TW201725202A - Novel substituted indazoles, processes for preparation thereof, pharmaceutical preparations comprising them and use thereof for production of medicaments - Google Patents

Abstract

The present application relates to novel substituted indazoles, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, of lymphoma, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disorders, insulin resistance, neoplastic disorders and psoriasis.

Description

Novel substituted carbazole, its preparation method, pharmaceutical preparation containing the same, and use thereof

The present invention relates to novel substituted carbazoles, to processes for their preparation, to intermediates useful in the preparation of such novel compounds, to the use of such novel substituted carbazoles for the treatment and/or prophylaxis of diseases, and to their use Prepared to treat and/or prevent diseases, especially proliferative disorders (eg autoimmune disorders), metabolic and inflammatory conditions (eg rheumatoid arthritis), spondylarthritis (especially psoriatic spondylarthritis and Behetylev) Bekhterev's disease, chronic obstructive pulmonary disease (abbreviation: COPD), multiple sclerosis, systemic lupus erythematosus, gout, metabolic syndrome, fatty liver hepatitis, insulin resistance, endometriosis and inflammation induction The use of a medicament for pain or chronic pain and lymphoma. The present invention relates to a novel substituted carbazole of the general formula (I) which inhibits the interleukin-1 receptor-associated kinase 4 (IRAK4).

Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammatory inhibitory substances. IRAK4 is expressed by a variety of cells and mediates steroid receptors (TLR) (except TLR3) and interleukin (IL)-1β family receptors (by IL-1R (receptor), IL-18R, IL-33R and IL) Signal transduction of -36R composition) (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010). IRAK4 knockout mice and human cells from patients lacking IRAK4 do not respond to TLR (except TLR3) and IL-1β family stimuli (Suzuki, Suzuki et al, Nature, 2002; Davidson, Currie et al, The Journal Of Immunology, 2006; Ku, von Bernuth et al, JEM, 2007; Kim, Staschke et al, JEM, 2007). Binding of TLR ligands or IL-1β family ligands to individual receptors results in the recruitment and binding of MyD88 [myeloid differentiation primary response gene (88)] to the receptor. Thus, MyD88 interacts with IRAK4, resulting in the formation of an active complex that interacts with the kinase IRAK1 or IRAK2 and activates the kinases (Kollewe, Mackensen et al, Journal of Biological Chemistry, 2004; Precious et al, J. Biol Chem., 2009). Thus, the NF (nuclear factor)-kappaB signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway are activated (Wang, Deng et al, Nature, 2001). Activation of the NF-κB signaling pathway and the MAPK signaling pathway can result in processes associated with different immune processes. For example, various inflammatory signaling molecules and enzymes (such as interleukins, chemokines, and COX-2 (cyclooxygenase-2)) have increased expression, and inflammation-related genes (such as COX-2, The mRNA stability of IL-6 (interleukin-6), IL-8) is increased (Holtmann, Enninga et al, Journal of Biological Chemistry, 2001; Datta, Novotny et al, The Journal of Immunology, 2004). In addition, these processes may be associated with proliferation and differentiation of specific cell types (eg, mononuclear spheres, 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). A direct comparison of wild-type (WT) mice with genetically modified animals with a kinase-deactivated form of IRAK4 (IRAK4 KDKI) has demonstrated an important role for IRAK4 in the pathology of various inflammatory conditions. In animal models of multiple sclerosis, atherosclerosis, myocardial infarction, and Alzheimer's disease, IRAK4 KDKI animals have improved clinical manifestations (Rekhter, Staschke et al, Biochemical and Biophysical Research Communication, 2008) Maekawa, Mizue et al., Circulation, 2009; Staschke, Dong et al, The Journal of Immunology, 2009; Kim, Febbraio et al, The Journal of Immunology, 2011; Cameron, Tse et al, The Journal of Neuroscience, 2012) . In addition, it was found that the absence of IRAK4 in animal models protects against viral-induced myocarditis due to improved antiviral responses and reduced systemic inflammation (Valaperti, Nishii et al., Circulation, 2013). It has also been shown that the performance of IRAK4 is associated with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang et al., PLoS ONE, 2014). In addition, the high correlation of IRAK4 to immune complex-mediated IFNα (interferon-α) production by plasmacytoid dendritic cells has demonstrated that this IFNα production is key in the pathogenesis of systemic lupus erythematosus (SLE). Process (Chiang et al., The Journal of Immunology, 2010). In addition, signaling pathways are associated with obesity (Ahmad, R., P. Shihab et al., Diabetology & Metabolic Syndrome, 2015). In addition to the essential role of IRAK4 in innate immunity, it is also suggested that IRAK4 affects the differentiation of cells known as Th17 T cells (adaptive immune components). In the absence of IRAK4 kinase activity, less IL-17 producing T cells (Th17 T cells) were produced compared to WT mice. Inhibition of IRAK4 enables prevention and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondylarthritis (especially psoriatic spondyloarthritis and Behdejelev's disease), lupus erythematosus, psoriasis , leukoplakia, giant cell arteritis, chronic inflammatory bowel disease and viral disorders (eg HIV (human immunodeficiency virus), hepatitis virus) (Staschke et al, The Journal of Immunology, 2009; Marquez et al, Ann Rheum Dis, 2014) ;Zambrano-Zaragoza et al, International Journal of Inflammation, 2014; Wang et al, Experimental and Therapeutic Medicine, 2015; Ciccia et al, Rheumatology, 2015). Since IRAK4 plays an important role in the TLR (except TLR3) and the MyD88-mediated signaling cascade of the IL-1 receptor family, inhibition of IRAK4 can be used to prevent and/or treat conditions mediated by the mentioned receptors. The components of the TLR and IL-1 receptor families are involved in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis (eg Behçet's disease, granulation with polyangiitis) Swollen disease and giant cell arteritis), pancreatitis, systemic lupus erythematosus, dermatomyositis and polymyositis, metabolic syndrome, including, for example, insulin resistance, hypertension, dyslipoproteinemia, and obesity , diabetes (type 1 and type 2), diabetic nephropathy, osteoarthritis, Sjögren syndrome, and sepsis (Yang, Tuzun et al, J Immunol, 2005; Candia, Marquez et al, The Journal of Rheumatology, 2007; Scanzello, Plaas et al. Curr Opin Rheumatol, 2008; Deng, Ma-Krupa et al, Circ Res, 2009; Roger, Froidevaux et al, PNAS, 2009; Devaraj, Tobias et al, Arterioscler Thromb Vasc 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 Sci, 2013; Caso, Costa et al, Mediators of Inflammation, 2014; Cordiglieri, Marolda et al, J Autoimmun, 2014; Jiaal, Major et al, J Diabetes Complications, 2014; Kaplan, Yazgan et al, Scand J Gastroenterol, 2014; Talabot-Aye et al, Cytokine, 2014; Zong, Dorph et al, Ann Rheum Di, 2014; Ballak, Stienstra et al., Cytokine, 2015; Timper, Seelig et al., J Diabetes Complications, 2015). Skin diseases (eg psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, abnormal acne and acne vulgaris) and IRAK4 Guided TLR signaling pathway or IL-1R family correlation (Schmidt, Mittnacht et al, J Dermatol Sci, 1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad et al, Archives of Dermatology, 2004; Niebuhr, Langnickel Et al, Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali et al, Am J Clin Dermatol, 2010; Viguier, Guigue et al, Annals of Internal Medicine, 2010; 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 Sci, 2013; Wollina, Koch et al I Ndian Dermatol Online, 2013; Foster, Baliwag et al., The Journal of Immunology, 2014). Pulmonary disorders such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoma-like disease, and pulmonary hypertension are also shown Various TLR-mediated signal pathway correlations. The pathogenesis of pulmonary disorders is a process mediated by infection or mediated by non-infectious methods (Ramirez Cruz, Maldonado Bernal et al, Rev Alerg Mex, 2004; Jeyaseelan, Chu et al, Infection and Immunity, 2005; Seki , Tasaka et al, Inflammation Research, 2010; Xiang, Fan et al, Mediators of Inflammation, 2010; Margaritopoulos, Antoniou et al, Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo et al, The FASEB Journal, 2011; Nadiger, 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). TLR and members of the IL-1R family are also involved in the pathogenesis of other inflammatory conditions such as allergies, Beth's disease, gout, lupus erythematosus, adult-onset Still's disease, pericarditis and Chronic inflammatory bowel disorders (eg, ulcerative colitis and Crohn's disease), transplant rejection, and graft versus host response, and thus inhibition of IRAK4 is a suitable preventive and/or therapeutic method (Liu-Bryan, Scott) Et al, Arthritis & Rheumatism, 2005; Piggott, Eisenbarth et al, J Clin Inves, 2005; Christensen, Shupe et al, Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen et al, The Journal of Immunology, 2010 ; Rakoff-Nahoum, Hao et al, Immunity, 2006; Heimesaat, Fischer et al, PLoS ONE, 2007; Heimesaat, Nogai et al, Gut, 2010; Kobori, Yagi et al, J Gastroenterol, 2010; Schmidt, Raghavan, etc. , Nat Immunol, 2010; Shi, Mucsi et al, Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin et al, Arthritis Res Ther, 2013; Hao, Liu et al, Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang et al, Pharmacology & Therapeutics, 2013; Walsh, Carthy et al, Cytokine & Growth Factor Reviews, 2013; Zhu , Jiang et al, Autoimmunity, 2013; Yap and Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen, et al, Contact Dermatitis, 2014; D'Elia, Brucato et al, Clin Exp Rheumatol, 2015; Jain, Thongprayoon, etc. Am J Cardiol., 2015; Li, Zhang et al., Oncol Rep., 2015). Gynecological disorders mediated by the TLR and IL-1R families (eg, uterine adenomyosis, dysmenorrhea, painful intercourse and endometriosis, especially endometriosis-related pain and other endometriosis) Sexual symptoms (such as dysmenorrhea, painful intercourse, dysuria, and difficulty in defecation) can be positively affected by the 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 Gynaecology Research, 2013; Santulli, Borghese et al, Human Reproduction, 2013). Prophylactic and/or therapeutic use of IRAK4 inhibitors can also have a positive effect on 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 Sci, 2013). In addition to the conditions already mentioned, already in ocular conditions (eg retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveal layer) The IRAK4-mediated TLR process is described in the pathogenesis of inflammation (Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic , Taylor et al, J Leukoc Biol, 2011; Chang, McCluskey et al, Clinical & Experimental Ophthalmology, 2012; Guo, Gao et al, Immunol Cell Biol, 2012; Lee, Hattori et al, Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao et al., Investigative Ophthalmology & Visual Science, 2014). Inhibition of IRAK4 is also a suitable treatment for fibrotic disorders (eg liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis) (Zhao, Zhao et al, Scand J Gastroenterol, 2011; Benias, Gopal, etc.) People, Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu et al, Biochim Biophys Acta., 2015). Since IRAK4 has a critical role in the conditions mediated by the TLR and IL-1R families, it is possible to treat chronic liver conditions, such as fatty liver hepatitis and especially nonalcoholic fatty liver, in a prophylactic and/or therapeutic manner using IRAK4 inhibitors. Disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) (Nozaki, Saibara et al, Alcohol Clin Exp Res, 2004; Csak, T., A. Velayudham et al, Am J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama et al, Gastroenterology, 2010; Kamari, Shaish et al, J Hepatol, 2011; Ye, Li et al, Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013; Ceccarelli, S., V. Nobili et al, World J Gastroenterol, 2014; Miura, Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic et al, World J Gastroenterol, 2014). Due to the important role of IRAK4 in TLR-mediated processes, inhibition of IRAK4 also enables the treatment and/or prevention of cardiovascular and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension (Oyama, Blais et al., Circulation) , 2004; Timmers, Sluijter et al, Circulation Research, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos et al, Clin Sci (Lond), 2012; Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013; Hernanz, Martínez-Revelles et al, British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015; Bomfim, Echem et al. , Life Sciences, 2015), and Alzheimer's disease, stroke, craniocerebral trauma, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Brough, Tyrrell et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng et al, The Journal of Immunol Ogy, 2011; Lim, Kou et al, The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson et al, Disease Models & Mechanisms, 2013; Noelker, Morel et al, Sci Rep., 2013; Wang, Wang et al., Stroke, 2013; Xiang, Chao et al., Rev Neurosci, 2015; Lee, Lee et al., J Neuroinflammation, 2015). Inhibition of IRAK4 is implicated in the context of pruritus and pain (including acute, chronic, inflammatory, and neuropathic pain) involving TLR-mediated signaling via IRAK4 and IL-1 receptor-mediated signaling. There is a therapeutic effect in the indications mentioned. Examples of pain include hyperesthesia, touch pain, premenstrual pain, endometriosis-related pain, post-operative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, Pain caused by spinal cord injury, inflammation-induced pain, lumbar pain, cancer pain, chemotherapy-related pain, HIV-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, Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha et al, European Journal Of Pharmacology, 2012; Kwok, Hutchinson et al, PLoS ONE, 2012; Nicotra, Loram et al, Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake et al, Neurobiology of Disease, 2013; Han , Zhao et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung et al., Jou Rnal 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, etc., Photochem Photobiol., 2015; Schrepf, Bradley et al, Brain Behav Immun, 2015; Wong, L., JD Done, etc. , Prostate, 2015). This also applies to some tumor conditions. Specific lymphomas (eg ABC-DLBCL (activated B-cell-diffuse large cell B-cell lymphoma), mantle cell lymphoma, and Waldenström's disease) as well as chronic lymphocytic leukemia, melanoma, pancreas Tumor and hepatocellular carcinoma are characterized by changes in MyD88 mutation or MyD88 activity, which can be treated by IRAK4 inhibitors (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). In addition, MyD88 plays an important role in ras-dependent tumors, and thus IRAK4 inhibitors are also suitable for the treatment of this tumor (Kfoury, A., KL Corf et al, Journal of the National Cancer Institute, 2013). It can also be inferred through the inhibition of IRAK4 in breast cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer, prostate cancer, because of the indications and signal transmission mentioned. Path correlation (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 disorders (eg, CAPS (Hidden Heat Protein Associated Cycle Syndrome), including FCAS (familial cold autologous) Inflammation group), MWS (Muckle-Wells syndrome), NOMID (neonatal onset multisystem inflammatory disease) and CONCA (chronic infant, nerve, skin and joint syndrome), FMF (family) Sexual Mediterranean fever), HIDS (high IgD syndrome), TRAPS (tumor syndrome associated with tumor necrosis factor receptor 1), juvenile idiopathic arthritis, adult onset Stil's disease, adalter-bescher Adamantiades-Behçet's disease, rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca, PAPA syndrome (suppurative arthritis, gangrenous pyoderma and acne), Schnitzler's syndrome And Xue Gelian The population can be treated by blocking the IL-1 signaling pathway; therefore, IRAK4 inhibitors are also suitable herein for the treatment of the mentioned 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, Annals of MedicinePetterson, 2012; , Brunner et al, New England Journal of Medicine, 2012; Nordström, Knight et al, The Journal of Rheumatology, 2012; Vijmasi, Chen et al, Mol Vis, 2013; Yamada, Arakaki et al, Opinion on Therapeutic Targets, 2013; De Koning, Clin Transl Allergy, 2014). The ligand IL-33 of IL-33R is specifically involved in the pathogenesis of acute renal failure, and thus inhibits IRAK4 for prevention and/or treatment of a suitable therapeutic method (Akcay, Nguyen et al., Journal of the American Society of Nephrology, 2011) ). The components of the IL-1 receptor family are associated with myocardial infarction, different pulmonary conditions (eg, asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS)), and It is therefore expected that inhibition by IRAK4 has a prophylactic and/or therapeutic effect in the mentioned indications (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, Bracket 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 People, The Journal of Clinical Investigation, 2013; Kawayama, Okamoto et al, J Interferon Cytokine Res, 2013; Martínez-González, Roca et al, American Journal of Respiratory Cell amd 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). The prior art discloses a variety of IRAK4 inhibitors (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133). US8293923 and US20130274241 disclose IRAK4 inhibitors having a 3-substituted carbazole structure. 2-substituted carbazoles are not illustrated. WO2013106254 and WO2011153588 disclose 2,3-disubstituted oxazole derivatives. WO2007091107 describes 2-substituted carbazole derivatives for the treatment of Duchenne muscular dystrophy. Only the carbazole derivatives having a phenyl group at the 2-position are specifically described. WO2015091426 describes carbazoles substituted at the 2-position vialamine, for example from WO2015091426-64. The unpublished application EP 14195032.9 (filed on November 26, 2014) describes a 2-substituted oxazole substituted with an alkyl group at the 6-position, wherein the alkyl group is substituted by a hydroxy group. A 2-substituted carbazole having a chlorine atom or an alkoxy group at the 6-position is not illustrated. WO2015104662 discloses 2-substituted carbazoles having the general formula: Wherein R ₂ is an alkyl group or a cycloalkyl group. The 2-substituted oxazoles having a methyl group, a 2-methoxyethyl group and a cyclopentyl group at the 2-position are exemplified (Examples 1, 4 and 76). Example 117 also illustrates a carbazole derivative having a hydroxyethyl substituent at the 1-position. However, a carbazole derivative having a 3-hydroxy-3-methylbutyl substituent at the 1- or 2-position is not illustrated. The oxazole having a hydroxy-substituted alkyl group at the 2-position is generally encompassed by the general formula, but it is not explicitly disclosed in WO2015104662. In addition to the above-described substitution patterns at the 1 and 2 positions on the carbazole, WO2015104662 describes substituted carbazoles at the 6 position, wherein R _{1 is} defined as follows: alkyl, cyano, -NR _a R _b or selected An optionally substituted group derived from a cycloalkyl, aryl or heterocyclic group, wherein the substituent is independently alkyl, alkoxy, halogen, hydroxy, hydroxyalkyl, amine, aminoalkyl, nitrate Base, cyano, haloalkyl, haloalkoxy, -OCOCH ₂ -O-alkyl, -OP(O)(O-alkyl) ₂ or -CH ₂ -OP(O)(O-alkyl) ₂ . Examples of substituents at the 6 position described for R ₁ in WO2015104662 are cyclopropyl, cyclohexyl, cyano, 3-fluorophenyl and saturated heterocyclic substituents. Therefore, a carbazole derivative having an alkoxy group or a chlorine atom at the 6-position is not explained. The problem addressed by the present invention is to provide novel compounds that act as inhibitors of interleukin-1 receptor-associated kinase-4 (IRAK4).

The present invention provides a compound of the formula (I) Wherein R ¹ represents chloro or OR ⁴ ; R ² represents C ₁ -C ₈ -alkyl, which may optionally be mono- or polysubstituted, respectively, via the same or different substituents selected from the group consisting of: 1 to 5 a fluorine atom, 1 to 3 hydroxyl groups, oxetanyl group, tetrahydrofuranyl group, pyranyl group, pendant oxy group, and C ₁ -C ₆ -alkoxy group, wherein the C ₁ -C ₆ -alkoxy group may be fluorine or Monosubstituted to trisubstituted by hydroxy or by C(=O)OH, C(=O)Me, C(=O)Et, C(=O)NH ₂ ; R ³ represents a group selected from the group consisting of: Wherein R ⁵ represents hydrogen, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may optionally be monosubstituted by cyclopropyl, cyano and hydroxy to three Substituting wherein each substituent may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; R ⁶ represents hydrogen, fluorine or methyl, or R ³ represents a group selected from the group consisting of: Wherein R ⁷ represents hydrogen, C ₃ -C ₆ -cycloalkyl, cyano, NH ₂ , NH(C ₁ -C ₆ -alkyl), N(C ₁ -C ₆ -alkyl) ₂ , pyrrolidine- 1-yl, hexahydropyridin-1-yl, morpholin-4-yl, 4-methylhexahydropyrazin-1-yl or a C ₁ -C ₆ -alkyl group, wherein C ₁ -C ₆ -alkane The group may be mono-substituted to trisubstituted by cyclopropyl, cyano and hydroxy, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted through a fluorine atom; R ⁸ , R ⁹ , R ¹⁰ represent hydrogen, A Base or fluorine, or R ³ represents Wherein R ¹¹ represents a C ₃ -C ₆ -cycloalkyl group or a C ₁ -C ₆ -alkyl group, wherein the C ₁ -C ₆ -alkyl group may be monosubstituted to trisubstituted by a cyclopropyl group, a cyano group and a hydroxy group, wherein Each substituent may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; and R ¹² represents hydrogen, fluorine or C ₁ -C ₆ -alkyl; or R ³ represents 6,7-dihydro-4H-pyridyl Zoxa[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2 -yl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl or represents pyrazolo[1,5-a]pyrimidin-3-yl, pyrrole [ 2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2,3-b]pyrazine-7- 5-Aminopyrazolo[1,5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, 2 -Aminopyrrolo[1,2-b]pyridazin-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl; R ⁴ represents a saturated 4- to 7-membered heterocyclic ring Or a C ₃ -C ₇ -cycloalkyl group, wherein the saturated heterocyclic group and the C ₃ -C ₇ -cycloalkyl group are optionally mono- or polysubstituted by the same or different substituents from the group consisting of: C ₁ -C ₆ -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl , C(=O)OH, C ₁ -C ₆ -alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, chloro, cyano, hydroxy, NH ₂ , NHR ^a And N(R ^a )R ^b , or represents C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may be mono- or polysubstituted by the same or different substituents from the group consisting of: Fluorine, chlorine, cyano, hydroxy, C(=O)OC ₁ -C ₆ -alkyl, C(=O)OH, C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , SC ₁ -C ₆ -alkyl, S(=O) ₂ -C ₁ -C ₆ -alkyl, S(=O) ₂ NH ₂ , C ₁ - C ₆ -alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, tetra An azole and a 4- to 7-membered saturated heterocyclic group, wherein the C ₃ -C ₇ -cycloalkyl group and the 4 to 7 membered saturated heterocyclic group are optionally monosubstituted by the same or different substituents from the group consisting of Tetrasubstituted: fluorine, C ₁ -C ₄ -alkyl, hydroxy, C(=O)OH, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, trifluoromethyl Oxyl, cyclopropyl, cyclopropylmethyl, methylsulfonyl, NH ₂ , NHR ^a , N(R ^a )R ^b ; R ^a represents C ₁ -C ₆ -alkyl or C ₃ -C ₇ a cycloalkyl group, wherein the C ₁ -C ₆ -alkyl group and the C ₃ -C ₇ -cycloalkyl group are optionally mono- or polysubstituted by the same or different substituents from the group consisting of fluorine, hydroxyl, cyanide a C ₁ -C ₄ -alkyl group, a C ₁ -C ₄ -alkoxy group and a C ₃ -C ₇ -cycloalkyl group; R ^b represents a C ₁ -C ₆ -alkyl group or a C ₃ -C ₇ - ring Alkyl; * at the bond indicates an attachment point in the molecule, and a solvate thereof, a non-image isomer, a mirror image isomer, a metabolite, a salt, a solvate or a salt. Novel IRAK4 inhibitors are particularly suitable for the treatment and prevention of proliferative, metabolic and inflammatory conditions characterized by an overreactive immune system. In particular, inflammatory skin disorders, cardiovascular disorders, pulmonary disorders, ocular disorders, neurological disorders, pain disorders and cancers should be mentioned herein. In addition, novel IRAK4 inhibitors are suitable for the treatment and prevention of autoimmune and inflammatory conditions, especially rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, spondyloarthritis and gout, • metabolic disorders, especially liver disorders ( For example, fatty liver), and • gynecological conditions, especially endometriosis and endometriosis-related pain and other endometriosis-related symptoms, such as dysmenorrhea, painful intercourse, dysuria, and feces difficult.

