule; R ⁴ is trifluoromethyl or 1,1-difluoroethyl and R ^{5 is} hydrogen;  as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts. 6. Compounds of general formula (I) according to any one of claims 2-5, namely  1 (±) - N - [2- (1,1-dioxotetrahydro-2 / f-thiopyran-3-yl) -5-mehoxy-1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide  1-1 7V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2- carboxamide (enantiomer A)  1-1 7V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-li7-benzimidazole] 6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide (enantiomer B)  2 (±) -6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazole-6 -yl] pyridine-2-carboxamide  2-1 (+) - 6- (1,1-Difluoro-ethyl) - / V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-one benzimidazol-6-yl] pyridine-2-carboxamide (enantiomer A)  2- 2 (-) - 6- (1,1-Difluoroethyl) -N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-benzimidazole -6-yl] pyridine-2-carboxamide (enantiomer B)  3 (±) - N - [2- (1,1-dioxotetrahydro-2 / f-thiopyran-3-yl) -5-mehoxy-1-methyl-1H-benzimidazol-6-yl] -4- (trifluoromethyl) - 1, 3-thiazole-2-carboxamide  3-1 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1-i-benzimidazole] 6-yl] -4- (trifluoromethyl) -1,3-thiazole-2-carboxamide (enantiomer A)  3- 2 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-3-yl) -5-methoxy-1-methyl-1i-benzimidazole] 6-yl] -4- (trifluoromethyl) -1,3-thiazole-2-carboxamide (enantiomer B)  4 (±) -7V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1-benzimidazol-6-yl] -6- (trifluoromethyl) -pyridine-2-carboxamide 4-1 7V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] ^■ 6- (trifluoromethyl) pyridine-2-carboxamide (enantiomer A) 4-2 7V- [2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1'-benzimidazol-6-yl] ^■ 6- (trifluoromethyl) pyridine-2-carboxamide (enantiomer B) 5 (+) - 6- (1 -Difluoremyl) -A ^r - [2- (1 -dioxidotetrah  1-benzimidazol-6-yl] pyridine-2-carboxamide  5-1 6- (1,1-difluoro-ethyl) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -pyridine 2-carboxamide (enantiomer A)  5-2 6- (1,1-difluoro-ethyl) - / V- [2- (1,1-dioxotetrahydrothiophen-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-yl] -pyridine 2-carboxamide (enantiomer B)  6 7V- [2- (1,1-dioxotetrahydro-2 / f-thiopyran-4-yl) -5-mehoxy-1-methyl-1-i-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 -carboxamide  7 6- (1,1-Difluoro-ethyl) - / V- [2- (1,1-dioxotetrahydro-2 / f-thiopyran-4-yl) -5-mehoxy-1-methyl-1-i-benzimidazole-6- yl] pyridine-2-carboxamide  8 7V- [2- (1,1-dioxotetrahydro-2 / f-thiopyran-4-yl) -5-mehoxy-1-methyl-7-benzimidazol-6-yl] -4- (trifluoromethyl) -1,3 -fhiazol-2-carboxamide  9 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -1-methyl-5- (2,2,2-trifluoroethoxy) - [H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2-carboxamide  10 N- [5- (2,2-Difluoroethoxy) -2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -1-methyl- \ H -benzimidazol-6-yl] -6- (trifluoromethyl ) pyridine-2-carboxamide  11 N- [5- (2,2-Difluoroethoxy) -2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -1-methyl- \ H -benzimidazol-6-yl] -6- (1 , 1 -difluoroethyl) pyridine-2-carboxamide  12 N- [5- (Cyclopropylmethoxy) -2- (1,1-dioxotetrahydro-2-i-thiopyran-4-yl) -1-methyl-IH-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine-2 -carboxamide  13 7V- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5- (2-methoxyethoxy) -1-methyl-1H-benzimidazol-6-yl] -6- (trifluoromethyl) pyridine -2-carboxamide  14 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -1-ethyl-1-pyrazole-3-carboxamide  15 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -5-fluoro-6-methylpyridine-2-carboxamide  16 N - [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-7-benzimidazol-6-yl] -2- (trifluoromethyl) pyrimidine-4-carboxamide  17 N- [2- (1,1-dioxotetrahydro-2ii-thiopyran-4-yl) -5-methoxy-1-methyl-1-i-benzimidazol-6-yl] -6-ethylpyridine-2-carboxamide 7. Process for the preparation of the compounds of the general formula (I) according to the invention as defined in any one of claims 1 to 6, characterized in that a compound of the general formula (XII)