In the case of the synthetic intermediates and working examples of the invention set forth below, any compound specified in the form of the corresponding base or acid salt will generally be a salt having an unknown exact stoichiometric composition, such as by separate preparation and / Or obtained by a purification process. Unless specified in more detail, in the case of such salts, the name and structural formula (eg "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF"₃ COOH", "x Na⁺ The addition of ") is not to be understood stoichiometrically, but only to the illustrative features of the salt-forming components present therein. If the synthetic intermediate or working example or a salt thereof is obtained by the preparation and/or purification process in the form of a solvate having an unknown stoichiometric composition (for example, a hydrate) if it has a defined type, this corresponds Suitable for use. If the compound encompassed by the formula (I) and mentioned below is not a solvate of a salt, a solvate or a salt, the compound of the invention is a solvent of a compound of the formula (I) and a salt, a solvate thereof and a salt thereof. And a solvate of a salt, a solvate and a salt thereof, which are encompassed by the formula (I) and which are exemplified by the formula (I) and which are cited below as working examples, and a salt, a solvate thereof and a solvate of a salt. Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. However, the invention also encompasses salts which are not themselves suitable for pharmaceutical use but which are useful, for example, for isolating or purifying the compounds of the invention. Physiologically acceptable salts of the compounds of the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as the following acid salts: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluene. Sulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds of the invention also include the salts of conventional bases, exemplified and preferred alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium); Ammonia or an ammonium salt of an organic amine having from 1 to 16 carbon atoms, such as, by way of example and preferred, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, two Ethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N -methylhexahydropyridine. Solvates are described in the context of the present invention as compounds of the invention in such forms as complexes formed in solid or liquid state by coordination with solvent molecules. The specific form of the solvate in which the hydrate system is coordinated to water. The compounds of the present invention may exist in different stereoisomeric forms depending on their structure, i.e., in the form of a conformational isomer or, if appropriate, as a conformational isomer (mirroromer and/or non-image isomer, including And so on in the case of configuration isomers). Accordingly, the present invention encompasses mirror image isomers and non-image isomers and individual mixtures thereof. The stereoisomerically homogeneous component can be isolated in a conventional manner from such mixtures of mirror image isomers and/or non-image isomers; preferably a chromatographic process, especially a non-pivoting or palm phase phase HPLC layer Analysis for this purpose. If a compound of the invention is present in tautomeric form, the invention encompasses all tautomeric forms. The invention also encompasses all suitable isotopic variations of the compounds of the invention. Herein, an isotopic variation of a compound of the invention is understood to mean a compound in which at least one atom in the compound of the invention has been replaced by another atom having the same atomic number but an atomic weight different from the atomic amount normally or predominantly present in nature. Examples of isotopes which may be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example² H (氘),³ H (氚),¹³ C,¹⁴ C,¹⁵ N,¹⁷ O,¹⁸ O,³² P,³³ P,³³ S,³⁴ S,³⁵ S,³⁶ S,¹⁸ F,³⁶ Cl,⁸² Br,¹²³ I,¹²⁴ I,¹²⁹ I and¹³¹ I. Particular isotopic variations of the compounds of the invention, such as, in particular, those in which one or more radioisotopes have been incorporated, may be beneficial, for example, for examining the mechanism of action or distribution of the active compound in vivo; Sexuality and detectability, in particular³ H or¹⁴ Compounds labeled with C isotope are suitable for this purpose. In addition, the incorporation of isotopes (e.g., guanidine) may result in a particular therapeutic benefit due to increased metabolic stability of the compound, e.g., increased half-life in vivo or reduced required dosage of the agent; therefore, such modified forms of the compounds of the invention In some cases, preferred embodiments of the invention may also be constructed. Isotopic variants of the compounds of the invention may be prepared by methods known to those skilled in the art (e.g., by the methods further set forth below and the procedures set forth in the working examples) by using the respective reagents and/or corresponding compounds Isotope modified forms are prepared. The invention further provides all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs are present as a single polymorph or a mixture of plural polymorphs in all concentration ranges. The invention also encompasses prodrugs of the compounds of the invention. The term "prodrug" in this context refers to a compound that is biologically active or inactive but that reacts (eg, metabolizes or hydrolyzes) during its residence time in the body to produce a compound of the invention. In the context of the present invention, unless otherwise indicated, a substituent has the following meaning:alkyl In the context of the present invention is a straight or branched alkyl group having the specified number of specific carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-B Propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl Base, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. Preferred are methyl, ethyl, n-propyl, n-butyl, 2-methylbutyl, 3-methylbutyl and 2,2-dimethylpropyl. In the context of the present invention,Cycloalkyl A monocyclic saturated alkyl group having the specified number of carbon atoms in each case. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the context of the present invention,Heterocycloalkyl, heterocyclic or heterocyclic A total of 3 to 10 ring atoms and one or two from N, O, S, SO, and/or SO₂ A saturated heterocyclic ring of a hetero atom of a ring of constituent groups. Mention may be made, for example, of the following: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolyl, tetrahydrofuranyl, hexahydropyridyl, hexahydropyrazinyl, tetrahydropyranyl, A phenyl group, a thiomorpholinyl group, a dioxo bridge thiomorpholinyl group, a dihydroindenyl group, and a dihydroisoindenyl group. Preferred are azetidinyl, oxetanyl, pyrrolidinyl, hexahydropyridyl, hexahydropyrazinyl and morpholinyl.Alkoxy In the context of the present invention is meant a linear or branched alkoxy group having the specified number of specific carbon atoms. From 1 to 6 carbon atoms are preferred. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, iso Pentyloxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexyloxy. More preferably, it is a linear or branched alkoxy group having 1 to 4 carbon atoms. Mention may be made, by way of example, of methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy. In the context of the present invention,halogen It is fluorine, chlorine and bromine. Preferred is fluorine.Hydroxyl In the context of the present invention is OH. The symbol * at the bond indicates the bonding site in the molecule. Unless otherwise specified, when a group in a compound of the invention is substituted, the groups may be mono- or polysubstituted. In the context of the present invention, all of the groups that occur more than once are defined independently of each other. Preferred are substituted by one, two or three identical or different substituents. R¹ The preferred embodiment is chlorine. R¹ Another preferred embodiment is an O-R⁴ . R² Preferred embodiment is C₂ -C₆ An alkyl group which is substituted by a hydroxyl group. Especially, R² Representative C₂ -C₅ An alkyl group which is substituted by a hydroxyl group. Extremely good among them R² A compound representing 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl or 3-hydroxy-3-methylbutyl. More preferred is hydroxy-3-methylbutyl. R² Another preferred embodiment is C₂ -C₆ An alkyl group substituted with two hydroxyl groups. Especially, R² Represents 2,3-dihydroxypropyl, 2,3-dihydroxy-3-methylbutyl or 2,3-dihydroxybutyl. Extremely better, R² Represents 2,3-dihydroxypropyl. R² Another preferred embodiment is C₁ -C₃ An alkyl group which is substituted by an oxetanyl group or a tetrahydrofuranyl group. Especially good among them R² A compound representing oxetan-3-ylmethyl, oxetan-2-ylmethyl, tetrahydrofuran-3-ylmethyl or tetrahydrofuran-2-ylmethyl. Extremely good among them R² A compound representing oxetan-3-ylmethyl or tetrahydrofuran-3-ylmethyl. R² Another preferred embodiment is C₂ -C₆ -alkyl, which is C₁ -C₃ - alkoxy substituted. Especially, R² Representative C₂ -C₆ An alkyl group which is substituted with a methoxy group. Extremely good among them R² A compound representing 3-methoxy-3-methylbutyl, 3-methoxypropyl or 2-methoxyethyl. R² Another preferred embodiment is C₂ -C₆ - an alkyl group substituted with a 2-hydroxyethoxy group. Especially good among them R² A compound representing 2-(2-hydroxyethoxy)ethyl or 3-(2-hydroxyethoxy)propyl. Particularly preferred is 2-(2-hydroxyethoxy)ethyl. R² Another preferred embodiment is C₂ -C₆ -alkyl, which is OCH₂ (C=O)OH or OCH₂ (C=O)OCH₃ Replace. Especially good among them R² Representative CH₂ CH₂ OCH₂ C(=O)OH or CH₂ CH₂ OCH₂ Compound of C(=O)OEt. R² Another preferred embodiment is a 3-oxo butyl group. Also preferred is where R² A compound of 4,4,4-trifluorobutyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl or 3,3-difluorobutyl. Especially, R² Represents 4,4,4-trifluorobutyl or 3,3,3-trifluoropropyl. Excellent is 4,4,4-trifluorobutyl. In a preferred embodiment, R³ Representative 2-(C₁ -C₆ -alkyl)-1,3-thiazol-4-yl, wherein C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-4-yl, 2-ethyl-1,3-thiazol-4-yl, 2-propyl-1,3-thiazol-4-yl, 2-isopropyl-1,3-thiazol-4-yl or 2-tert-butyl-1,3-thiazol-4-yl. In another preferred embodiment, R³ Represents 2-cyclopropyl-1,3-thiazol-4-yl. In another preferred embodiment, R³ Representative 4-(C₁ -C₆ -alkyl)-1,3-thiazol-2-yl, wherein C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 4-(trifluoromethyl)-1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl, 4-ethyl-1,3-thiazol-2-yl, 4-isopropyl-1,3-thiazol-2-yl or 4-tert-butyl-1,3-thiazol-2-yl. Extremely better, R³ Represents 4-(trifluoromethyl)-1,3-thiazol-2-yl. In another preferred embodiment, R³ Represents 4-cyclopropyl-1,3-thiazol-2-yl. In another preferred embodiment, R³ Representative 2-(C₁ -C₆ -alkyl)-1,3-oxazol-4-yl, of which C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 2-methyl-1,3-oxazol-4-yl, 2-(trifluoromethyl)-1,3-oxazol-4-yl, 2-ethyl-1,3-oxazole-4 -yl, 2-(1,1-difluoroethyl)-1,3-oxazol-4-yl, 2-(2,2,2-trifluoroethyl)-1,3-oxazole-4 -yl, 2-isopropyl-1,3-oxazol-4-yl, 2-tert-butyl-1,3-oxazol-4-yl or 2-(cyclopropylmethyl)-1, 3-oxazol-4-yl. Extremely better, R³ Represents 2-(trifluoromethyl)-1,3-oxazol-4-yl. In another preferred embodiment, R³ Represents 2-cyclopropyl-1,3-oxazol-4-yl. In another preferred embodiment, R³ Representative 2-(C₁ -C₆ -alkyl)-1,3-oxazol-5-yl, of which C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 2-methyl-1,3-oxazol-5-yl, 2-ethyl-1,3-oxazol-5-yl, 2-isopropyl-1,3-oxazol-5-yl. Extremely better, R³ Represents 2-methyl-1,3-oxazol-5-yl. In another preferred embodiment, R³ Representative 1-(C₁ -C₆ -alkyl)-1H-pyrazol-3-yl, wherein C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-( 2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 1-isopropyl-1H-pyrazol-3-yl, 1-propyl-1H-pyrazol-3-yl, 1-Terbutyl-1H-pyrazol-3-yl, 1-isobutyl-1H-pyrazol-3-yl. Extremely better, R³ Represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-isopropyl-1H-pyrazol-3-yl. In another preferred embodiment, R³ Representative 6-(C₁ -C₆ -alkyl)pyridin-2-yl, wherein C₁ -C₆ The alkyl substituent may optionally be monosubstituted with a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom and optionally monosubstituted with a hydroxy group. Especially, R³ Represents 6-methylpyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-ethylpyridin-2-yl, 6 -(1,1-difluoroethyl)pyridin-2-yl, 6-(pentafluoroethyl)pyridin-2-yl, 6-(2,2,2-trifluoroethyl)pyridin-2-yl , 6-propylpyridin-2-yl, 6-isopropylpyridin-2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-t-butylpyridine-2- base. Extremely better, R³ Represents 6-(1,1-difluoroethyl)pyridin-2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl , 6-(pentafluoroethyl)pyridin-2-yl or 6-(trifluoromethyl)pyridin-2-yl. Especially, R³ Represents 6-(1,1-difluoroethyl)pyridin-2-yl or 6-(trifluoromethyl)pyridin-2-yl. In another preferred embodiment, R³ Represents 6-aminopyridin-2-yl, 6-((C₁ -C₄ -alkyl)amino)pyridin-2-yl, 6-(di-(C₁ -C₄ -alkyl)amino)pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl, 6-(hexahydropyridin-1-yl)pyridin-2-yl, 6-( Polin-4-yl)pyridin-2-yl, 6-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl. Especially, R³ Represents 6-aminopyridin-2-yl, 6-(methylamino)pyridin-2-yl, 6-(ethylamino)pyridin-2-yl or 6-(dimethylamino)pyridine- 2-based. Extremely better, R³ Represents 6-aminopyridin-2-yl. In another preferred embodiment, R³ Represents 6-cyclopropylpyridin-2-yl. In another preferred embodiment, R³ Represents 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazole [1,5-a]pyrazin-2-yl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a Pyrimidin-3-yl, pyrrolo[2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2] ,3-b]pyrazin-7-yl, 5-aminopyrazolo[1,5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1,2, 4] Triazin-7-yl, 2-aminopyrrolo[1,2-b]pyridazin-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl. Especially, R³ Represents 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, pyrazolo[1,5-a]pyrimidin-3-yl. R⁴ Preferred examples are cyclopropyl, hexahydropyridin-4-yl, 1-methylhexahydropyridin-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, aza Cyclobut-3-yl, 1-methylazetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl. Especially, R⁴ Represents oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl. Extremely better, R⁴ Represents oxetan-3-yl or tetrahydrofuran-3-yl. R⁴ Another preferred embodiment is C₁ -C₆ -alkyl. Especially, R⁴ Represents methyl, ethyl or isopropyl. Extremely better, R⁴ Represents methyl or ethyl. R⁴ Another preferred embodiment is C₂ -C₆ An alkyl group which is substituted by a hydroxyl group. Especially, R⁴ Representative C₂ -C₄ An alkyl group which is substituted by a hydroxyl group. Extremely better, R⁴ Represents 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl. Especially, R⁴ Represents 2-hydroxyethyl. R⁴ Another preferred embodiment is C₂ -C₆ An alkyl group substituted with a group selected from the group consisting of C(=O)OMe, C(=O)OEt, C(=O)OH, C(=O)NH₂ , SMe, SEt, S(=O)₂ Me, S(=O)₂ Et, methoxy, ethoxy, N (CH)₃ )₂ , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl and tetrahydro-2H-pyran-4-yl. In a particularly preferred embodiment, R⁴ Represents cyclopropylmethyl, oxetan-3-ylmethyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl, 2-(methylthio) Ethyl, CH₂ C(=O)OEt, CH(CH₃ )C(=O)OH or CH₂ C(=O)OH, CH₂ CH₂ C(=O)OH. Extremely better, R⁴ Represents cyclopropylmethyl or oxetan-3-ylmethyl. In the context of another preferred embodiment, R⁴ Represents trifluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl. Especially, R⁴ Represents trifluoromethyl. Preferably, R⁶ Represents hydrogen or fluorine. Especially, R⁶ Represents hydrogen. Preferably, R⁸ Represents hydrogen or fluorine. Especially, R⁸ Represents hydrogen. Preferably, R⁹ Represents hydrogen or fluorine. Especially, R⁹ Represents hydrogen. Preferably, R¹⁰ Represents hydrogen or fluorine. Especially, R¹⁰ Represents hydrogen. Preferably, R¹² Represents hydrogen or fluorine. Especially, R¹² Represents hydrogen. Preferably, R^a Represents methyl, ethyl or cyclopropyl. Preferably, R^b Represents methyl, ethyl or cyclopropyl. One embodiment of the present invention provides R² Representative C₁ -C₈ An alkyl group, which may optionally be mono- or polysubstituted, independently of one another, via the same or different substituents selected from the group consisting of 1 to 5 fluorine atoms, 1 to 3 hydroxyl groups, oxetanyl groups, tetrahydrofuranyl groups. , pyranyl and C₁ -C₆ - alkoxy, where C₁ -C₆ - alkoxy groups may be fluorine or via hydroxyl groups or via C(=O)OH, C(=O)Me, C(=O)Et, C(=O)NH₂ Monosubstituted to trisubstituted; and substituted R¹ And R³ All have the meanings mentioned above. Preferred are compounds of formula (I) wherein R¹ Represents chlorine or O-R⁴ , R² Representative C₁ -C₆ An alkyl group, which may optionally be mono- or polysubstituted, independently of one another, via the same or different substituents selected from the group consisting of 1 to 3 fluorine atoms, 1 to 2 hydroxyl groups, oxetanyl groups, tetrahydrofuranyl groups. And C₁ -C₃ - alkoxy, where C₁ -C₃ - alkoxy group may be substituted by hydroxyl group or by C(=O)OH, C(=O)Me, C(=O)Et; or R² Representative 3-sided oxybutyl; R³ Represents a group selected from the following: , where R⁵ Represents hydrogen, cyclopropyl or C₁ -C₆ -alkyl, where C₁ -C₆ - an alkyl group may optionally be mono-substituted to trisubstituted with a cyclopropyl group, a cyano group and a hydroxy group, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted via a fluorine atom;⁶ Represents hydrogen; or R³ Representative groupWhere R⁷ Represents hydrogen, cyclopropyl, cyano, NH₂ , NH (C1-C₆ -alkyl), N(C₁ -C₆ -alkyl)₂ , pyrrolidin-1-yl, hexahydropyridin-1-yl, morpholin-4-yl, 4-methylhexahydropyrazin-1-yl or C₁ -C₆ -alkyl, where C₁ -C₆ - an alkyl group may optionally be mono-substituted to trisubstituted with a cyclopropyl group, a cyano group and a hydroxy group, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted via a fluorine atom;⁸ , R⁹ , R¹⁰ Represents hydrogen or R³ Representative groupWhere R¹¹ Representative C₃ -C₆ -cycloalkyl or C₁ -C₆ -alkyl, where C₁ -C₆ - an alkyl group may optionally be mono-substituted to trisubstituted with a cyclopropyl group, a cyano group and a hydroxy group, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted via a fluorine atom;¹² Represents hydrogen or R³ Represents 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazole [1,5-a]pyrazin-2-yl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, or represents pyrazolo[1,5 -a]pyrimidin-3-yl, pyrrolo[2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno [2,3-b]pyrazin-7-yl, 5-aminopyrazolo[1,5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1, 2,4]triazin-7-yl, 2-aminopyrrolo[1,2-b]pyridazin-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl ; R⁴ Represents cyclopropyl, hexahydropyridin-4-yl, 1-methylhexahydropyridin-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, azetidin-3- , 1-methylazetidin-3-yl, oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl, wherein oxetane-3- Mono-, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl may optionally be mono- or disubstituted with methyl, or represent C₁ -C₆ -alkyl, where C₁ -C₆ - The alkyl group may be substituted by the following: hydroxy, C(=O)OMe, C(=O)OEt, C(=O)OH, C(=O)NH₂ , SMe, SEt, S(=O)₂ Me, S(=O)₂ Et, methoxy, ethoxy, N (CH)₃ )₂ , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or trifluoromethyl, 2,2 , 2-trifluoroethyl or 2,2-difluoroethyl; and pharmaceutically acceptable solvates thereof, non-imagewise isomers, mirror image isomers, metabolites, salts, solvates or salts. Further preferred are compounds of formula (I) wherein R¹ Represents chlorine or O-R⁴ ; R² Representative C₂ -C₅ - an alkyl group which may be 1 to 2 hydroxyl groups or via oxetan-3-yl or tetrahydrofuran-3-yl or via group OCH₂ C(=O)OH, OCH₂ C(=O)OMe, OCH₂ CH₂ OH or via C₁ -C₃ - alkoxy substitution, where C₁ -C₃ - alkoxy group may be substituted by hydroxyl group or by C(=O)OH, C(=O)Me, C(=O)Et; or R² Represents 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or 3-sided oxybutyl; R³ Representative 1-(C₁ -C₆ -alkyl)-1H-pyrazol-3-yl, wherein C₁ -C₆ The alkyl substituent may optionally be mono-substituted with a cyclopropyl group, monosubstituted to penta-substituted with a fluorine atom and optionally substituted by a hydroxy group, or represented by 2-cyclopropyl-1,3-thiazol-4-yl or 2- (C₁ -C₆ -alkyl)-1,3-thiazol-4-yl, wherein C₁ -C₆ - an alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted by fluorine atom and optionally substituted by hydroxy, or as 4-(C)₁ -C₆ -alkyl)-1,3-thiazol-2-yl, wherein C₁ -C₆ The alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted with fluorine atom and optionally substituted by hydroxy group, or represented by 2-cyclopropyl-1,3-oxazol-4-yl or -(C₁ -C₆ -alkyl)-1,3-oxazol-4-yl, of which C₁ -C₆ - an alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted with a fluorine atom and optionally substituted by hydroxy, or as 2-(C)₁ -C₆ -alkyl)-1,3-oxazol-5-yl, of which C₁ -C₆ - an alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted by fluorine atom and optionally substituted by hydroxy, or 6-(C₁ -C₆ -alkyl)pyridin-2-yl, wherein C₁ -C₆ - Alkyl substituents may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted by fluorine atom and optionally substituted by hydroxy group, or represented by 6-aminopyridin-2-yl, 6-(C₁ -C₄ -alkyl)amino)pyridin-2-yl, 6-(di-(C₁ -C₄ -alkyl)amino)pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl, 6-(hexahydropyridin-1-yl)pyridin-2-yl, 6-( Phenyl-4-yl)pyridin-2-yl, 6-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl, or 6,7-dihydro-4H-pyrazolo[5 , 1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl or 4 , 5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, or represents pyrazolo[1,5-a]pyrimidin-3-yl, pyrrolo[2,1 -f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2,3-b]pyrazin-7-yl, 5 -aminopyrazolo[1,5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, 2-amino group Pyrrolo[1,2-b]pyridazin-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl; R⁴ Representative C₁ -C₄ -alkyl or represents oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl or represents 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl , 2-hydroxy-2-methylpropyl or represents CH₂ C(=O)OMe, CH₂ C(=O)OEt, CH₂ C(=O)OH, CH₂ CH₂ SMe, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl, 2-methoxyethyl, 2-ethoxyethyl, CH₂ CH₂ N (CH₃ )₂ , cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, oxetan-3-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl or Represents trifluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; R⁵ Represents hydrogen or fluorine; and pharmaceutically acceptable solvates thereof, non-image isomers, mirror image isomers, metabolites, salts, solvates or salts. Also preferred are compounds of formula (I) wherein R¹ Represents chlorine or O-R⁴ ; R² Representative 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 4-hydroxybutyl, 4-hydroxypentyl, 2,3-dihydroxypropyl , 2,3-dihydroxy-2-methylpropyl, 2-hydroxypropyl, oxetan-3-ylmethyl, oxetan-3-ylethyl, tetrahydrofuran-3-ylmethyl , tetrahydrofuran-3-ylethyl, 3-oxobutyl, 3-methoxy-3-methylbutyl, 3-methoxypropyl, 2-methoxyethyl, 4,4, 4-trifluorobutyl, 3,3,3-trifluoropropyl, 2-(2-hydroxyethoxy)ethyl, CH₂ CH₂ OCH₂ C(=O)OH, CH₂ CH₂ OCH₂ C(=O)OEt; R³ Represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-( 2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, 1-isopropyl-1H-pyrazol-3-yl, 1-propyl-1H-pyrazol-3-yl, 1-t-butyl-1H-pyrazol-3-yl, 1-isobutyl-1H-pyrazol-3-yl, 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-4-yl, 2-ethyl-1,3-thiazol-4-yl, 2-propyl-1,3-thiazol-4-yl, 2-isopropyl -1,3-thiazol-4-yl, 2-tert-butyl-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-thiazol-4-yl, 4-(trifluoromethyl) -1,3-1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl, 4-ethyl-1,3-thiazol-2-yl, 4-isopropyl-1 , 3-thiazol-2-yl, 4-tert-butyl-1,3-thiazol-2-yl, 4-cyclopropyl-1,3-thiazol-2-yl, 2-methyl-1,3 -oxazol-4-yl, 2-(trifluoromethyl)-1,3-oxazol-4-yl, 2-ethyl-1,3-oxazol-4-yl, 2-(1,1 -difluoroethyl)-1,3-oxazol-4-yl, 2-(2,2,2-trifluoroethyl)-1,3-oxazol-4-yl, 2-isopropyl- 1,3-oxazol-4-yl, 2-tert-butyl-1,3-oxazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-(cyclo Propylmethyl)-1,3-oxazol-4-yl, 2-methyl-1,3-oxazol-5-yl 2-ethyl-1,3-oxazol-5-yl, 2-isopropyl-1,3-oxazol-5-yl, 6-methylpyridin-2-yl, 6-(difluoromethyl Pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-ethylpyridin-2-yl, 6-(1,1-difluoroethyl)pyridin-2-yl, 6 -(pentafluoroethyl)pyridin-2-yl, 6-(2,2,2-trifluoroethyl)pyridin-2-yl, 6-propylpyridin-2-yl, 6-isopropylpyridine- 2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-t-butylpyridin-2-yl, 6-cyclopropylpyridin-2-yl, 6-aminopyridine -2-yl, 6-(methylamino)pyridin-2-yl, 6-(ethylamino)pyridin-2-yl, 6-(dimethylamino)pyridin-2-yl, 6, 7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1, 5-a]pyrazin-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyrimidine- 3-yl, pyrrolo[2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2,3- b] pyrazin-7-yl; R⁴ Represents methyl, ethyl, isopropyl, propyl, cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl, tetrahydrofuran-3-yl, 2-hydroxyethyl , trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl , 2-(methylthio)ethyl, CH₂ C(=O)OEt, CH₂ C(=O)OH; R⁵ Represents hydrogen; and its non-image, isomer, metabolite, salt, solvate or salt solvate. Very particularly preferred are the following compounds: where R¹ Represents chlorine or O-R⁴ ; R² Representative 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 2,3-dihydroxypropyl, oxetan-3-ylmethyl, Tetrahydrofuran-3-ylmethyl, 3-oxobutyl, 3-methoxy-3-methylbutyl, 3-methoxypropyl, 2-methoxyethyl, 4,4,4 -trifluorobutyl, 2-(2-hydroxyethoxy)ethyl, CH₂ CH₂ OCH₂ C(=O)OH, CH₂ CH₂ OCH₂ C(=O)OEt; R³ Represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-isopropyl-1H-pyrazol-3-yl, 2- (trifluoromethyl)-1,3-oxazol-4-yl, 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazole- 4-yl, 2-methyl-1,3-oxazol-5-yl, 2-methyl-1,3-thiazol-4-yl, 4-(trifluoromethyl)-1,3-thiazole- 2-Based, 6-(1,1-difluoroethyl)pyridin-2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-(difluoromethyl)pyridine- 2-yl, 6-(pentafluoroethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6,7-dihydro-4H-pyrazolo[5,1-c ][1,4]oxazin-2-yl, 6-aminopyridin-2-yl, pyrazolo[1,5-a]pyrimidin-3-yl; R⁴ Represents methyl, ethyl, isopropyl, cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl, tetrahydrofuran-3-yl, 2-hydroxyethyl, tri Fluoromethyl, 3-(methylsulfonyl)propyl, 2-(methylthio)ethyl, CH₂ C(=O)OEt, CH₂ C(=O)OH; and a solvate thereof, a non-image isomer, a mirror image isomer, a metabolite, a salt, a solvate or a salt. Also very popular are the following compounds: where R¹ On behalf of O-R⁴ ; R² Represents 3-hydroxy-3-methylbutyl; R³ Represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 2-(trifluoromethyl)-1,3-oxazole-4 -yl, 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-methyl-1,3-oxazole -5-yl, 2-methyl-1,3-thiazol-4-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 6-(1,1-difluoroethyl Pyridin-2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridine-2 -yl,6-aminopyridin-2-yl, pyrazolo[1,5-a]pyrimidin-3-yl; R⁴ Represents methyl, ethyl, isopropyl, cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl, 2-hydroxyethyl; and their non-image isomers a solvate of a mirror image isomer, a metabolite, a salt, a solvate or a salt. In particular, the invention provides the following compounds: Among the compounds mentioned above, the following compounds are preferred: 1-(difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy- 2H-carbazol-5-yl]-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5 -yl]-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide 1-(difluoromethyl)-N-[6-ethoxy-2-(3-hydroxy-3) -Methylbutyl)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl) -2H-carbazol-5-yl]-2-methyl-1,3-thiazole-4-carboxamide 2-cyclopropyl-N-[6-ethoxy-2-(3-hydroxy-3) -Methylbutyl)-2H-indazol-5-yl]-1,3-oxazole-4-carboxamide 6-amino-N-[6-ethoxy-2-(3-hydroxy- 3-methylbutyl)-2H-indazol-5-yl]pyridine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H- Oxazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3 -yloxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6 -(oxetan-3-yloxy)-2H-indazol-5-yl]-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide 1-(difluoromethyl) Base)-N-[2-(3-hydroxy-3-甲Butyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide 6-(difluoromethyl)- N-[2-(3-Hydroxy-3-methylbutyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]pyridine-2-carboxamide N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazole-5-yl-2-methyl-1,3 -oxazol-5-carbamide N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazole-5-yl -6-(trifluoromethyl)pyridine-2-carboxamide 6-amino-N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yl Oxy]-2H-indazol-5-ylpyridin-2-carboxamide 6-(difluoromethyl)-N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl) -2H-carbazol-5-yl]pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-ylmethoxy) -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(2-hydroxyethoxy)-2-(3-hydroxy-3-methyl Benzyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 6-(1,1-difluoroethyl)-N-[6-ethoxy Benzyl-2-(3-hydroxy-3-methylbutyrate -2H-carbazol-5-yl]pyridine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5- 1-ethyl-1H-pyrazole-3-carboxamide. The compounds of the invention act as inhibitors of IRAK4 kinase and have a surprisingly useful spectrum of pharmacological activity. Thus, in addition to the subject matter mentioned above, the invention also provides the use of a compound of the invention for the treatment and/or prevention of diseases in humans and animals. Particularly preferred is the use of the IRAK4 inhibitors of the invention to treat and/or prevent gynecological conditions, inflammatory skin conditions, cardiovascular disorders, pulmonary disorders, ocular disorders, autoimmune disorders, pain disorders, metabolic disorders, gout, liver Conditions, metabolic syndrome, insulin resistance and cancer. The compounds of the present invention are suitable for the prevention and/or treatment of various conditions and disease-related conditions, particularly those directly mediated by IRAK4, which are mediated by TLR (except TLR3) and/or the IL-1 receptor family and/or pathology. IRAK4-related conditions include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Gert-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondylarthritis And arthritis. The compounds of the invention are also useful for the prevention and/or treatment of conditions mediated by MyD88 and TLR (except TLR3). This includes multiple sclerosis, rheumatoid arthritis, spondylarthritis (especially psoriatic spondyloarthritis and Behdelev's disease), metabolic syndrome (including insulin resistance, diabetes), osteoarthritis, and Schüegen's syndrome , giant cell arteritis, sepsis, polymyositis and dermatomyositis, skin disorders (eg psoriasis, atopic dermatitis, alopecia areata, abnormal acne and acne vulgaris), lung disorders (eg pulmonary fibrosis, chronic Obstructive Pulmonary Disease (COPD), Acute Respiratory Syndrome (ARDS), Acute Lung Injury (ALI), Interstitial Lung Disease (ILD), Sarcoma-like Disease, and Pulmonary Hypertension). Due to the mechanism of action of the compounds of the invention, it is suitable for the prevention and/or treatment of TLR-mediated disorders such as Behcet's disease, gout, endometriosis and endometriosis-related pain and other endometrium Ectopic-related symptoms (such as dysmenorrhea, painful intercourse, difficulty urinating, and difficulty in defecation). In addition, the compounds of the invention are suitable for the prevention and/or treatment of transplant rejection, lupus erythematosus, adult onset Stil's disease and chronic inflammatory bowel disorders (eg, ulcerative colitis and Crohn's disease). In addition to the conditions listed, the use of the compounds of the invention is also suitable for the treatment and/or prevention of ocular conditions such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis; Vascular disorders such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension, and neurological disorders (eg, Alzheimer's disease, stroke, and Parkinson's disease). The mechanism of action of the compounds of the invention also enables the prevention and/or treatment of liver disorders mediated by the TLR and IL-1 receptor families, particularly NAFLD, NASH, ASH, liver fibrosis and cirrhosis. The compounds of the invention may also prevent and/or treat pruritus and pain, particularly acute, chronic, inflammatory and neuropathic pain. Due to the mechanism of action of the compounds of the invention, they are suitable for the prevention and/or treatment of neoplastic disorders such as lymphoma, chronic lymphoid leukemia, melanoma and hepatocellular carcinoma, breast cancer and Ras dependent tumors. Furthermore, the compounds of the invention are suitable for the treatment and/or prevention of conditions mediated by the IL-1 receptor family. These conditions include CAPS (Hidden Heat Protein Related Cycle Syndrome) (including FCAS (familial cold autologous inflammatory syndrome), MWS (Mu-Wei's syndrome), NOMID (neonatal onset multi-system inflammatory disease) and CONCA (chronic infant, nerve, skin and joint syndrome), FMF (familial Mediterranean fever), HIDS (high IgD syndrome), TRAPS (tumor necrosis factor receptor 1 related cycle syndrome), juvenile idiopathic arthritis , adult onset Stil's disease, adalter-Bercher's disease, rheumatoid arthritis, psoriasis, arthritis, Behdejelev's disease, osteoarthritis, keratoconjunctivitis sicca and Sjogren's syndrome , multiple sclerosis, lupus erythematosus, alopecia areata, type 1 diabetes, type 2 diabetes, and sequelae of myocardial infarction. Pulmonary disorders (eg, asthma, COPD, idiopathic interstitial pneumonia and ARDS), gynecological conditions (eg endometriosis and endometriosis-related pain and other endometriosis) Symptoms (eg, dysmenorrhea, painful intercourse, dysuria, and difficulty in defecation), chronic-inflammatory bowel disorders (eg, Crohn's disease and ulcerative colitis) are associated with disorders of the IL-1 receptor family and are suitable for treatment and/or The compounds of the invention are used prophylactically. The compounds of the invention are also useful for the treatment and/or prevention of neurological disorders mediated by the IL1 receptor family (eg, stroke, Alzheimer's disease, traumatic brain injury) and dermatological conditions (eg, psoriasis, atopic dermatitis, Abnormal acne, alopecia areata and allergic contact dermatitis). Additionally, the compounds of the invention are suitable for the treatment and/or prevention of pain conditions, especially acute, chronic, inflammatory and neuropathic pain. This preferably includes hyperesthesia, touch pain, arthritic pain (eg osteoarthritis, rheumatoid arthritis and spinal arthritis), premenstrual pain, endometriosis-related pain, post-operative pain, interstitial Cystitis pain, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis pain, pain caused by spinal cord injury, inflammation-induced pain, lumbar pain, cancer pain, chemotherapy-related pain, HIV treatment induction Neuropathy, burn-induced pain, and chronic pain. The invention also further provides a method of treating and/or preventing a condition, particularly a condition as mentioned above, using an effective amount of at least one of the compounds of the invention. In the context of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, suppressing, alleviating, attenuating, limiting, reducing, inhibiting, regressing or curing a disease, condition, condition, injury or health problem, or The occurrence, duration or progression of symptoms of such states and/or such states. The term "therapy" is understood herein to be synonymous with the term "treatment." The terms "prevention, prophylaxis and "prevention" are used synonymously in the context of the present invention and refer to avoiding or reducing infection, experience, suffering or suffering from a disease, condition, disorder, injury or health problem or such condition and/or Or the risk of the occurrence or progression of symptoms of such conditions. The disease, condition, condition, injury or health problem can be treated or prevented in part or in whole. The compounds of the invention may be used alone or in combination with other active compounds if desired. The invention further provides an agent comprising at least one of the compounds of the invention and one or more additional active compounds, in particular for use in the treatment and/or prevention of the conditions mentioned above. Preferred examples of suitable active compounds include: The following active compounds are generally mentioned: for example, antibacterial substances (for example, penicillins, vancomycin, ciprofloxacin), antiviral substances (eg aciclovir, oseltamivir) and antifungal substances (eg naftifin, nystatin) and gamma immunoglobulin), immunomodulation and immunity Inhibitory compounds (eg cyclosporin, Methotrexat®, TNF antagonists (eg Humira®, etanercept, infliximab), IL-1 inhibitors (eg anakinbine) Anakinra, Canakinumab, Rilonacept, phosphodiesterase inhibitors (eg Apremilast), Jak/STAT inhibitors (eg tofacitinib) (Tofacitinib), Baricitinib, GLPG0634), leflunomid, cyclophosphamide, rituximab, belimumab, tacrolimus (tacrolimus), rapamycin, mycophenolate mofetil, dry Interferon, corticosteroids (eg, prednisone, prednisolone, methylpresino, hydrocortisone, betamethasone, cyclophosphamide, Azathioprine and sulfasalazine; acetaminophen, non-steroidal