 (XII)  in which R ¹ and R ^{2 have} the meaning given in claim 1 with a compound of general formula (XIII), R ³ C (= 0) R ⁷  (XIII)  in which R ^{3 has} the meaning given in claim 1 and R ^{7 is} OH or chlorine; is implemented. Compounds of the general formula (XII),

 (XII) wherein R ^{1 stands} for a ru e of the general formula (II)

 in which  * represents the point of attachment of the group to the rest of the molecule;  m stands for 0 or 1 and  n is 1 or 2; R ^{2 is} cyclopropylmethyl, 2-cyclopropylethyl, methyl or C 2 -C 6 -alkyl, which may be monosubstituted to trisubstituted by fluorine or simply by C 1 -C 6 -alkoxy, and their diastereomers, enantiomers, their metabolites, their salts, theirs Solvates or the solvates of their salts. Compounds of general formula (XII) according to claim 8, namely  (XII) -1 (±) -2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine  (XII) - 1-1 (+) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-amine  (XII) - 1-2 (-) - 2- (1,1-dioxotetrahydro-2H-thiopyran-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine (XII) -2 (±) -2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H- benzimidazol-6-amine  (XII) -2- 1 (+) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine  (XII) -2-2 (-) - 2- (1,1-dioxotetrahydrothiophene-3-yl) -5-methoxy-1-methyl-1H-benzimidazole-6-amine  (XII) -3 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -5-methoxy-1-methyl-1H-benzimidazol-6-amine  (XII) -4 2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-5- (2,2,2-trifluoroethoxy) -1 H-benzimidazole-6-amine  (XII) -5- (2,2-Difluoroethoxy) -2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -l-methyl  1H-benzimidazole-6-amine  (XII) -6- (Cyclopropylmethoxy) -2- (1,1-dioxotetrahydro-2H-thiopyran-4-yl) -1-methyl-1H-benzimidazole-6-amine  (XII) -7 2- (1,1-dioxotetrahydro-2 / f-thiopyran-4-yl) -5- (2-methoxy-hexoxy) -1-methyl  1-benzimidazole-6-amine  10. A compound of the general formula (I) as defined in any one of claims 1 to 6 for use in a method for the treatment and / or prophylaxis of diseases. 11. A compound of general formula (I) as defined in any one of claims 1 to 6 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, metabolic diseases, liver diseases, kidney diseases, inflammatory diseases, autoimmune diseases and pain. A compound of general formula (I) as defined in any one of claims 1 to 6 for use in a method for the treatment and / or prophylaxis of lymphoma, 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 dysmenorrhea, dyspareunia, dysuria and dyschezia. A compound of the general formula (I) as defined in any one of claims 1 to 6 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), premenstrual pain, endometriosis-associated pain, postoperative 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. Use of a compound of general formula (I) as defined in any one of claims 1 to 6 for the manufacture of a medicament. 15. Use according to claim 14, 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. 16. Use according to claims 14 or 15 for the treatment and / or prophylaxis of lymphoma, 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. Use according to claims 14 or 15 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), premenstrual pain, endometriosis-associated Pain, postoperative pain, pain in interstitial cystitis, 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. 18. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 6, in combination with an inert, non-toxic, pharmaceutically suitable Excipient.