anti-inflammatory substances (NSAIDS) (aspirin, ibuprofen, naproxen) , etodolac, celecoxib, colchicine. For tumor therapy, the following should be mentioned: immunotherapy (eg, aldesleukin, alemtuzumab, basiliximab, catusmaxomab, west) Celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, temimumomab -tiuxetan), imiquimod, interferon-α, interferon-β, interferon-γ, ipilimumab, lenalidomid, lenograstim , mifamurtid, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sagstatin Sargramostim), sipuleucel-T, tasonermin, teceleukin, tocilizumab, antiproliferative substances such as, but not limited to, ampoule Alpha (amsacrine), agrarabi (arglabin), arsenic trioxide, aspartate, bleomycin, busulfan An), actinomycin D, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, Obutuzuzumab, ofatumumab, tositumomab, aromatase inhibitors (eg exemestane, fadrozole, formamide) (formestane), letrozole, anastrozole, vorozole, antiestrogens (eg chlormadinone, fulvestrant, melamine) Mepitiostane), tamoxifen, raloxifen, toremifen, estrogen (eg estradiol, poly-estradiol phosphate), progesterone (eg methymidine) Progesterone (medroxyprogesteron), megestrol (megestrol), topoisomerase I inhibitor (eg irinotecan, topotecan), topoisomerase II inhibitor (eg amrubicin, daunorubicin, elliptinium acetate, etoposide, idarubi (idarubi) Cin), mitoxantrone, teniposide, microtubule actives (eg cabazitaxel, eribulin, paclitaxel, vinblastine) Vinblastine), vincristine, vindesine, vinorelbine, telomerase inhibitors (eg imetelstat), alkylated substances and tissue proteins Enzyme inhibitors (eg, bendamustine, carmustine, chlormethine, dacarbazine, estramustine, ifosfamid) , lomustine, mitobronitol, mitolactol, nimustine, prednimustine, procarbazine, Ramimustine, streptozotocine, temozolomide, thiotepa, treosulfan, trofosfamid, vorinostat ), romidepsin, panobinostat; affecting cells Substances of the differentiation process, such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptide mimetica, non-peptide mimetics, and tetracycline) For example, Marimastat, BAY 12-9566, BMS-275291, clodronic acid, prinomastat, doxycycline, and mTOR inhibitors (eg sirolimus) Sirolimus), everolimus, temsirolimus, zotarolimus, antimetabolites (eg clofarabine, deoxyuridine, amine methotrexate) (methotrexate), 5-fluorouracil, cladribine, cytarabine, fludarabine, sputum, pemetrexed, raltitrexed, Tegafur, thioguanine, platinum compounds (eg carboplatin, cisplatin, cisplatinum, eptaplatin, lobaplatin, Milli Platinum (miriplatin), nedaplatin, oxaliplatin; anti-angiogenesis Compound (such as bevacizumab), antiandrogen compound (such as bevacizumab, enzalutamide, flutamide, nilutamide, ratio Bicalutamide, cyproterone, cyproterone acetate, proteasome inhibitors (eg bortezomib, carfilzomib, opozomib) , ONYX0914), gonadotropin-releasing agonists and antagonists (eg, abarelix, buserelin, deslorelin, ganirelix, Gosher Goserelin, histrelin, triptorelin, degarelix, leuprorelin, methionine aminopeptidase inhibitor ( For example, benamide derivatives, TNP-470, PPI-2458), heparanase inhibitors (eg SST0001, PI-88); inhibitors of genetically modified Ras proteins (eg farnesyltransferase) Inhibitors, such as lonafarnib, tipifarnib, HSP90 inhibitors (eg, geldamycin derivatives, For example, 17-acrylamide geldanamycin, 17-desmethoxygeldanamycin (17AAG), 17-DMAG, retaspimycin hydrochloride, IPI-493, AUY922, BIIB028, STA -9090, KW-2478), spindle kinesin inhibitors (eg SB715992, SB743921, pentamidine/chlorpromazine), MEK (mitogen-activated protein kinase kinase) inhibitors (eg song Trametinib, BAY 86-9766 (refametinib), AZD6244), kinase inhibitors (eg, sorafenib, regorafenib, lapatinib) (lapatinib), sutent, dasatinib, cetuximab, BMS-908662, GSK2118436, AMG 706, erlotinib, gefitinib Gefitinib), imatinib, nilotinib, pazopanib, roniciclib, sunitinib, vandetanib, Vemurafenib), hedgehog signaling inhibitors (eg cyclopamine, vismodegib), BTK (brutton tyramine) Inhibitors of the kinase (Bruton's tyrosine kinase) (eg, ibrutinib), JAK/pan-JAK (Janus kinase) inhibitors (eg, SB-1578, baricitinib) , tofacitinib, pacitinib, momolotinib, ruxotinib, VX-509, AZD-1480, TG-101348), PI3K inhibitor ( For example, 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) inhibitors (eg, fostamatinib, Excellair, PRT-062607), p53 gene therapy, double Phosphonates (eg etidronate, clodronate, tiludronate, pamidronate, alendronic acid, ibandronate) Ibandronate, risedronate, zoledronate. For the combination, the following active compounds should also be mentioned, such as, but not limited to, rituximab, cyclophosphamide, doxorubicin, a combination of doxorubicin and estrone, vincristine, Chlorambucil, fludarabine, dexamethasone, cladribine, praisson, 131I-chTNT, abirateron, aclarubicin, aqu Alitretinoin, bisantrene, leucovorin, calcium leucovorin, capecitabin, carmofur, clodronate, romiplostim, gram Crisantaspase, darbepoetin alfa, decitabin, denosumab, dibrospidium chloride, eltrombopag ), endostatin, epitiostanol, epoetin alfa, filgrastim, fotemustin, gallium nitrate, gemcitabine, gru Glutoxim, histamine dihydrochloride, hydroxyurea, improsulfan, ixabepilon, Lerectin, lentinan, levamisole, lisurid, lonidamin, masoprocol, methyl ketone, methoxsalen, amine Methyl ketone (methyl aminolevulinate), miltefosin, mitoguazon, mitomycin, mitotan, nelarabin, nimotuzumin Anti-nitricium, nitracilin, omeprazol, palifermin, panitumumab, parmozyme, PEG epotine beta (methoxy-PEG) Epoetin β), polyethylene glycol filgrastim, peginterferon alfa-2b, pentazocin, pentostatin, perfosfamid, pyrrole Pilarubicin, plicamycin, poliglusam, porfimer-sodium, pralatrexate, quinagolid, razori ( Razoxan), sizofiran, sobuzuxan, sodium glycididazole, tamibarroten, tegafur and gem Combination of gimeracil and orteracil, testosterone, tetrofosmin, thalidomide, thymalfasin, trabectedin, retinoic acid , trilostan, tryptophan, ubenimex, vapreotid, 钇-90 glass microbeads, zristatin, netstatin (zinostatin) Stimalamer). Also suitable for tumor therapy such as chemotherapy (eg, azacitidine, belototecan, enocitabine, melphalan, valrubicin) , vinflunin, zorubicin, radiation therapy (eg, I-125 grain, palladium-103 grain, radium chloride-223) or phototherapy (eg temoporfin) a combination of non-pharmacological therapies such as talaporfin, which is accompanied by a drug that utilizes the IRAK4 inhibitor of the present invention, or in a non-drug tumor therapy (eg, chemotherapy, radiation therapy, or phototherapy) After the end, it is supplemented by a drug treatment using the IRAK4 inhibitor of the present invention. In addition to those mentioned above, the IRAK4 inhibitors of the invention may also be combined with the following active compounds: active compounds for Alzheimer's therapy, such as acetylcholinesterase inhibitors (eg multiple Donepezil, rivastigmine, galantamin, tacrine, NMDA (N-methyl-D-aspartate) receptor antagonism Agent (eg memantine); L-DOPA/carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-A) for the treatment of Parkinson's disease Base transferase inhibitors (eg, entacapon), dopamine agonists (eg, ropinrol, pramipexol, bromocriptine), MAO-B (monoamine) Base oxidase-B) inhibitors (such as selegiline), anticholinergic agents (such as trihexyphenidyl), and NMDA antagonists (such as amantadin); Multiple sclerosis beta interferon (IFN-β) (eg IFN β-1b, IFN β-1a Avonex® and Betaferon®), glatiramer acetate, immunoglobulin, natalizumab ( Natalizumab), fingolimod and immunosuppressants (such as mitoxantrone, azathioprine and cyclophosphamide); substances used to treat pulmonary disorders, such as beta-2-sympathomimetics ( For example, salbutamol, anticholinergic agents (such as pyrrose), methylxanthine (such as theophylline), leukotriene receptor antagonists (such as montelukast), PDE-4 (4) Type phosphodiesterase inhibitors (eg, roflumilast), amine methotrexate, IgE antibodies, azathioprine and cyclophosphamide, cortisol-containing preparations; substances for the treatment of osteoarthritis, For example, non-steroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, for rheumatoid conditions (such as rheumatoid arthritis, spondylarthritis and juvenile idiopathic arthritis), mention should be made of methotrexate and for B cell and T cell therapy. Biological agents (eg rituximab, abatacept). Neurotrophic substances such as acetylcholinesterase inhibitors (eg, donepezil), MAO (monoamine oxidase) inhibitors (eg, selegiline), interferons, and anticonvulsants (eg gabapentin) Gabapentin)); an active compound for the treatment of cardiovascular disorders, such as beta blockers (eg metoprolol), ACE inhibitors (eg benazepril), vasoconstrictor receptor blockers Broken agents (such as losartan, valsartan), diuretics (such as hydrochlorothiazide), calcium channel blockers (such as nifedipine), statins (such as Simvastatin, fluvastatin; antidiabetic drugs such as metformin, glinide (eg nateglinide), DPP-4 (dipeptidyl peptidase) -4) Inhibitors (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT2 (sodium/glucose co-transporter 2) Inhibitor/gliflozin (eg dapagliflozin, empagliflozin), intestine Insulinotropic mimetics (hormone glucose-dependent insulinotropic peptide (GIP) and glycoside-like peptide 1 (GLP-1) analogues/agonists) (eg exenatide, liraglutide) ), lixisenatide, alpha-glucosidase inhibitors (eg, acarbose, miglitol, voglibiose) and sulfonylurea (eg Glibenclamide, tolbutamide, insulin sensitizers (eg pioglitazone) and insulin therapy (eg NPH insulin, insulin lispro) for the treatment of hypoglycemia A substance used to treat diabetes and metabolic syndrome. Lipid lowering agents, such as fibrates (eg, bezafibrate, etofibrate, fenofibrate, gemfibrozil), niacin-derived (eg niacin/laropiprant), ezetimib, statins (eg simvastatin, fluvastatin), anion exchangers (eg colestyramine) , colestipol, colesevelam). Active compounds for the treatment of chronic inflammatory bowel disorders, such as mesalazine, sulfasalazine, azathioprine, 6-oxime or amidoxime, probiotics (Mutaflor) , VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624 , Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917, antibiotics (eg ciprofloxacin and metronidazole), antibiotics Diarrhea (such as loperamide) or laxative (bisacodyl). Immunosuppressive agents for the treatment of lupus erythematosus, such as glucocorticoids and non-steroidal anti-inflammatory substances (NSAID), cortisone, chloroquin, cyclosporine, azathioprine, belimizumab, rituximab Infliximab, cyclophosphamide. Drugs for organ transplantation, such as, but not limited to, calcineurin inhibitors (such as tacrolimus and cyclosporine), cell division inhibitors (such as azathioprine, mycophenolate mofetil, mildew) Mycophenolic acid, everolimus or sirolimus, rapamycin, basiliximab, daclizumab, anti-CD3 antibody, anti-T-lymphocyte immunoglobulin /Anti-lymphocyte immunoglobulin. Vitamin D3 analogues for dermatological conditions, such as calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate, legally Elemizumab. For the treatment and/or prophylaxis of the above-mentioned conditions, reference should also be made to inclusion of at least one of the compounds of the invention and one or more other active compounds (specifically EP4 inhibitors (prostaglandin E2 receptor 4 inhibition) Agent, P2X3 inhibitor (P2X嘌呤 receptor 3), PTGES inhibitor (prostaglandin E synthase inhibitor) or AKR1C3 inhibitor (aldosterone reductase family 1 member C3 inhibitor)). The compounds of the invention may act systemically and/or locally. For this purpose, it can be administered in a suitable manner, for example by oral, parenteral, transpulmonary, nasal, sublingual, translingual, buccal, rectal, transdermal, transdermal, or conjunctival routes. Through the ear or as an implant or stent. The compounds of the invention may be administered in a form suitable for administration in such administration routes. Suitable forms for oral administration include the following: working according to the prior art and releasing the compound according to the invention rapidly and/or in a modified manner and containing the invention in crystalline and/or amorphous and/or dissolved form A compound, such as a lozenge (uncoated or coated lozenge, for example, an anti-gastric solution or a delayed dissolution or insoluble coating having a release controlling the release of a compound of the invention), a tablet or film that is rapidly disintegrating in the oral cavity Agents, films/lyophiles, capsules (such as hard or soft gelatin capsules), sugar-coated lozenges, granules, pills, powders, emulsions, suspensions, aerosols or solutions. Parenteral administration may avoid reabsorption steps (eg, by intravenous, intraarterial, intracardiac, intraspinal or intralumbar route) or include resorption (eg, by intramuscular, subcutaneous, intradermal, transdermal or The intraperitoneal route) is achieved. Formulations suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders. Suitable examples of other routes of administration are inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays; for lozenges, sublingual or buccal administration of lozenges, films/blinds or Capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, oscillating mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, Powder, graft or stent. Preferred are administered orally or parenterally, especially by oral administration. The compounds of the invention can be converted to the stated dosage forms. This can be achieved in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. Such excipients include carriers (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycol), emulsifiers, and dispersing or wetting agents (eg, sodium lauryl sulfate, poly Oxysorbol oleate), binders (eg polyvinylpyrrolidone), synthetic and natural polymers (eg albumin), stabilizers (eg oxidizing agents such as ascorbic acid), colorants (eg inorganic pigments, eg oxidation Iron) and flavoring agents and / or flavoring agents. The invention further provides medicaments comprising at least one of the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the above mentioned purposes. In general, in the case of parenteral administration, it is advantageous to administer from about 0.001 mg/kg body weight to 1 mg/kg body weight, preferably from about 0.01 mg/kg body weight to 0.5 mg/kg body weight, to achieve effective results. . In the case of oral administration, the dosage is from about 0.01 mg/kg body weight to 100 mg/kg body weight, preferably from about 0.01 mg/kg body weight to 20 mg/kg body weight, and optimally from 0.1 mg/kg body weight to 10 mg. /kg body weight. However, deviations from such amounts may be necessary in some instances, particularly as a function of body weight, route of administration, reaction of the individual to the active compound, the nature of the formulation, and the time or interval at which the administration takes place. Therefore, in some cases, it may be sufficient to control less than the minimum amount mentioned above, while in other cases the upper limit mentioned must be exceeded. In the case of administration of larger amounts, these may be appropriately divided into individual doses and administered throughout the day. The following working examples illustrate the invention. The invention is not limited to the examples. Unless otherwise stated, the percentages in the following tests and examples are percentages by weight; parts are parts by weight. The solvent ratio, dilution ratio and concentration data of the liquid/liquid solution are in each case based on volume. The preparation of the substance of the formula (I) of the present invention is illustrated in the following Synthesis Schemes 1 to 6. As shown in Synthesis Scheme 1, 6-chloro-5-nitro-1H-carbazole (CAS 101420-98-8) can be converted to the intermediate 1 by an alkylation reaction or a Mitsunobu reaction. The reactants suitable for the alkylation reaction are optionally substituted alkyl chlorides, alkyl bromides, alkyl iodides or alkyl 4-toluenesulfonates. The alkyl halide or alkyl 4-toluenesulfonate used may be commercially available or may be prepared in a manner similar to that known from the literature (in the preparation of alkyl 4-toluenesulfonate, one An example is the reaction of a suitable alcohol with 4-toluenesulfonyl chloride in the presence of triethylamine or pyridine; see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12 4277 - 4294). Optionally, an alkali metal iodide such as potassium iodide or sodium iodide may be added in the case of using an alkyl chloride or an alkyl bromide. The base used may be, for example, potassium carbonate, cesium carbonate or sodium hydride. In the case of a reactive alkyl halide, N-cyclohexyl-N-methylcyclohexylamine can also be used in some cases. Useful solvents include, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF. Optionally, the alkyl halide or alkyl 4-toluenesulfonate used has a functional group which has been previously protected by a protecting group (see also P. G. M. Wuts, T. W. Greene,Greene's Protective Groups in Organic Synthesis , Fourth Edition, ISBN: 9780471697541). If, for example, an alkyl halide having one or more hydroxyl groups or an alkyl 4-toluenesulfonate is used, the hydroxyl groups may be familiar to the third butyl (dimethyl) oxime familiar to those skilled in the art. Protected by a base or similar hydrazine-containing protecting group. Alternatively, the hydroxy group can also be protected with a tetrahydro-2H-pyran (THP) group or with an acetamino group or a benzamidine group. The protecting group used can then be removed after synthesis of intermediate 1 or intermediate 2, or after synthesis of (I)-a. If, for example, a t-butyl(dimethylhydrazino) group is used as the protecting group, tetrabutylammonium fluoride can be used, for example, in a solvent such as THF to be liberated. The THP protecting group can be detached using, for example, 4-toluenesulfonic acid, optionally in the form of a monohydrate. The acetamino group or the benzamidine group can be detached by treatment with an aqueous solution of sodium hydroxide. The alkyl halide or alkyl 4-toluenesulfonate employed may optionally contain a functional group which can be converted to an alternative functional group by a reaction known to those skilled in the art. The examples mentioned are oxidation or reduction reactions or hydrolysis reactions of alkyl carboxylates (for example comparison)Science of Synthesis , Georg Thieme Verlag). Alternatively, 6-chloro-5-nitro-1H-indazole can be converted to a 6-chloro-5-nitro-1H-carbazole using an optionally substituted alkyl alcohol in a light delay reaction (see, for example, KCK Swamy et al. Chem. Rev. 2009, 109, 2551-2651). Intermediate 1. Various phosphines such as triphenylphosphine, tributylphosphine or 1,2-diphenylphosphinoethane can be used with diisopropyl azodicarboxylate (CAS 2446-83-5) or in the literature Combinations of other diazene derivatives mentioned (KCK Swamy et al. Chem. Rev. 2009, 109, 2551-2651). Preferred are triphenylphosphine and diisopropyl azodicarboxylate. If the alkyl alcohol has a functional group, a known protecting group strategy can be used (as in the case of the reaction with an alkyl halide as mentioned above) (for additional instructions see PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541) and an oxidation or reduction step can be carried out after synthesis of intermediate 1 or after synthesis of intermediate 2 or after synthesis of a compound of formula (I) according to the invention (as in the above) Reference is made to the case of reaction with an alkyl halide). Intermediate 1 can be converted to intermediate 2 by reduction of the nitro group. Iron and ammonium chloride in water and ethanol can be used for this purpose (see also, for example, Journal of the Chemical Society, 1955, 2412-2419). To prepare a subset (I)-a of the compound of formula (I) of the present invention from intermediate 2, it can be synthesized using indoleamine. Can be used in the literature (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3 - Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12 - Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606) Various coupling agents are known. For example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride can be used with 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475; Bioorg Med. Chem. Lett., 2008, 18, 2093), tetrafluoroboric acid (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethylammonium salt (TBTU, CAS 125700-67-6), hexafluorophosphoric acid (dimethylamino)-N,N-dimethyl (3H-[1,2,3]triazolo[4,5-b]pyridine -3-yloxy)methylammonium salt (HATU, CAS 148893-10-1), propanephosphonic anhydride (formed as a solution in ethyl acetate or DMF, CAS68957-94-8) or bis-1H-imidazole- A combination of 1-methyl ketone (CDI) is used as a coupling agent, and a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine can be added to the reaction mixture in each case. Preferred are HATU and N-ethyl-N-isopropylpropan-2-amine used in DMF.Synthetic Scheme 1 A subset (I)-a of a compound of formula (I) of the present invention (wherein R¹ Preparation of = Cl). R² And R³ It is as defined for the general formula (I). Another subset (I)-b of the compounds of formula (I) of the present invention can be obtained as shown in Synthetic Scheme 2. Here, 6-chloro-1H-indazole-5-amine (CAS 221681-75-0) was reacted with a carboxylic acid. The method of indoleamine synthesis described in Synthetic Scheme 1 is suitable for this purpose. Preferred are 1-hydroxy-1H-benzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and triethylamine in THF. . This gave intermediate 3 which was then reacted with an alkyl halide in a similar manner to that of the scheme 1 to afford (I)-b.Synthetic Scheme 2 A subset (I)-b of a compound of formula (I) of the present invention (wherein R¹ Preparation of = Cl). R² And R³ It is as defined for the general formula (I). Another subset (I)-c of the compounds of formula (I) of the present invention can be obtained as shown in Synthetic Scheme 3. Here, 5-nitro-1H-indazole-6-ol (CAS 1082041-56-2) was converted to the intermediate 4. The preparation of some intermediates 4 is known (for example, WO2013174744, WO201574986, Bioorganic and Medicinal Chemistry, 2004, 12, 2115-2137). A preferred retardation reaction for the preparation of intermediate 4 from 5-nitro-1H-indazole-6-ol (Comparative Synthesis Scheme 1). More preferred are triphenylphosphine and diisopropyl azodicarboxylate in THF. Starting from intermediate 4, intermediate 5 is obtained by reduction reaction (comparative synthesis 1 for iron and ammonium chloride used in water and ethanol; however, carbon-supported palladium in a hydrogen atmosphere can also be used (WO2015/74986 Or tin (II) chloride in methanol (compare WO2013174744)). Indoleamine synthesis as described in Synthetic Scheme 1 yields Intermediate 6. Similar to the synthesis scheme 1, the alkylation reaction gives (I)-c.Synthetic Scheme 3 A subset (I)-c of a compound of formula (I) of the present invention (wherein R¹ = OR⁴ Preparation of .R² , R³ And R⁴ It is as defined for the general formula (I). Another subset (I)-d of the compounds of formula (I) of the present invention can be obtained as shown in Synthetic Scheme 4. Intermediate 4 as set forth in Scheme 1 is converted to Intermediate 7 in an alkylation reaction. Reduction of the nitro group (Comparative Synthesis Scheme 4) yielded intermediate 8, which was then converted to (I)-d by indoleamine synthesis (Comparative Scheme 1).Synthetic Scheme 4 A subset (I)-d of a compound of formula (I) of the present invention (wherein R¹ = OR⁴ Preparation of. R² , R³ And R⁴ It is as defined for the general formula (I). Intermediate 8 can be prepared from intermediate 5 by an alternative route as set forth in Scheme 5. The intermediate 5 was first protected with a third butoxycarbonyl group (comp. WO2015091426) and thereafter alkylated as described in Synthetic Scheme 1 and the protecting group was removed in the presence of trifluoroacetic acid in dichloromethane.Synthetic Scheme 5 Alternative Preparation of Intermediate 8. R² And R⁴ It is as defined for the general formula (I). Substituent R can also be introduced by alkylation of an alkyl halide or an alkyl 4-toluenesulfonate starting from intermediates 11, 12 and 13 according to Scheme 6.⁴ This allows the intermediate 6 (subsets (I)-e) of the compound of the formula (I) of the invention and the intermediate 10 to be obtained. Preferred herein is the alkylation reaction using alkyl bromide and potassium carbonate in DMF. The alkyl halide used may optionally have a functional group which can be converted to other functional groups by a transformation known to those skilled in the art after the alkylation reaction. An example which may be mentioned is the reduction of the alkyl carboxylate group to an alcohol group using sodium borohydride or the hydrolysis of the alkyl carboxylate to a carboxylic acid group using lithium hydroxide in water and THF.Synthetic Scheme 6 A subset (I)-e of a compound of formula (I) of the invention (wherein R¹ = OR⁴ Preparation of the intermediates and preparation of intermediates 6 and 10. R² , R³ And R⁴ It is as defined for the general formula (I).Synthesis of example compounds Abbreviations and descriptions The term saturated brine means a saturated aqueous solution of sodium chloride. Chemical names for intermediates and examples were generated using ACD / LABS (Batch 12.01.) software.method In some cases, the compounds of the invention and their precursors and/or intermediates are analyzed by LC-MS. Method A1: UPLC (MeCN-HCOOH): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Mobile phase A: Water + 0.1% by volume of formic acid (99%), flow Phase B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ESI+, ESI-, scan range 160-1000 m/z; ELSD. Method A2: UPLC (MeCN-NH₃ ): Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Mobile phase A: water + 0.2% by volume of formic acid (32%), mobile phase B: acetonitrile; Gradient: 0 -1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; MS ESI+, ESI-, scan range 160 -1000 m/z; ELSD. Method A3: (LC-MS) Instrument: Agilent 1290 Infinity LC; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; mobile phase A: water + 0.05 vol% formic acid, mobile phase B: acetonitrile + 0.05 vol% formic acid; Gradient: 0-1.7 min 2-90% B, 1.7-2.0 min 90% B; flow rate 1.2 ml/min; temperature: 60 ° C; injection: 2 μl; DAD scan: 190-390 nm; MS: Agilent TOF 6230. Method A4: (LC-MS) Instrument: Waters Acquity; column: Kinetex (Phenomenex), 50 x 2 mm; mobile phase A: water + 0.05 vol% formic acid, mobile phase B: acetonitrile + 0.05 vol% formic acid; gradient: 0-1.9 min 1-99% B, 1.9-2.1 min 99% B; flow rate 1.5 ml/min; temperature: 60 ° C; injection: 0.5 μl; DAD scan: 200-400 nm. In some instances, the compounds of the invention and their precursors and/or intermediate systems are purified by the following exemplary preparative HPLC method: Method P1: System: Waters Self-purification System: Pump 2545, Sample Tube Controller 2767, CFO , DAD 2996, ELSD 2424, SQD; column: XBridge C18 5μm 100×30 mm; mobile phase: A: water + 0.1% by volume of formic acid, mobile phase B: acetonitrile; gradient: 0-8 min 10-100% B, 8-10 min 100% B; flow rate: 50 ml/min; temperature: room temperature; solution: maximum 250 mg / maximum 2.5 ml DMSO or DMF; injection: 1 × 2.5 ml; detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scanning range 160-1000 m/z. Method P2: System: Waters self-purification system: pump 254, sample controller 2767, CFO, DAD 2996, ELSD 2424, SQD 3100; column: XBridge C18 5μm 100×30 mm; mobile phase: A: water + 0.2 Volume % ammonia (32%), mobile phase B: methanol; gradient: 0-8 min 30-70% B; flow rate: 50 ml/min; temperature: room temperature; detection: DAD scan range 210-400 nm; MS ESI+ , ESI-, scanning range 160-1000 m / z; ELSD. Method P3: System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV Detector: Knauer UVD 2.1S; Column: XBridge C18 5μm 100×30 mm; Mobile Phase A: Water+ 0.2 vol% ammonia (25%), mobile phase B: acetonitrile; gradient: 0-1 min 15% B, 1-6.3 min 15-55% B, 6.3-6.4 min 55-100% B, 6.4-7.4 min 100 % B; flow rate: 60 ml/min; temperature: room temperature; solution: maximum 250 mg / 2 ml DMSO; injection: 2 × 2 ml; detection: UV 218 nm; software: SCPA PrepCon5. Method P4: System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV Detector: Knauer UVD 2.1S; Column: Chromatorex RP C18 10 μm 125×30 mm, Mobile Phase: A: Water + 0.1% by volume formic acid, mobile phase B: acetonitrile; Gradient: 0 - 15 min 65 – 100% B; Flow rate: 60 ml/min; Temperature: room temperature; Solution: Max 250 mg / 2 ml DMSO; Injection: 2 × 2 ml; detection: UV 254 nm; software: SCPA PrepCon5. Method P5: System: Sepiatec: Prep SFC100; column: Chiralpak IA 5 μm 250×20 mm; mobile phase A: carbon dioxide, mobile phase B: ethanol; gradient: isocratic 20% B; flow rate: 80 ml/min; 40 ° C; solution: maximum 250 mg / 2 ml DMSO; injection: 5 × 0.4 ml detection: UV 254 nm. Method P6: System: Agilent: Prep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Dispenser 215; Column: Chiralcel OJ-H 5 μm 250×20 mm; Mobile Phase A: Hexane, Mobile Phase B: Ethanol; Gradient: isocratic 30% B; flow rate: 25 ml/min; temperature: 25 ° C; solution: 187 mg / 8 ml ethanol/methanol; injection: 8 × 1.0 ml detection: UV 280 nm. Method P7: System: Labomatic, pump: HD-5000, fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; column: XBridge C18 5μm 100×30 mm; mobile phase A: water + 0.1% by volume formic acid, mobile phase B: acetonitrile; gradient: 0-3 min: 65% B isocratic, 3-13 min: 65-100% B; flow rate: 60 ml/min; temperature: room temperature; solution: max. 250 mg / 2 ml DMSO; injection: 2 × 2 ml; detection: UV 254 nm. Method P8: System: Agilent: Prep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Dispenser 215; Column: Chiralpak IF 5 μm 250×20 mm; Mobile Phase A: Ethanol, Mobile Phase B: Methanol; Gradient : isocratic 50% B; flow rate: 25 ml/min; temperature: 25 ° C; solution: 600 mg / 7 ml N,N-dimethylformamide; injection: 10 × 0.7 ml detection: UV 254 nm. For the preparation of some of the compounds of the invention and their precursors and/or intermediates, Isolera from Biotage is used on silicone^® The device was subjected to column chromatography purification ("quick chromatography"). This is done using a column from Biotage (for example, "SNAP Cartridge, KP_SIL" columns of different sizes and "Interchim Puriflash Silica HP 15UM Boiling Tower" columns of different sizes from Interchim).Intermediate 1-1 6- chlorine -2-(3- Methoxy -3- Methyl butyl )-5- Nitro -2H- Carbazole First, 500 mg (2.53 mmol) of 6-chloro-5-nitro-1H-carbazole (CAS No.: 101420-98-8) and 390 μl (3.0 mmol) of 3-methoxy-3 were charged in 5 ml of THF. -Methylbutan-1-ol and 996 mg (3.80 mmol) of triphenylphosphine, 540 μl (2.8 mmol) of diisopropyl azodicarboxylate were slowly added dropwise and the mixture was stirred at 25 ° C for 21.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Interchim 15[mu]m column, KP-Sil, mobile phase: hexane/ethyl acetate). This gave 792 mg (crude) of the title compound. LC-MS (Method A1): R_t = 1.22 min (UV detector: TIC Smooth), mass measurement 297.00¹ H-NMR (500MHz, DMSO-d6, selected signal): δ = 2.10 - 2.16 (m, 1H), 3.12 (s, 1H), 4.50 - 4.55 (m, 1H), 8.00 (d, 1H), 8.67 (s, 1H), 8.82 (d, 1H).Intermediate 2-1 6- chlorine -2-(3- Methoxy -3- Methyl butyl )-2H- Carbazole -5- amine 791 mg of 6-chloro-2-(3-methoxy-3-methylbutyl)-5-nitro-2H-carbazole (crude) was dissolved in 8 ml of ethanol and 2 ml of water was added. Then 1.48 g (26.6 mmol) of iron powder and 71.1 mg (1.33 mmol) of ammonium chloride were added, and the mixture was stirred at 90 ° C for 1.5 hours. The reaction mixture was cooled and filtered through celite. The filtrate was washed three times with ethanol and concentrated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered (hydrophobic filter) and concentrated. This gave 715 mg of the title compound as a crude material. LC-MS (Method A1): R_t = 0.92 min (UV detector: TIC Smooth), mass measurement 267.00.Intermediate 3-1 N-(6- chlorine -1H- Carbazole -5- base )-6-( Difluoromethyl ) Pyridine -2- Formamide 2.00 g (11.9 mmol) of 6-chloro-1H-indazole-5-amine (CAS number: 221681-75-0), 2.48 g (14.3 mmol) of 6-(difluoromethyl)pyridine-2-carboxylic acid, 1.83 g (11.9 mmol) 1-hydroxy-1H-benzotriazole hydrate, 4.58 g (23.9 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride A mixture of 5.0 ml (36 mmol) of triethylamine in 40 ml of THF was stirred at 25 ° C for 20.5 hours. The reaction mixture was diluted with water and concentrated. The solid was filtered off with suction and washed three times with water and three times with diethyl ether. Then ether was added and the mixture was stirred. The solid was filtered off with suction, washed three times with diethyl ether and dried under reduced pressure. This gave 3.45 g of the title compound as a crude product. LC-MS (Method A1): R_t = 1.09 min (UV detector: TIC Smooth), mass measurement 322.00.Intermediate 4-1 5- Nitro -6-( Oxetane -3- Baseoxy )-1H- Carbazole First, 4.00 g (22.3 mmol) of 5-nitro-1H-indazole-6-ol (CAS No.: 1082041-56-2), 1.74 g (23.4 mmol) of oxetane-3- was charged in 50 ml of THF. Alcohol and 8.79 g (33.5 mmol) of triphenylphosphine were slowly added dropwise 6.5 ml (33 mmol) of diisopropyl azodicarboxylate and the mixture was stirred at 25 ° C for 17.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave a crude product of 4.58 g of the title compound. LC-MS (Method A1): R_t = 0.78 min (UV detector: TIC Smooth), mass measurement 235.00¹ H NMR (500MHz, DMSO-d6): δ = 4.59 - 4.64 (m, 2H), 4.95 - 5.02 (m, 2H), 5.50 - 5.56 (m, 1H), 6.84 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 13.33 (s, 1H).Intermediate 4-2 5- Nitro -6-( Oxetane -3- Methoxy )-1H- Carbazole First, fill 2.50 g (11.2 mmol) of 5-nitro-1H-indazole-6-ol (CAS number: 1082041-56-2), 1.03 g (11.7 mmol) of oxetane-3- in 25 ml of THF. Methanol and 4.39 g (16.7 mmol) of triphenylphosphine were slowly added dropwise 3.2 ml (17 mmol) of diisopropyl azodicarboxylate and the mixture was stirred at 25 ° C for 18.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave 1.03 g of the crude title compound. LC-MS (Method A1): R_t = 0.79 min (UV detector: TIC Smooth), mass measurement 249.00¹ H NMR (500MHz, DMSO-d 6 ): δ = 3.41 - 3.48 (m, 1H), 4.40 (d, 2H), 4.48 (t, 2H), 4.70 (dd, 2H), 7.28 (s, 1H), 8.20 (s, 1H), 8.43 (s, 1H), 13.38 (s, 1H).Intermediate 4-3 5- Nitro -6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-1H- Carbazole First, 2.50 g (11.2 mmol) of 5-nitro-1H-indazole-6-ol (CAS number: 1082041-56-2), 940 μl (12 mmol) (3S)-tetrahydrofuran-3 were charged in 25 ml of THF. - Alcohol and 4.39 g (16.7 mmol) of triphenylphosphine, 3.2 ml (17 mmol) of diisopropyl azodicarboxylate were slowly added dropwise and the mixture was stirred at 25 ° C for 67 hours. The reaction mixture was concentrated and purified by flash chromatography (EtOAc EtOAc EtOAc (EtOAc) This gave 3.08 g of the title compound. LC-MS (Method A1): R_t = 0.82 min (UV detector: TIC Smooth), mass measurement 249.00.Intermediate 6-1 N-(6- Isopropoxy -1H- Carbazole -5- base )-6-( Trifluoromethyl ) Pyridine -2- Formamide First, 7.02 g (36.73 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid and 13.48 g (41.98 mmol) of O-(benzotriazol-1-yl)-N,N were charged in 400 ml of THF. N', N'-tetramethyluronium tetrafluoroborate and 7.31 ml (41.98 mmol) of N,N-diisopropylethylamine. The mixture was stirred at 25 ° C for 30 minutes, and then 6.69 g (34.98 mmol) of 6-isopropoxy-1H-indazole-5-amine (CAS number: 1498329-80-8) was added. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated and the residue was partitioned between water andEtOAc. The mixture was extracted twice with ethyl acetate and the combined organic phases were washed with saturated sodium chloride, filtered and concentrated with a The residue was purified by flash chromatography (Biotage SNAP cartridge (340 g; KP-Sil), mobile phase: hexane/ethyl acetate). The combined product fractions were concentrated, suspended in water and stirred vigorously for 20 min. The product was filtered off with suction and washed with water and diethyl ether. This gave 8.56 g of the title compound. LC-MS (Method A1): R_t = 1.23 min (UV detector: TIC Smooth), mass measurement 364.00¹ H NMR (400 MHz, DMSO-d6): δ = 1.41 (d, 6 H), 4.85 (spt, 1 H), 7.18 (s, 1 H), 8.01 (s, 1 H), 8.21 (dd, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.81 (s, 1 H), 10.67 (s, 1 H), 12.85 (s, 1 H).Intermediate 6-2 6-( Difluoromethyl )-N-(6- Ethoxy -1H- Carbazole -5- base ) Pyridine -2- Formamide 512 mg (2.89 mmol) 6-ethoxy-1H-indazole-5-amine, 600 mg (3.47 mmol) 6-(difluoromethyl)pyridine-2-carboxylic acid, 442 mg (2.89 mmol) 1- Hydroxy-1H-benzotriazole hydrate, 1.11 g (5.78 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.2 ml (8.7 mmol) of three The mixture of ethylamine in 10 ml of THF was stirred at 25 ° C for 20.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. Diethyl ether was added to the residue, the mixture was stirred and the solid formed was filtered off with suction, washed three times with diethyl ether and dried. This gave 499 mg of the title compound. LC-MS (Method A1): R_t = 1.10 min (UV detector: TIC Smooth), mass measurement 332.00¹ </ RTI> <RTIgt; 8.26 - 8.36 (m, 2H), 8.76 (s, 1H), 10.71 (s, 1H), 12.86 (s, 1H).Intermediate 6-3 N-[6-( Benzyloxy )-1H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide First, 5.40 g (22.57 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid and 10.87 g (33.85 mmol) of O-(benzotriazol-1-yl)-N,N were charged in 150 ml of THF. N', N'-tetramethyluronium tetrafluoroborate and 5.90 ml (33.85 mmol) of N,N-diisopropylethylamine. The mixture was stirred at 25 ° C for 30 minutes, and then 5.40 g (22.57 mmol) of 6-(benzyloxy)-1H-indazole-5-amine (CAS No.: 1499162-36-5) was added. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated and the residue was partitioned between water andEtOAc. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. Diethyl ether was added to the crude product, and the mixture was stirred vigorously for 10 minutes and the formed precipitate was filtered off with suction. This gave 6.72 g of the title compound. LC-MS (Method A1): R_t = 1.28 min (UV detector: TIC Smooth), mass measurement 412.00¹ H NMR (400 MHz, DMSO-d6): δ = 5.34 (s, 2 H), 7.31 (s, 1 H), 7.41 (d, 3 H), 7.58 (dd, 2 H), 8.04 (s, 1 H), 8.18 (d, 1 H), 8.40 (d, 1 H), 8.45 - 8.53 (m, 1 H), 8.85 (s, 1 H), 10.41 (s, 1 H), 12.97 (s, 1 H).Intermediate 6-4 N-[6-( Cyclopropylmethoxy )-1H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 1.00 g of N-(6-hydroxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 20 ml of DMF and add 1.72 g with stirring ( 12.41 mmol) potassium carbonate. The suspension was stirred at 25 ° C for 30 minutes and then 431 μl (4.65 mmol) of (bromomethyl)cyclopropane was added. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was then diluted with water and the solid formed was filtered with suction, washed with diethyl ether and dried under reduced pressure. This gave 585 mg of the title compound. LC-MS (Method A1): R_t = 1.25 min (UV detector: TIC Smooth), mass measurement 376.00¹ H NMR (300 MHz, DMSO-d6): δ = 0.40 - 0.51 (m, 2 H), 0.59 - 0.71 (m, 2 H), 1.27 - 1.41 (m, 1 H), 4.05 (d, 2 H) , 7.08 (s, 1 H), 8.01 (s, 1 H), 8.16 - 8.25 (m, 1 H), 8.41 (t, 1 H), 8.48 (d, 1 H), 8.82 (s, 1 H) , 10.65 (s, 1 H), 12.90 (s, 1 H).Intermediate 6-5 N-[6-( Trifluoromethoxy )-1H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 600 mg of 6-(trifluoromethoxy)-1H-indazole-5-amine (CAS number: 1491 916-39-8, used as a crude product) and 673 mg (3.52 mmol) of 6-(trifluoromethyl) Pyridine-2-carboxylic acid was dissolved in 15 ml of THF, and 360 mg (2.35 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 900 mg (4.70 mmol) 1-(3-di) was added at 25 °C. Methylaminopropyl)-3-ethylcarbodiimide hydrochloride and 980 μl (7.0 mmol) of triethylamine. The reaction mixture was stirred at RT for 24 hours and then diluted with water and a solid precipitated was filtered. The solid was washed with water and diethyl ether and dried under reduced pressure. This gave 406 mg of the title compound. LC-MS (Method A1): R_t = 1.26 min (UV detector: TIC Smooth) with a mass measurement of 390.00.Intermediate 6-6 2- Cyclopropyl -N-(6- Methoxy -1H- Carbazole -5- base )-1,3- Oxazole -4- Formamide 586 mg (3.59 mmol) of 6-methoxy-1H-indazole-5-amine (CAS number: 749223-61-8) and 500 mg (3.27 mmol) of 2-cyclopropyl-1,3-oxazole 4-carboxylic acid (CAS number: 1060816-04-7) was dissolved in 10 ml of THF, and 500 mg (3.3 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.25 g (6.5) was added at 25 °C. Methyl) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.37 ml (9.8 mmol) of triethylamine. Water was added, the solvent was partially removed and the solid was filtered, washed with water and diethyl ether and dried. This gave 758 mg of the title compound. LC-MS (Method A1): R_t = 1.05 min (UV detector: TIC Smooth), mass measurement 298.00.Intermediate 6-7 N-(6- Methoxy -1H- Carbazole -5- base )-6-( Pyrrolidine -1- base ) Pyridine -2- Formamide Add 692 mg HATU to 248 mg of 6-methoxy-1H-indazole-5-amine, 350 mg of 6-(pyrrolidin-1-yl)pyridine-2-carboxylic acid and 0.79 ml of N,N-diisopropyl The mixture was stirred in 5.3 ml of THF and the mixture was stirred at room temperature overnight. Water was added and the solid was filtered off with suction and dried under reduced pressure. This gave 503 mg of the title compound as a crude material.¹ H-NMR (400MHz, DMSO-d₆ ): δ [ppm] = 1.98 - 2.07 (m, 4H), 3.46 - 3.58 (m, 4H), 4.00 (s, 3H), 6.74 (d, 1H), 7.10 (s, 1H), 7.33 (d, 1H), 7.72 (dd, 1H), 7.98 (s, 1H), 8.74 (s, 1H), 10.85 (s, 1H), 12.88 (s, 1H).Intermediate 7-1 4-(6- Ethoxy -5- Nitro -2H- Carbazole -2- base )-2- Methyl butyl -2- alcohol First, 10 g (48 mmol) of 6-ethoxy-5-nitro-1H-carbazole (see WO2015091426) and 20 g of potassium carbonate were charged in 100 ml of DMF, and the mixture was stirred for 15 minutes. Then 8.8 ml (72.3 mmol) of 4-bromo-2-methylbutan-2-ol was added and the mixture was stirred at 70 ° C overnight. Another 2.9 ml (24 mmol) of 4-bromo-2-methylbutan-2-ol and 6.6 g of potassium carbonate were added and stirring was continued at 70 ° C for another night. The mixture was filtered off with suction and the filtrate was taken up in toluene and washed three times with water. The mixture was washed with a saturated sodium chloride solution and dried over magnesium sulfate and then concentrated. Rapid chromatography (Biotage, hexane/ethyl acetate gradient) gave 4. LC-MS (Method A1): R_t = 0.99 min (UV detector: TIC Smooth), mass measurement 293.00. 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.15 (s, 6 H) 1.35 (t, 3H) 1.99 - 2.06 (m, 2 H) 4.14 – 4.21 (q, 2 H) 4.45 - 4.53 (m, 2 H) 4.54 (s, 1H) 7.23 (s, 1H) 8.37 ( s, 1 H) 8.60 (s, 1 H)Intermediate 7-2 2- methyl -4-[5- Nitro -6-( Oxetane -3- Baseoxy )-2H- Carbazole -2- base ] Ding -2- alcohol 4.58 g of 5-nitro-6-(oxetan-3-yloxy)-1H-indazole (crude product) was dissolved in 50 ml of DMF and 6.06 g (43.8 mmol) of carbonic acid was added with stirring. Potassium and 7.16 g (used as a crude product) 3-hydroxy-3-methylbutyl-4-toluenesulfonate (M. Shimizu et al.,Bioorganic and Medicinal Chemistry 2006 ,14, 4277 – 4294). The reaction mixture was stirred at 80 &lt;0&gt;C for 18 h, diluted with H~~~~ The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage SNAP cartridge, KP-Sil, mobile phase: hexane / ethyl acetate). This gave 627 mg of the title compound. LC-MS (Method A1): R_t = 0.87 min (UV detector: TIC Smooth), mass measurement 321.00¹ H NMR (500MHz, DMSO-d6): δ = 1.14 (s, 6H), 1.99 - 2.04 (m, 2H), 4.47 - 4.51 (m, 2H), 4.53 (s, 1H), 4.57 (dd, 2H) , 4.97 - 5.02 (m, 2H), 5.42 - 5.49 (m, 1H), 6.90 (s, 1H), 8.47 (s, 1H), 8.63 (d, 1H).Intermediate 7-3 2- methyl -4-[5- Nitro -6-( Oxetane -3- Methoxy )-2H- Carbazole -2- base ] Ding -2- alcohol Dissolve 1.03 g of 5-nitro-6-(oxetan-3-ylmethoxy)-1H-indazole (crude) in 7.5 ml DMF and add 777 mg (4.65 mmol) with stirring 4-bromo-2-methylbutan-2-ol and 1.29 g (9.30 mmol) of potassium carbonate. The reaction mixture was stirred at 100 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. This gave 287 mg of the title compound. LC-MS (Method A1): R_t = 0.84 min; MS (ESIpos): m/z = 335 [M+H]^{+ 1} H NMR (500MHz, DMSO-d6): δ = 1.15 (s, 6H), 2.00 - 2.06 (m, 2H), 3.40 - 3.47 (m, 1H), 4.35 (d, 2H), 4.46 (t, 2H) , 4.48 - 4.52 (m, 2H), 4.70 (dd, 2H), 7.30 (s, 1H), 8.39 (s, 1H), 8.61 (d, 1H).Intermediate 7-4 2- methyl -4-{5- Nitro -6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-2H- Carbazole -2- base } Ding -2- alcohol 3.08 g of 5-nitro-6-[(3S)-tetrahydrofuran-3-yloxy]-1H-indazole (crude) was dissolved in 50 ml of DMF and 3.84 g (27.8 mmol) was added with stirring. Potassium carbonate and 4.55 g (used as a crude product) 3-hydroxy-3-methylbutyl-4-toluenesulfonate. The reaction mixture was stirred at 80 ° C for 22 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave 618 mg of the title compound as a crude material. LC-MS (Method A1): R_t = 0.91 min (UV detector: TIC Smooth), mass measurement 335.00.Intermediate 8-1 [5- Amine -6-( Cyclopropylmethoxy )-2H- Carbazole -2- base ] Ethyl acetate Add 5.52 ml (71.6 mmol) of trifluoroacetic acid to 2.79 g (7.16 mmol) of {5-[(t-butoxycarbonyl)amino]-6-(cyclopropylmethoxy) in 50 ml of dichloromethane Ethyl 2-H-oxazol-2-yl}acetate, and the mixture was stirred at 25 ° C for 6 hours. The mixture was poured into saturated sodium bicarbonate solution and stirred for 10 minutes, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. This gave 2.03 g of the title compound. LC-MS (Method A1): R_t = 0.75 min (UV detector: TIC Smooth), mass 289.00 1H NMR (400 MHz, DMSO-d6): δ = 0.32 - 0.43 (m, 2 H), 0.53 - 0.64 (m, 2 H), 1.20 (t, 3 H), 1.29 (s, 1 H), 3.86 (d, 2 H), 4.14 (q, 2 H), 4.65 (br. s., 2 H), 5.17 (s, 2 H), 6.65 (s, 1 H), 6.76 (s, 1 H), 7.84 (d, 1 H).Intermediate 8-2 4-[5- Amine -6-( Benzyloxy )-2H- Carbazole -2- base ]-2- Methyl butyl -2- alcohol Add 2.06 ml (26.79 mmol) of trifluoroacetic acid to 1.14 g (2.68 mmol) of [6-(benzyloxy)-2-(3-hydroxy-3-methylbutyl) in 20 ml of dichloromethane -2H-carbazol-5-yl] carbamic acid tert-butyl ester, and the mixture was stirred at 25 ° C for 3 hours. The mixture was poured into a saturated sodium bicarbonate solution. The solid formed was filtered off with suction, washed with water and dried. This gave 840 mg of the title compound. LC-MS (Method A1): R_t = 0.82 min (UV detector: TIC Smooth), mass measurement 325.00 1H NMR (400 MHz, DMSO-d6): δ = 1.12 (s, 6 H), 1.90 - 2.02 (m, 2 H), 4.21 - 4.38 (m, 2 H), 4.46 (s, 1 H), 4.76 (br. s., 2 H), 5.17 (s, 2 H), 6.67 (s, 1 H), 6.91 (s, 1 H), 7.28 - 7.36 (m, 1 H), 7.36 - 7.45 (m, 2 H), 7.48 - 7.55 (m, 2 H), 7.85 (s, 1 H).Intermediate 8-3 4-(5- Amine -6- Methoxy -2H- Carbazole -2- base )-2- Methyl butyl -2- alcohol 610 mg of [2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indazol-5-yl]carbamic acid tert-butyl ester in 10 ml of dichloromethane and 1.3 The mixture in ml (16 mmol) trifluoroacetic acid was stirred at 25 ° C for 19.5 hours. The mixture was poured into saturated sodium bicarbonate solution and stirred for 10 minutes, the phases were separated and dichloromethane was extracted twice. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. This gave 318 mg of the title compound as a crude material. LC-MS (Method A2): R_t = 0.72 min (UV detector: TIC Smooth), mass measurement 249.00.Intermediate 8-4 6- Methoxy -2-[3-( Tetrahydrogen -2H- Pyran -2- Baseoxy ) Propyl ]-2H- Carbazole -5- amine First, fill 789 mg (0.95 mmol) of {6-methoxy-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2H-carbazole in 5 ml of dichloromethane. -5-yl} tert-butyl carbamic acid. 735 μl (9.53 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 25 ° C for 22 hours. Another 735 μl (9.53 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 25 ° C for 68 hours. The reaction mixture was extracted with water and washed with dichloromethane three times. The combined organic phases were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, filtered (hydrophobic filter) and concentrated. Once again, a saturated sodium bicarbonate solution (pH about equal to 9) was added to the aqueous solution, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered (hydrophobic filter) and concentrated. Sodium chloride and ethyl acetate were added to the aqueous phase and the mixture was stirred for 30 minutes. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phase was combined by filtration (hydrophobic filter) and concentrated. This gave 199 mg of the title compound. LC-MS (Method A2): R_t = 0.55 min (UV detector: TIC Smooth), mass measurement 221.00.Intermediate 8-5 4-(5- Amine -6- Ethoxy -2H- Carbazole -2- base )-2- Methyl butyl -2- alcohol 4.87 g (16.6 mmol) of 4-(6-ethoxy-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol was dissolved in 164 ml of THF and 70 ml of methanol And hydrogenation was carried out for 3 hours at 25 ° C in a hydrogen atmosphere using 1.46 g (0.1 mmol) of palladium on activated carbon. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. This gave 4.37 g of the title compound. 1H-NMR (400MHz, DMSO-d6): δ = 1.13 (s, 6 H), 1.40 (t, 3H), 1.92 – 1.99 (m, 2 H), 4.00 – 4.07 (q, 2 H), 4.26 - 4.34 (m, 2 H), 4.49 (s, 1H), 4.57 (s, 2H), 6.62 (s, 1H), 6.80 ( s, 1 H), 7.83 (s, 1 H).Intermediate 8-6 4-[5- Amine -6-( Oxetane -3- Baseoxy )-2H- Carbazole -2- base ]-2- Methyl butyl -2- alcohol Dissolve 616 mg of 2-methyl-4-[5-nitro-6-(oxetan-3-yloxy)-2H-indazol-2-yl]butan-2-ol in 12 ml of ethanol Medium and add 3 ml of water. Then 963 mg (17.3 mmol) of iron powder and 46.1 mg (863 μmol) of ammonium chloride were added, and the mixture was stirred at 90 ° C for 17 hours. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. This gave 574 mg of the title compound as a crude material. LC-MS (Method A2): R_t = 0.68 min (UV detector: TIC Smooth), mass measurement 291.00.Intermediate 8-7 4-[5- Amine -6-( Oxetane -3- Methoxy )-2H- Carbazole -2- base ]-2- Methyl butyl -2- alcohol Dissolve 281 mg of 2-methyl-4-[5-nitro-6-(oxetan-3-ylmethoxy)-2H-indazol-2-yl]butan-2-ol in 7.5 ml Add in ethanol and add 2.5 ml of water. Then 426 mg (7.62 mmol) of iron powder and 20.4 mg (381 μmol) of ammonium chloride were added, and the mixture was stirred at 90 ° C for 21 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was taken up in EtOAc, filtered and concentrated. This gave 227 mg of the title compound as a crude material. LC-MS (Method A2): R_t = 0.70 min (UV detector: TIC Smooth), mass measurement 303.00.Intermediate 8-8 4-{5- Amine -6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-2H- Carbazole -2- base }-2- Methyl butyl -2- alcohol 610 mg 2-methyl-4-{5-nitro-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-2-yl}butan-2-ol (crude) Dissolve in 10 ml of ethanol and add 3 ml of water. Then 843 mg (15.1 mmol) of iron powder and 40 mg of ammonium chloride were added, and the mixture was stirred at 90 ° C for 5 hours. The reaction mixture was cooled and filtered through celite. The filtrate was concentrated and the residue was taken up in EtOAc, filtered and concentrated. The residue was taken up in 2 mL DMF and purified by preparative HPLC. This gave 348 mg of the title compound as a crude material. LC-MS (Method A4): R_t = 0.72 min; MS (ESIpos): m/z = 305 [M+H]⁺ .Intermediate 9-1 (6- Methoxy -1H- Carbazole -5- base ) Tert-butyl carbamic acid The synthesis is described in WO2015091426.Intermediate 10-1 [2-(3- Hydroxyl -3- Methyl butyl )-6- Methoxy -2H- Carbazole -5- base ] Tert-butyl carbamic acid 2.00 g (7.60 mmol) of (6-methoxy-1H-indazol-5-yl)carbamic acid tert-butyl ester was dissolved in 20 ml of 1-methyl-2-pyrrolidone and stirred 1.90 g (11.4 mmol) of 4-bromo-2-methylbutan-2-ol, 3.15 g (22.8 mmol) of potassium carbonate and 1.89 g (11.4 mmol) of potassium iodide were added. The suspension was stirred at 80 ° C for 21 hours. Another 525 mg (3.8 mmol) potassium carbonate and 630 mg (3.8 mmol) potassium iodide were added, and the mixture was stirred at 80 ° C for an additional 6 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage EtOAc EtOAc (EtOAc) The combined product fractions were concentrated and dried. This gave 610 mg of the title compound. LC-MS (Method A1): R_t = 1.16 min (UV detector: TIC Smooth), mass measurement 349.00¹ H-NMR (500MHz, DMSO-d 6 ): δ = 1.13 (s, 6H), 1.46 (s), 1.96 - 2.03 (m, 2H), 3.85 (s, 3H), 4.36 - 4.41 (m, 2H) , 4.50 (s, 1H), 6.97 (s, 1H), 7.77 (s, 1H), 7.89 (br. s., 1H), 8.17 (d, 1H).Intermediate 10-2 {6- Methoxy -2-[3-( Tetrahydrogen -2H- Pyran -2- Baseoxy ) Propyl ]-2H- Carbazole -5- base } Tert-butyl carbamic acid Dissolve 1.00 g of (3-methoxy-1H-indazol-5-yl)carbamic acid tert-butyl ester in 15 ml of DMF and add 967 μl (5.7 mmol) 2-(3- Bromopropoxy)tetrahydro-2H-pyran, 1.58 g (11.4 mmol) potassium carbonate and 757 mg (4.6 mmol) potassium iodide. The reaction mixture was stirred at 100 ° C for 20 hours. Another 484 μl (2.9 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran was added, and the mixture was stirred at 100 ° C for 24 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and the phases were separated and filtered thru a filtered filter. The residue was taken up in dichloromethane and adsorbed onto Isolute during concentration. The residue was purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). The combined product fractions were concentrated and dried. This gave 790 mg of the title compound. LC-MS (Method A1): R_t = 1.33 min (UV detector: TIC Smooth) with a mass measurement of 405.00.Intermediate 10-3 [6-( Benzyloxy )-2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ] Tert-butyl carbamic acid 3.50 (10.3 mmol) of [6-(benzyloxy)-1H-indazol-5-yl]carbamic acid tert-butyl ester (CAS number: 1799835-17-8) was dissolved in 30 ml of DMF. 4.28 g (30.94 mmol) potassium carbonate and 1.71 g (10.31 mmol) potassium iodide were added with stirring. The suspension was stirred at 25 ° C for 30 minutes and then 2.58 g (15.47 mmol) of 4-bromo-2-methylbutan-2-ol was added. The reaction mixture was stirred at 100 ° C for 16 hours. Another 1.72 g (10.31 mmol) of 4-bromo-2-methylbutan-2-ol and 1.42 g (10.31 mmol) of potassium carbonate were added, and the mixture was stirred at 100 ° C for another 24 hours. The reaction mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage SNAP cartridge (340 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave 1.14 g of the title compound. LC-MS (Method A1): R_t = 1.35 min (UV detector: TIC Smooth), mass measurement 425.00 1H NMR (400 MHz, DMSO-d6): δ = 1.13 (s, 6 H), 1.45 (s, 9 H), 1.92 - 2.02 (m , 2 H), 4.34 - 4.42 (m, 2 H), 4.47 (s, 1 H), 5.20 (s, 2 H), 7.03 (s, 1 H), 7.29 - 7.37 (m, 1 H), 7.37 - 7.44 (m, 2 H), 7.53 (d, 2 H), 7.81 - 7.87 (m, 2 H), 8.18 (s, 1 H).Intermediate 10-4 {5-[( Third butoxycarbonyl ) Amine ]-6-( Cyclopropylmethoxy )-2H- Carbazole -2- base } Ethyl acetate 3.00 g (8.95 mmol) of {5-[(t-butoxycarbonyl)amino]-6-hydroxy-2H-indazol-2-yl}acetate was dissolved in 45 ml of DMF with stirring Add 3.71 g (26.84 mmol) of potassium carbonate. The suspension was stirred at 25 ° C for 10 minutes and then 995 μl (10.73 mmol) of (bromomethyl)cyclopropane was added. The reaction mixture was stirred at 25 ° C for 16 hours and at 80 ° C for 4 hours. The reaction mixture was partitioned between water and ethyl acetate and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and concentrated. The residue was purified by flash chromatography (Biotage SNAP cartridge (340 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave 2.79 g of the title compound. LC-MS (Method A1): R_t = 1.37 min (UV detector: TIC Smooth), mass 389.00 1H NMR (400 MHz, chloroform-d): δ = 0.36 - 0.44 (m, 2 H), 0.66 - 0.74 (m, 2 H), 1.28 (t, 3 H), 1.32 - 1.42 (m, 1 H), 1.57 (s, 9 H), 3.91 (d, 2 H), 4.25 (q, 2 H), 5.10 (s, 2 H), 6.92 (s, 1 H), 7.30 (s, 1 H), 7.81 (s, 1 H), 8.28 (br. s., 1 H).Intermediate 11-1 N-(6- Hydroxyl -1H- Carbazole -5- base )-6-( Trifluoromethyl ) Pyridine -2- Formamide 7.20 g (17.5 mmol) of N-[6-(benzyloxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 400 ml of methanol The flask was evacuated and then rinsed with nitrogen (this operation was repeated twice more). 9.29 g (8.73 mmol) of palladium on carbon was added and the flask was evacuated and rinsed with hydrogen. The reaction mixture was hydrogenated at 25 ° C for 3 hours under standard hydrogen pressure. The flask was then evacuated and filled with nitrogen. 5.50 g of ammonium formate was added and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was filtered through celite and concentrated. This gave 499 mg of the title compound. LC-MS (Method A1): R_t = 0.95 min (UV detector: TIC Smooth), mass 322.00 1H NMR (400 MHz, DMSO-d6): δ = 6.98 (s, 1 H), 7.95 (s, 1 H), 8.17 - 8.23 (m , 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.72 (s, 1 H), 10.46 (s, 1 H), 10.76 (br. s., 1 H), 12.63 ( s, 1 H).Intermediate 12-1 N-[6- Hydroxyl -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide step A :840 mg (2.58 mmol) 4-[5-Amino-6-(benzyloxy)-2H-indazol-2-yl]-2-methylbutan-2-ol and 542 mg (2.84 mmol) 6-(Trifluoromethyl)pyridine-2-carboxylic acid was dissolved in 50 ml of THF, and 395 mg (2.58 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 990 mg (5.16 mmol) 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.1 ml of triethylamine and the mixture was stirred at 25 ° C for 2 hours. After concentrating the solution, water was added to the formed precipitate and the precipitate was filtered off with suction, washed with water and diethyl ether and dried under reduced pressure. This gave 1.02 g of N-[6-(benzyloxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine 2-carbamamine. LC-MS (Method A1): R_t = 1.37 min (UV detector: TIC Smooth), mass determined 498.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6H), 1.99 - 2.06 (m, 2H), 4.40 - 4.46 (m , 2H), 4.51 (s, 1H), 5.30 (s, 2H), 7.32 (s, 1H), 7.37 - 7.45 (m, 3H), 7.54 - 7.60 (m, 2H), 8.18 (dd, 1H), 8.33 (s, 1H), 8.38 (t, 1H), 8.46 (d, 1H), 8.77 (s, 1H), 10.46 (s, 1H).step B : 940 mg (1.89 mmol) N-[6-(benzyloxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl) The pyridyl-2-carboxamide was dissolved in 94 ml of methanol, and the flask was evacuated and then flushed with nitrogen (this operation was repeated twice more). 201 mg (0.20 mmol) of palladium on carbon was added and the flask was evacuated and rinsed with hydrogen. The reaction mixture was hydrogenated at 25 ° C for 3 hours under standard hydrogen pressure. The reaction mixture was filtered through celite and washed with methanol, and filtrate was concentrated. This gave 731 mg of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidine. amine. LC-MS (Method A1): R_t = 1.03 min (UV detector: TIC Smooth), mass determined 408.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.93 - 2.04 (m, 2 H), 4.28 - 4.44 (m, 2 H), 4.50 (s, 1 H), 6.93 (s, 1 H), 8.21 (d, 1 H), 8.26 (s, 1 H), 8.40 (t, 1 H), 8.47 (d , 1 H), 8.66 (s, 1 H), 10.53 (s, 1 H), 10.61 (s, 1 H).Intermediate 13-1 {5-[( Third butoxycarbonyl ) Amine ]-6- Hydroxyl -2H- Carbazole -2- base } Ethyl acetate 4.50 g (10.6 mmol) of {6-(benzyloxy)-5-[(t-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (CAS number: 1799835- 24-7) Dissolved in 225 ml of ethanol, and the flask was evacuated and then rinsed with nitrogen (this procedure was repeated twice more). 1.13 g (1.06 mmol) of palladium on carbon was added and the flask was evacuated and rinsed with hydrogen. The reaction mixture was hydrogenated at 25 ° C for 4 hours under standard hydrogen pressure. The reaction mixture was filtered through celite and concentrated. This gave 3.44 g of the title compound. LC-MS (Method A1): R_t = 1.05 min (UV detector: TIC Smooth), mass measurement 335.00 1H NMR (300 MHz, DMSO-d6): δ = 1.21 (t, 3 H), 1.47 (s, 9 H), 4.15 (q, 2 H), 5.24 (s, 2 H), 6.82 (s, 1 H), 7.64 (s, 1 H), 7.93 (s, 1 H), 8.10 - 8.16 (m, 1 H), 10.26 (s, 1 H). Under ExpNo UBOT8758-1Instance 1 1-( Difluoromethyl )-N-[2-(3- Hydroxyl -3- Methyl butyl )-6- Methoxy -2H- Carbazole -5- base ]-1H- Pyrazole -3- Formamide 158 mg (66% pure, 418 μmol) 4-(5-amino-6-methoxy-2H-indazol-2-yl)-2-methylbutan-2-ol (CAS number: 1799835- 12-3), 81.4 mg (502 μmol) 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid, 191 mg (502 μmol) HATU and 87 μl (500 μmol) N,N-diisopropyl The ethylamine was dissolved in 2 ml of THF. The mixture was stirred at 25 ° C for 23 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 95.2 mg of the title compound. LC-MS (Method A2): R_t = 1.01 min (UV detector: TIC Smooth), mass measurement 393.00¹ </ RTI> <RTIgt; 1H), 7.04 (d, 1H), 7.12 (s, 1H), 7.98 (t, 1H), 8.30 (s, 1H), 8.46 (d, 1H), 8.50 (s, 1H), 9.39 (s, 1H) ).Instance 2 N-[2-(3- Hydroxyl -3- Methyl butyl )-6- Methoxy -2H- Carbazole -5- base ]-2-( Trifluoromethyl )-1,3- Oxazole -4- Formamide 158 mg (66% pure, 418 μmol) 4-(5-Amino-6-methoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 90.9 mg (502 μmol) 2-(Trifluoromethyl)-1,3-oxazole-4-carboxylic acid, 191 mg (502 μmol) HATU and 87 μl (500 μmol) N,N-diisopropylethylamine dissolved in 2 ml THF in. The mixture was stirred at 25 ° C for 23 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 133 mg of the title compound. LC-MS (Method A3): R_t = 1.12 min (UV detector: TIC Smooth), mass measurement 412.00¹ </ RTI> <RTIgt; ), 7.13 (s, 1H), 8.32 (s, 1H), 8.44 (s, 1H), 9.23 (s, 1H), 9.41 (s, 1H).Instance 3 6-( Difluoromethyl )-N-[2-(3- Hydroxypropyl )-6- Methoxy -2H- Carbazole -5- base ] Pyridine -2- Formamide 100 mg (0.45 mmol) of 3-(5-amino-6-methoxy-2H-indazol-2-yl)propan-1-ol and 94 mg (0.54 mmol) of 6-(difluoromethyl) Pyridine-2-carboxylic acid was dissolved in 3.0 ml of DMF, and 69 mg (0.45 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 173 mg (0.90 mmol) of 1-(3-dimethylaminopropyl) was added. -3-ethylcarbodiimide hydrochloride and 189 μl (1.36 mmol) of triethylamine and the mixture was stirred at 25 ° C for 27 hours. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC (column: YMC-Triart 5[mu]m 100 x 30 mm). The fractions containing the product are lyophilized. This gave 18 mg of the title compound. LC-MS (Method A1): R_t = 1.02 min (UV detector: TIC Smooth), mass measurement 376.00¹ H NMR (500 MHz, DMSO-d6): δ = 2.04 (five peaks, 2 H), 3.37 - 3.43 (m, 2 H), 4.00 (s, 3 H), 4.40 (t, 2 H), 4.62 (t, 1 H), 7.15 (t, 1 H), 7.14 (s, 1 H), 7.95 - 8.02 (m, 1 H), 8.26 - 8.36 (m, 3 H), 8.69 (s, 1 H) , 10.55 (s, 1 H).Instance 4 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-4-( Trifluoromethyl )-1,3- Thiazole -2- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 90 mg in 2 ml DMF 0.45 mmol) 4-(Trifluoromethyl)-1,3-thiazole-2-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 95 mg (70%) of desired compound. LC-MS (Method A1): R_t = 1.29 min (UV detector: TIC Smooth), mass 442.00 1H-NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6 H) 1.45 (t, 3H) 1.98 – 2.06 (m, 2 H 4.16 – 4.25 (q, 2 H) 4.38 - 4.48 (m, 2 H) 4.52 (s, 1H) 7.14 (s, 1H) 8.33 ( s, 1 H) 8.46 (s, 1 H) 8.90 (s, 1H) ) 9.92 (s, 1H).Instance 5 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-2-( Trifluoromethyl )-1,3- Thiazole -4- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 90 mg in 2 ml DMF 0.45 mmol) 2-(Trifluoromethyl)-1,3-thiazole-4-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 90 mg (67%) of desired compound. LC-MS (Method A1): R_t = 1.27 min (UV detector: TIC Smooth), mass 442.00 1H-NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6 H) 1.47 (t, 3H) 1.98 – 2.05 (m, 2 H 4.15 – 4.24 (q, 2 H) 4.38 - 4.46 (m, 2 H) 4.53 (s, 1H) 7.11 (s, 1H) 8.31 ( s, 1 H) 8.57 (s, 1 H) 8.87 (s, 1H) ) 9.98 (s, 1H).Instance 6 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-2- methyl -1,3- Oxazole -5- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 58 mg (2 mg) in 2 ml DMF 0.45 mmol) 2-methyl-1,3-oxazole-5-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 80 mg (70%) of desired compound. LC-MS (Method A1): R_t = 0.91 min (UV detector: TIC Smooth), mass 372.00 1H-NMR (400MHz, DMSO-d6): δ = 1.14 (s, 6H), 1.43 (t, 3H), 1.98 – 2.05 (m, 2H ), 2.54 (s, 3H), 4.11 - 4.29 (q, 2H), 4.38 - 4.45 (m, 2H), 4.52 (s, 1H), 7.07 (s, 1H), 7.82 ( s, 1H), 8.17 ( s, 1H), 8.29 (s, 1H), 9.21 (s, 1H).Instance 7 1-( Difluoromethyl )-N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-1H- Pyrazole -3- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 74 mg (2 mg) in 2 ml DMF 0.45 mmol) 1-(Difluoromethyl)-1H-pyrazole-3-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 20 mg (16%) of title compound. LC-MS (Method A1): R_t = 1.05 min (UV detector: TIC Smooth), mass 407.00 1H-NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6 H) 1.46 (t, 3H), 1.97 – 2.05 (m, 2 H), 4.16 – 4.25 (q, 2H), 4.37 - 4.45 (m, 2H), 4.52 (s, 1H), 7.03 (m, 1H), 7.10 ( s, 1H), 7.96 (t, 1H), 8.29 (s, 1 H), 8.48 (m, 1H), 8.52 (s, 1H), 9.53 (s, 1H).Instance 8 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-2- methyl -1,3- Thiazole -5- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 65 mg (2 ml) in 2 ml DMF 0.45 mmol) 2-methyl-1,3-thiazole-5-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 70 mg (59%) of desired compound. LC-MS (Method A1): R_t = 1.12 min (UV detector: TIC Smooth), mass measurement 388.00 1H-NMR (400MHz, DMSO-d6): δ = 1.14 (s, 6 H), 1.49 (t, 3 H), 1.96 – 2.06 (m , 2 H), 2.75 (s, 3 H), 4.16 – 4.25 (q, 2 H), 4.36 - 4.45 (m, 2 H), 4.52 (s, 1 H), 7.09 (s, 1 H), 8.29 (m, 2 H), 8.61 (s, 1 H), 10.03 (s, 1 H).Instance 9 2- Cyclopropyl -N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-1,3- Oxazole -4- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 70 mg (2 ml) in 2 ml DMF 0.45 mmol) 2-cyclopropyl-1,3-oxazole-4-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred at RT overnight. Purification by preparative HPLC gave 65 mg (53%) of desired compound. LC-MS (Method A1): R_t = 1.15 min (UV detector: TIC Smooth), mass determined 398.00 1H-NMR (400MHz, DMSO-d6): δ = 1.00 – 1.06 (m, 2 H), 1.11 – 1.18 (m, 8 H), 1.48 (t, 3 H), 1.96 – 2.04 (m, 2 H), 2.17 – 2.26 (m, 1 H), 4.15 – 4.23 (q, 2 H), 4.36 - 4.44 (m, 2 H), 4.52 (s , 1 H), 7.09 (s, 1 H), 8.27 (s, 1 H), 8.54 (s, 1 H), 8.64 (s, 1 H), 9.55 (s, 1 H).Instance 10 6- Amine -N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ] Pyridine -2- Formamide 160 mg (0.6 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 126 mg (4 mg) in 4 ml DMF 0.91 mmol) 6-Aminopyridine-4-carboxylic acid, 127 μl (0.91 mmol) of triethylamine and 347 mg (0.91 mmol) of HATU were stirred at RT overnight. Purification by preparative HPLC gave 100 mg (43%) of desired compound. LC-MS (Method A1): R_t = 0.94 min (UV detector: TIC Smooth), mass 383.00 1H-NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.53 (t, 3 H), 1.96 – 2.06 (m , 2 H), 4.16 – 4.27 (q, 2 H), 4.35 - 4.45 (m, 2 H), 4.51 (s br, 1 H), 6.22 (s br, 2 H), 6.72 (d, 1 H) , 7.08 (s, 1 H), 7.31 (d, 1 H), 7.62 (t, 1 H), 8.26 (s, 1 H), 8.66 (s, 1 H), 10.58 (s, 1 H).Instance 11 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 80 mg (0.3 mmol) of 4-(5-amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 87 mg (1.5 mg) in 1.5 ml DMF 0.45 mmol) 6-(Trifluoromethyl)pyridine-2-carboxylic acid, 63 μl (0.45 mmol) of triethylamine and 174 mg (0.45 mmol) of HATU were stirred overnight at RT. Purification by preparative HPLC gave 100 mg (75%) of title compound. LC-MS (Method A1): R_t = 1.25 min (UV detector: TIC Smooth), mass measurement 436.00 1H-NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.51 (t, 3 H) 1.98 – 2.06 (m, 2 H) 4.16 – 4.25 (q, 2 H), 4.38 - 4.46 (m, 2 H), 4.53 (s, 1 H), 7.12 (s, 1 H), 8.22 (d, 1 H) 8.32 (s, 1 H) 8.37 – 8.49 (m, 2 H), 8.70 (s, 1 H), 10.74 (s, 1 H).Instance 12 N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Baseoxy )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 150 mg (515 μmol) of 4-[5-amino-6-(oxetan-3-yloxy)-2H-indazol-2-yl]-2-methylbutan-2-ol, 118 mg (618 μmol) 6-(trifluoromethyl)pyridine-2-carboxylic acid, 198 mg (618 μmol) 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra Methylurea quinone tetrafluoroborate and 110 μl (620 μmol)N ,N - Diisopropylethylamine was dissolved in 3 ml of THF. The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 117 mg of the title compound. LC-MS (Method A1): R_t = 0.90 min (UV detector: TIC Smooth), mass measurement 464.00¹ </ RTI> <RTIgt; ), 5.10 (t, 2H), 5.50 (five peaks, 1H), 6.82 (s, 1H), 8.23 (dd, 1H), 8.34 (s, 1H), 8.39 - 8.45 (m, 1H), 8.46 - 8.50 (m, 1H), 8.73 (s, 1H), 10.70 (s, 1H).Instance 13 N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Baseoxy )-2H- Carbazole -5- base ]-2-( Trifluoromethyl )-1,3- Thiazole -4- Formamide 80.0 mg (275 μmol) of 4-[5-amino-6-(oxetan-3-yloxy)-2H-indazol-2-yl]-2-methylbutan-2-ol, 65.0 mg (329 μmol) 2-(trifluoromethyl)-1,3-thiazole-4-carboxylic acid, 125 mg (329 μmol) HATU and 57 μl (330 μmol)N ,N -Diisopropylethylamine was dissolved in 2 ml of THF. The mixture was stirred at 25 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative. The combined product fractions were lyophilized. This gave 64.1 mg of the title compound. LC-MS (Method A3): R_t = 0.90 min (UV detector: TIC Smooth), mass measurement 470.00¹ </ RTI> <RTIgt; ), 5.07 (t, 2H), 5.44 - 5.51 (m, 1H), 6.80 (s, 1H), 8.33 (s, 1H), 8.56 (s, 1H), 8.88 (s, 1H), 9.96 (s, 1H).Instance 14 N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Baseoxy )-2H- Carbazole -5- base ]-4-( Trifluoromethyl )-1,3- Thiazole -2- Formamide 80.0 mg (275 μmol) of 4-[5-amino-6-(oxetan-3-yloxy)-2H-indazol-2-yl]-2-methylbutan-2-ol, 65.0 mg (329 μmol) 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid, 125 mg (329 μmol) HATU and 57 μl (330 μmol)N ,N -Diisopropylethylamine was dissolved in 2 ml of THF. The mixture was stirred at 25 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 61 mg of the title compound. LC-MS (Method A3): R_t = 0.95 min (UV detector: TIC Smooth), mass measurement 470.00¹ </ RTI> <RTIgt; ,,,,,,,,,,,,,, 1H).Instance 15 1-( Difluoromethyl )-N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Methoxy )-2H- Carbazole -5- base ]-1H- Pyrazole -3- Formamide 113 mg (63% pure, 233 μmol) 4-[5-amino-6-(oxetan-3-ylmethoxy)-2H-indazol-2-yl]-2-methylbutyl -2-ol, 45.3 mg (280 μmol) 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid, 89.8 mg (280 μmol) 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate and 49 μl (280 μmol)N ,N -Diisopropylethylamine was dissolved in 2 ml of THF. The mixture was stirred at 25 ° C for 67.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 66.5 mg of the title compound. LC-MS (Method A3): R_t = 0.95 min (UV detector: TIC Smooth), mass measurement 449.00¹ H NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6H), 1.97 - 2.07 (m, 2H), 3.46 - 3.66 (m, 1H), 4.33 - 4.47 (m, 4H), 4.53 (s, 1H), 4.58 (t, 2H), 4.78 (dd, 2H), 7.02 (d, 1H), 7.17 (s, 1H), 7.90 (t, 1H), 8.31 (s, 1H), 8.45 (d, 1H) ), 8.50 (s, 1H), 9.58 (s, 1H).Instance 16 6-( Difluoromethyl )-N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Methoxy )-2H- Carbazole -5- base ] Pyridine -2- Formamide 113 mg (63% pure, 233 μmol) 4-[5-amino-6-(oxetan-3-ylmethoxy)-2H-indazol-2-yl]-2-methylbutyl -2-ol, 48.4 mg (280 μmol) 6-(difluoromethyl)-pyridine-2-carboxylic acid, 89.8 mg (280 μmol) 2-(1H-benzotriazol-1-yl)-1,1 , 3,3-tetramethyluronium tetrafluoroborate and 49 μl (280 μmol)N ,N -Diisopropylethylamine was dissolved in 2 ml of THF. The mixture was stirred at 25 ° C for 67.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 66.0 mg of the title compound. LC-MS (Method A3): R_t = 1.07 min (UV detector: TIC Smooth), mass measurement 460.00¹ H NMR (400MHz, DMSO-d6): δ = 1.15 (s, 6H), 1.98 - 2.07 (m, 2H), 3.53 - 3.66 (m, 1H), 4.37 (d, 2H), 4.39 - 4.48 (m, 2H), 4.53 (s, 1H), 4.65 (t, 2H), 4.82 (dd, 2H), 7.12 (t, 1H), 7.19 (s, 1H), 8.00 (dd, 1H), 8.26 - 8.40 (m , 3H), 8.76 (s, 1H), 10.65 (s, 1H).Instance 17 N-{2-(3- Hydroxyl -3- Methyl butyl )-6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-2H- Carbazole -5- base }-2- methyl -1,3- Oxazole -5- Formamide 116 mg (379 μmol) 4-{5-amino-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-2-yl}-2-methylbutan-2-ol 57.8 mg (455 μmol) 2-methyl-1,3-oxazole-5-carboxylic acid, 173 mg (455 μmol) HATU and 79 μl (460 μmol)N ,N - Diisopropylethylamine was dissolved in 2 ml. The mixture was stirred at 25 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was taken up in 2 mL DMF and purified by preparative HPLC. The combined product fractions were lyophilized. This gave 96.9 mg of the title compound. LC-MS (Method A3): R_t = 0.93 min (UV detector: TIC Smooth), mass measurement 414.00¹ </ RTI> <RTIgt; , 3 H), 3.79 - 3.92 (m, 2H), 3.95 - 4.04 (m, 2H), 4.38 - 4.46 (m, 2H), 4.52 (s, 1H), 5.23 (dd, 1H), 7.12 (s, 1H), 8.30 (s, 1H), 8.56 (s, 1H), 8.68 (s, 1H), 9.47 (s, 1H).Instance 18 N-{2-(3- Hydroxyl -3- Methyl butyl )-6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-2H- Carbazole -5- base }-6-( Trifluoromethyl ) Pyridine -2- Formamide 116 mg (379 μmol) 4-{5-amino-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-2-yl}-2-methylbutan-2-ol , 87.0 mg (455 μmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 173 mg (455 μmol) of HATU and 79 μl (460 μmol)N ,N - Diisopropylethylamine was dissolved in 2 ml. The mixture was stirred at 25 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was taken up in 2 mL DMF and purified by preparative HPLC. The combined product fractions were lyophilized. This gave 105 mg of the title compound. LC-MS (Method A3): R_t = 1.14 min (UV detector: TIC Smooth), mass measurement 478.00¹ </ RTI> <RTIgt; (m, 3H), 4.06 (dd, 1H), 4.39 - 4.46 (m, 2H), 4.54 (s, 1H), 7.12 (s, 1H), 8.22 (dd, 1H), 8.33 (s, 1H), 8.38 - 8.49 (m, 2H), 8.73 (s, 1H), 10.63 (s, 1H).Instance 19 6- Amine -N-{2-(3- Hydroxyl -3- Methyl butyl )-6-[(3S)- Tetrahydrofuran -3- Baseoxy ]-2H- Carbazole -5- base } Pyridine -2- Formamide 116 mg (379 μmol) 4-{5-amino-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-2-yl}-2-methylbutan-2-ol 62.9 mg (455 μmol) 6-aminopyridine-2-carboxylic acid, 173 mg (455 μmol) HATU and 79 μl (460 μmol)N ,N - Diisopropylethylamine was dissolved in 2 ml. The mixture was stirred at 25 ° C for 16.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 18.9 mg of the title compound. LC-MS (Method A3): R_t = 0.89 min (UV detector: TIC Smooth), mass measurement 425.00¹ </ RTI> <RTIgt; , 3H), 4.36 - 4.47 (m, 2H), 4.53 (s, 1H), 5.25 (br d, 1H), 6.17 (s, 2H), 6.73 (dd, 1H), 7.12 (s, 1H), 7.31 (dd, 1H), 7.63 (dd, 1H), 8.29 (s, 1H), 8.66 (s, 1H), 10.61 (s, 1H).Instance 20 N-[6- chlorine -2-(3- Methoxy -3- Methyl butyl )-2H- Carbazole -5- base ]-6-(2- Hydroxypropyl -2- base ) Pyridine -2- Formamide 150 mg (20% pure, 112 μmol) of 6-chloro-2-(3-methoxy-3-methylbutyl)-2H-indazole-5-amine, 36.9 mg (168 μmol) 6-( Potassium 2-hydroxyprop-2-yl)pyridine-2-carboxylate (see WO2015091426), 46.9 mg (123 μmol) HATU and 21 μl (120 μmol)N ,N - Diisopropylethylamine was dissolved in 2 ml of DMF. The mixture was stirred at 25 ° C for 17.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 33.5 mg of the title compound. LC-MS (Method A3): R_t = 1.22 min (UV detector: TIC Smooth), mass measurement 430.00¹ H-NMR (400MHz, DMSO-d6): δ = 1.17 (s, 6H), 1.57 (s, 6H), 2.09 - 2.17 (m, 2H), 3.14 (s, 3H), 4.41 - 4.50 (m, 2H ), 5.49 (s, 1H), 7.92 - 7.98 (m, 2H), 8.01 - 8.12 (m, 2H), 8.53 (d, 1H), 8.71 (s, 1H), 10.88 (s, 1H).Instance twenty one N-[6- chlorine -2-(3- Methoxy -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 150 mg (20% pure, 112 μmol) 6-chloro-2-(3-methoxy-3-methylbutyl)-2H-indazole-5-amine, 32.1 mg (168 μmol) 6-( Trifluoromethyl)pyridine-2-carboxylic acid, 46.9 mg (123 μmol) HATU and 21 μl (120 μmol)N ,N - Diisopropylethylamine was dissolved in 2 ml of DMF. The mixture was stirred at 25 ° C for 17.5 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 48 mg of the title compound. LC-MS (Method A3): R_t = 1.43 min (UV detector: TIC Smooth), mass measurement 440.00 1H-NMR (400MHz, DMSO-d6): δ = 1.17 (s, 6H), 2.10 - 2.17 (m, 2H), 3.14 (s, 3H ), 4.43 - 4.50 (m, 2H), 7.93 (s, 1H), 8.24 (dd, 1H), 8.39 - 8.45 (m, 1H), 8.45 - 8.50 (m, 1H), 8.54 (s, 1H), 8.63 (s, 1H), 10.52 (s, 1H).Instance twenty two N-[6- Isopropoxy -2-(2- Methoxyethyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 150 mg (0.41 mmol) N-(6-isopropoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 171 mg (1.24 mmol) Potassium and 34 mg (0.21 mmol) of potassium iodide were suspended in 2.0 ml of DMF, and the mixture was stirred at 25 ° C for 30 minutes. Subsequently, 58 μl (0.62 mmol) of 2-bromoethyl methyl ether was added, and the mixture was stirred at 25 ° C for 16 hours and at 80 ° C for 48 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 41 mg of the title compound. LC-MS (Method A1): R_t = 1.31 min (UV detector: TIC Smooth), mass 422.00 1H NMR (400 MHz, DMSO-d6): δ = 1.41 (d, 6 H), 3.31 (s, 3 H), 3.81 (t, 2 H), 4.50 (t, 2 H), 4.84 (dt, 1 H), 7.19 (s, 1 H), 8.21 (dd, 1 H), 8.28 (s, 1 H), 8.37 - 8.43 (m, 1 H), 8.43 - 8.48 (m, 1 H), 8.72 (s, 1 H), 10.73 (s, 1 H).Instance twenty three N-[6- Isopropoxy -2-(3- Methoxypropyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 150 mg (0.41 mmol) N-(6-isopropoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 170 mg (1.24 mmol) Potassium and 34 mg (0.21 mmol) of potassium iodide were suspended in 2.0 ml of DMF, and the mixture was stirred at 25 ° C for 30 minutes. Subsequently, 69 μl (0.62 mmol) of 1-bromo-3-methoxypropane was added, and the mixture was stirred at 25 ° C for 16 hours and at 80 ° C for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 45 mg of the title compound. LC-MS (Method A1): R_t = 1.35 min (UV detector: TIC Smooth), mass measurement 436.00 1H NMR (400 MHz, DMSO-d6): δ = 1.41 (d, 6 H), 2.12 (five peaks, 2 H), 3.24 (s , 3 H), 3.32 - 3.35 (m, 2 H), 4.39 (t, 2 H), 4.84 (five peaks, 1 H), 7.19 (s, 1 H), 8.21 (dd, 1 H), 8.28 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.72 (s, 1 H), 10.73 (s, 1 H).Instance twenty four 6-( Difluoromethyl )-N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ] Pyridine -2- Formamide Dissolve 150 mg (89% pure, 402 μmol) of 6-(difluoromethyl)-N-(6-ethoxy-1H-indazol-5-yl)pyridine-2-carboxamide in 4 ml DMF Medium and 101 mg (603 μmol) of 4-bromo-2-methylbutan-2-ol, 167 mg (1.21 mmol) of potassium carbonate and 100 mg (603 μmol) of potassium iodide were added under stirring. The suspension was stirred at 120 ° C for 6 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 36.6 mg of the title compound. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass measurement 418.00¹ </ RTI> <RTIgt; 2H), 4.50 (s, 1H), 6.93 - 7.27 (m, 2H), 7.98 (dd, 1H), 8.27 - 8.36 (m, 3H), 8.69 (s, 1H), 10.78 (s, 1H).Instance 25 N-[6-( Cyclopropylmethoxy )-2-(3- Methoxypropyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 200 mg (0.53 mmol) N-[6-(cyclopropylmethoxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide, 220 mg ( 1.59 mmol) potassium carbonate and a spatula potassium iodide were suspended in 3.0 ml of DMF, and the mixture was stirred at 25 ° C for 30 minutes. Subsequently, 89 μl (0.80 mmol) of 1-bromo-3-methoxypropane was added, and the mixture was stirred at 25 ° C for 72 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 25 mg of the title compound. LC-MS (Method A1): R_t = 1.37 min (UV detector: TIC Smooth), mass measurement 448.00¹ H-NMR (400 MHz, DMSO-d6): δ = 0.41 - 0.47 (m, 2 H), 0.60 - 0.69 (m, 2 H), 1.30 - 1.40 (m, 1 H), 2.12 (five peaks, 2 H), 3.24 (s, 3 H), 3.30 (t, 2 H), 4.02 (d, 2 H), 4.38 (t, 2 H), 7.09 (s, 1 H), 8.21 (dd, 1 H ), 8.28 (s, 1 H), 8.41 (t, 1 H), 8.47 (d, 1 H), 8.74 (s, 1 H), 10.69 (s, 1 H).Instance 26 N-[6-( Cyclopropylmethoxy )-2-(2- Methoxyethyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 280 mg (0.74 mmol) N-[6-(cyclopropylmethoxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide, 308 mg ( 2.23 mmol) potassium carbonate and 148 mg (0.89 mmol) of potassium iodide were suspended in 5.0 ml of DMF, and the mixture was stirred at 25 ° C for 30 minutes. Subsequently, 105 μl (1.12 mmol) of 2-bromomethyl methyl ether was added, and the mixture was stirred at 25 ° C for 72 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 50 mg of the title compound. LC-MS (Method A1): R_t = 1.33 min (UV detector: TIC Smooth), mass 434.00 1H NMR (400 MHz, DMSO-d6): δ = 0.39 - 0.47 (m, 2 H), 0.63 - 0.69 (m, 2 H), 1.29 - 1.40 (m, 1 H), 3.23 (s, 3 H), 3.80 (t, 2 H), 4.02 (d, 2 H), 4.49 (t, 2 H), 7.08 (s, 1 H), 8.21 (dd, 1 H), 8.26 - 8.29 (m, 1 H), 8.38 - 8.44 (m, 1 H), 8.45 - 8.50 (m, 1 H), 8.74 (s, 1 H), 10.70 (s, 1 H).Instance 27 N-[6-( Cyclopropylmethoxy )-2-( Oxetane -3- Methyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 200 mg (0.53 mmol) N-[6-(cyclopropylmethoxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide, 220 mg ( 1.59 mmol) potassium carbonate and a spatula potassium iodide were suspended in 3.0 ml of DMF, and the mixture was stirred at 25 ° C for 30 minutes. Subsequently, 120 mg (0.80 mmol) of 3-bromomethyloxetane was added, and the mixture was stirred at 25 ° C for 72 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC according to Method P4. Freeze dry product fractions. Method P2 was used by preparative HPLC (column: YMC Triart C18 5 μm 100×30 mm, gradient: 0–0.5 min 25 ml/min to 70 ml/min 52% B; 0.5-5.5 min 52-61% B; Flow rate: 70 ml/min) The lyophilizate was repurified. Freeze dry product fractions. This gave 14 mg of the title compound. LC-MS (Method A1): R_t =1.28 min (UV detector: TIC Smooth), mass measurement 446.00 1H NMR (400 MHz, DMSO-d6): δ = 0.38 - 0.47 (m, 2 H), 0.59 - 0.70 (m, 2 H), 1.29 - 1.40 (m, 1 H), 3.44 - 3.58 (m, 1 H), 4.02 (d, 2 H), 4.47 (t, 2 H), 4.62 - 4.70 (m, 4 H), 7.08 (s, 1 H), 8.18 - 8.24 (m, 1 H), 8.33 (s, 1 H), 8.37 - 8.45 (m, 1 H), 8.45 - 8.50 (m, 1 H), 8.73 (s, 1 H), 10.69 (s, 1 H).Instance 28 N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Trifluoromethoxy )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 406 mg (94% pure, 978 μmol) of N-[6-(trifluoromethoxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 245 mg (1.47 mmol) of 4-bromo-2-methylbutan-2-ol, 405 mg (2.93 mmol) of potassium carbonate and 244 mg (1.47 mmol) of potassium iodide were added in 5 ml of DMF with stirring. The suspension was stirred at 120 ° C for 19 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 19 mg of the title compound. LC-MS (Method A1): R_t = 1.33 min (UV detector: TIC Smooth), mass measurement 476.00¹ </ RTI> <RTIgt; ), 8.39 - 8.43 (m, 1H), 8.46 (t, 1H), 8.56 (s, 1H), 8.69 (s, 1H), 10.38 (s, 1H).Instance 29 2- Cyclopropyl -N-[6- Methoxy -2-(3- Methoxypropyl )-2H- Carbazole -5- base ]-1,3- Oxazole -4- Formamide Dissolve 378 mg (0.63 mmol) of 2-cyclopropyl-N-(6-methoxy-1H-indazol-5-yl)-1,3-oxazol-4-carboxamide in 4 ml of DMF And, under stirring, 108 μl (0.95 mmol) of 1-bromo-3-methoxypropane, 263 mg (1.90 mmol) of potassium carbonate and 158 mg (0.95 mmol) of potassium iodide were added. The reaction mixture was stirred at 100 ° C for 23 hours. Subsequently, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 36 mg of the title compound. LC-MS (Method A4): R_t = 1.12 min (UV detector: TIC Smooth), mass measurement 370.00¹ </ RTI> <RTIgt; (s, 3H), 3.27 - 3.30 (m, 2H), 3.97 (s, 3H), 4.38 (t, 2H), 7.11 (s, 1H), 8.24 (s, 1H), 8.54 (s, 1H), 8.60 (s, 1H), 9.34 (s, 1H).Instance 30 N-[6- chlorine -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Difluoromethyl ) Pyridine -2- Formamide 3.15 g (51% pure, 4.98 mmol) of N-(6-chloro-1H-indazol-5-yl)-6-(difluoromethyl)pyridine-2-carboxamide was dissolved in 20 ml of DMF. 1.25 g (7.47 mmol) of 4-bromo-2-methylbutan-2-ol, 2.06 g (14.9 mmol) of potassium carbonate and 1.24 g (7.47 mmol) of potassium iodide were added with stirring. The suspension was stirred at 120 ° C for 16.5 hours. Another 1.03 mg (7.5 mmol) potassium carbonate and 620 mg (3.8 mmol) potassium iodide were added, and the mixture was stirred at 120 ° C for additional 24 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (Biotage EtOAc EtOAc (EtOAc) The combined product fractions are concentrated. The solid was filtered off with suction, washed three times with diethyl ether and dried. The filtrate was concentrated and the residue was purified by preparative. The combined product fractions were lyophilized. This gave a total of 314 mg of the title compound. LC-MS (Method A1): R_t = 1.17 min (UV detector: TIC Smooth), mass measurement 408.00¹ </ RTI> <RTIgt; ), 8.03 (dd, 1H), 8.29 - 8.40 (m, 2H), 8.52 (s, 1H), 8.63 (s, 1H), 10.59 (s, 1H).Instance 31 N-[2-(2- Hydroxyethyl )-6- Isopropoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:Dissolve 200 mg (0.55 mmol) of N-(6-isopropoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 2 ml of DMF and 228 mg (1.65 mmol) potassium carbonate and 46 mg (0.27 mmol) potassium iodide were added with stirring. The suspension was stirred at 25 ° C for 30 minutes, and then 177 μl (0.82 mmol) of (2-bromoethoxy)(t-butyl)dimethyl decane was added. The reaction mixture was stirred at 25 ° C for 16 hours and at 80 ° C for 4 hours. The reaction mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by flash chromatography (EtOAc EtOAc: EtOAc (EtOAc) This gave 56 mg of N-[2-(2-{[t-butyl(dimethyl)indolyl]oxy}ethyl)-6-isopropoxy-2H-indazol-5-yl]- 6-(Trifluoromethyl)pyridine-2-carbamide. LC-MS (Method A1): R_t = 1.71 min (UV detector: TIC Smooth), mass 522.00 1H NMR (400 MHz, DMSO-d6): δ = -0.13 - -0.10 (m, 6 H), 0.76 - 0.79 (m, 9 H) , 1.41 (d, 6 H), 4.03 (t, 2 H), 4.42 (t, 2 H), 4.84 (dt, 1 H), 7.19 (s, 1 H), 8.21 (dd, 1 H), 8.25 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.72 (s, 1 H), 10.73 (s, 1 H). Step B:53 mg (0.10 mmol) N-[2-(2-{[T-butyl(dimethyl)indenyl]oxy}ethyl)-6-isopropoxy-2H-indazole-5- The benzyl-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 0.5 ml of THF and mixed with a solution of 304 μl (0.30 mmol) of tetrabutylammonium fluoride in THF in 1 M. The reaction mixture was stirred at 25 ° C for 2 hours and added to 10 ml of water, and the formed precipitate was filtered off with suction, washed with water and diethyl ether and dried under reduced pressure. This gave 29 mg of N-[2-(2-hydroxyethyl)-6-isopropoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass determined 408.00 1H NMR (400 MHz, DMSO-d6): δ = 1.41 (d, 6 H), 3.85 (q, 2 H), 4.38 (t, 2 H), 4.84 (dt, 1 H), 4.94 (t, 1 H), 7.18 (s, 1 H), 8.21 (dd, 1 H), 8.27 (s, 1 H), 8.40 (t, 1 H) , 8.46 (d, 1 H), 8.73 (s, 1 H), 10.73 (s, 1 H).Instance 32 N-[2-(3- Hydroxypropyl )-6- Isopropoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:Dissolve 200 mg (0.55 mmol) of N-(6-isopropoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 2 ml of DMF and 228 mg (1.65 mmol) potassium carbonate and 46 mg (0.27 mmol) potassium iodide were added with stirring. The suspension was stirred at 25 ° C for 30 minutes, and then 191 μl (0.82 mmol) of (3-bromopropoxy) (t-butyl) dimethyl decane was added. The reaction mixture was stirred at 25 ° C for 16 hours and at 80 ° C for 48 hours. The reaction mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by flash chromatography (EtOAc EtOAc: EtOAc (EtOAc) The crude product obtained was purified by preparative HPLC. This gave 59 mg of N-[2-(3-{[t-butyl(dimethyl)indenyl]oxy}propyl)-6-isopropoxy-2H-indazol-5-yl]- 6-(Trifluoromethyl)pyridine-2-carbamide. LC-MS (Method A1): R_t = 1.75 min (UV detector: TIC Smooth), mass determined 536.00 1H NMR (400 MHz, DMSO-d6): δ = 0.03 (s, 6 H), 0.87 (s, 9 H), 1.41 (d, 6 H), 2.09 (five peaks, 2 H), 3.60 (t, 2 H), 4.40 (t, 2 H), 4.84 (five peaks, 1 H), 7.18 (s, 1 H), 8.21 (dd , 1 H), 8.26 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.72 (s, 1 H), 10.73 (s, 1 H). Step B:59 mg (0.11 mmol) N-[2-(3-{[T-butyl(dimethyl)indenyl]oxy}propyl)-6-isopropoxy-2H-indazole-5- The group]-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 0.5 ml of THF and mixed with 330 μl (0.33 mmol) of tetrabutylammonium fluoride in 1 M solution in THF. The reaction mixture was stirred at 25 ° C for 90 minutes and added to 10 ml of water, and the formed precipitate was filtered off with suction, washed with water and diethyl ether and dried under reduced pressure. This gave 15 mg of N-[2-(3-hydroxypropyl)-6-isopropoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ = 1.41 (d, 6 H), 1.99 - 2.09 (m, 2 H), 3.41 (q, 2 H), 4.40 (t, 2 H), 4.62 (t , 1 H), 4.79 - 4.88 (m, 1 H), 7.18 (s, 1 H), 8.21 (dd, 1 H), 8.28 (s, 1 H), 8.40 (t, 1 H), 8.46 (d , 1 H), 8.72 (s, 1 H), 10.73 (s, 1 H).Instance 33 N-2-(3- Hydroxyl -3- Methyl butyl )-6-[3-( Methylsulfonyl ) Propoxy ]-2H- Carbazole -5- base -6-( Trifluoromethyl ) Pyridine -2- Formamide 50 mg (0.12 mmol) of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 - Methionine was dissolved in 735 μl of DMF and 33 mg (0.24 mmol) of potassium carbonate and 29 mg (0.15 mmol) of 1-bromo-3-(methylsulfonyl)propane were added with stirring. The reaction mixture was stirred in a microwave at 100 ° C for 60 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was dissolved in 2 mL EtOAc and purified by preparative HPLC. Freeze dry product fractions. This gave 46 mg of the title compound. LC-MS (Method A1): R_t = 1.04 min (UV detector: TIC Smooth), mass determined 528.00 1H NMR (300 MHz, DMSO-d6): δ = -1.15 (s, 6 H), 1.95 - 2.07 (m, 2 H), 2.23 - 2.37 (m, 2 H), 3.01 (s, 3 H), 3.34 - 3.40 (m, 2 H), 4.30 (t, 2 H), 4.37 - 4.46 (m, 2 H), 4.51 (s, 1 H ), 7.13 (s, 1 H), 8.22 (d, 1 H), 8.33 (s, 1 H), 8.41 (t, 1 H), 8.47 (d, 1 H), 8.71 (s, 1 H), 10.55 (s, 1 H).Instance 34 N-{2-(3- Hydroxyl -3- Methyl butyl )-6-[2-( Methylthio ) Ethoxy ]-2H- Carbazole -5- base }-6-( Trifluoromethyl ) Pyridine -2- Formamide 50 mg (0.12 mmol) of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 - Promethamine was dissolved in 1 ml of DMF and 33 mg (0.24 mmol) of potassium carbonate and 23 mg (0.15 mmol) of 2-bromoethylmethyl sulfide were added with stirring. The reaction mixture was stirred in a microwave at 100 ° C for 60 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 32 mg of the title compound. LC-MS (Method A1): R_t = 1.26 min (UV detector: TIC Smooth), mass 482.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.97 - 2.06 (m, 2 H), 2.15 (s , 3 H), 2.98 (t, 2 H), 4.35 (t, 2 H), 4.39 - 4.46 (m, 2 H), 4.51 (s, 1 H), 7.19 (s, 1 H), 8.22 (dd , 1 H), 8.32 (s, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.71 (s, 1 H), 10.60 (s, 1 H).Instance 35 {[2-(3- Hydroxyl -3- Methyl butyl )-5-({[6-( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine )-2H- Carbazole -6- base ] Oxyl } Ethyl acetate 170 mg (0.42 mmol) of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 - Methionine was dissolved in 2.5 ml of DMF and 115 mg (0.83 mmol) of potassium carbonate and 56 μl (0.50 mmol) of ethyl bromoacetate were added with stirring. The reaction mixture was stirred in a microwave at 100 ° C for 60 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 143 mg of the title compound. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass 494.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.21 (t, 3 H), 1.95 - 2.05 (m , 2 H), 4.20 (q, 2 H), 4.39 - 4.46 (m, 2 H), 4.50 (s, 1 H), 5.00 (s, 2 H), 7.18 (s, 1 H), 8.21 (dd , 1 H), 8.34 (s, 1 H), 8.40 (t, 1 H), 8.48 (d, 1 H), 8.72 (s, 1 H), 10.54 (s, 1 H).Instance 36 N-[2-(3- Hydroxyl -3- Methyl butyl )-6-( Oxetane -3- Methoxy )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 75 mg (0.18 mmol) of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 - Methionine was dissolved in 1.1 ml of DMF and 50 mg (0.37 mmol) of potassium carbonate and 42 mg (0.28 mmol) of 3-(bromomethyl)oxetane were added with stirring. The reaction mixture was stirred in a microwave at 100 ° C for 60 minutes. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 50 mg of the title compound. LC-MS (Method A1): R_t = 1.12 min (UV detector: TIC Smooth), mass determined 478.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.98 - 2.06 (m, 2 H), 3.43 - 3.54 (m, 1 H), 4.33 - 4.56 (m), 4.79 (dd, 2 H), 7.20 (s, 1 H), 8.21 (dd, 1 H), 8.32 (s, 1 H), 8.36 - 8.44 ( m, 1 H), 8.44 - 8.48 (m, 1 H), 8.72 (s, 1 H), 10.44 (s, 1 H).Instance 37 N-[6-( Cyclopropylmethoxy )-2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 68 mg (0.17 mmol) of N-[6-hydroxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 - Promethamine was dissolved in 1 ml of DMF and 46 mg (0.33 mmol) of potassium carbonate and 19 μl (0.20 mmol) of (bromomethyl)cyclopropane were added with stirring. The suspension was stirred in a microwave at 100 ° C for 60 minutes, and then 431 μl (4.65 mmol) of (bromomethyl)cyclopropane was added. The reaction mixture was stirred at 25 ° C for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. Freeze dry product fractions. This gave 45 mg of the title compound. LC-MS (Method A1): R_t = 1.33 min (UV detector: TIC Smooth), mass 462.00 1H NMR (400 MHz, DMSO-d6): δ = 0.39 - 0.47 (m, 2 H), 0.62 - 0.69 (m, 2 H), 1.15 (s, 6 H), 1.29 - 1.39 (m, 1 H), 1.98 - 2.04 (m, 2 H), 4.02 (d, 2 H), 4.38 - 4.45 (m, 2 H), 4.49 (s, 1 H), 7.07 (s, 1 H), 8.21 (dd, 1 H), 8.30 (s, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.73 (s, 1 H) , 10.69 (s, 1 H).Instance 38 N-[6-( Cyclopropylmethoxy )-2-(3- Hydroxypropyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:280 mg (0.74 mmol) of N-[6-(cyclopropylmethoxy)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-methyl in 4.2 ml DMF Indoleamine, 308 mg (2.23 mmol) of potassium carbonate and a spatula of potassium iodide were stirred at 25 ° C for 30 minutes. Subsequently, 253 μl (1.49 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran was added, and the mixture was stirred at 25 ° C for 72 hours. The reaction mixture was partitioned between ethyl acetate and water. Separate the phases. The organic phase was washed twice with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. This gave 91 mg of N-{6-(cyclopropylmethoxy)-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2H-indazol-5-yl }-6-(Trifluoromethyl)pyridine-2-carbamide. LC-MS (Method A1): R_t = 1.47 min (UV detector: TIC Smooth), mass determined 518.00 1H NMR (400 MHz, DMSO-d6, selected signal): δ = 0.40 - 0.48 (m, 2 H), 0.61 - 0.69 (m, 2 H), 1.30 - 1.39 (m, 1 H), 1.39 - 1.54 (m, 4 H), 1.56 - 1.67 (m, 1 H), 1.67 - 1.79 (m, 1 H), 2.15 (五重峰, 2 H), 3.36 - 3.44 (m, 1 H), 3.63 (dt, 1 H), 3.73 (ddd, 1 H), 3.98 - 4.07 (m, 2 H), 4.42 (t, 2 H), 4.53 (t , 1 H), 7.08 (s, 1 H), 8.17 - 8.24 (m, 1 H), 8.29 (s, 1 H), 8.41 (t, 1 H), 8.47 (d, 1 H), 8.74 (s , 1 H), 10.69 (s, 1 H). Step B:88 mg (0.17 mmol) N-{6-(cyclopropylmethoxy)-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2H-carbazole- 5-Base}-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 1.1 ml of dichloromethane, and 96 mg (0.51 mmol) of p-toluenesulfonic acid was added. The reaction mixture was stirred at 25 ° C for 19 hours. Saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. This gave 46 mg of N-[6-(cyclopropylmethoxy)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- Formamide. LC-MS (Method A1): R_t = 1.22 min (UV detector: TIC Smooth), mass 434.00 1H NMR (400 MHz, DMSO-d6): δ = 0.39 - 0.47 (m, 2 H), 0.62 - 0.70 (m, 2 H), 1.29 - 1.41 (m, 1 H), 2.03 (five peaks, 2 H), 3.36 - 3.42 (m, 2 H), 4.02 (d, 2 H), 4.39 (t, 2 H), 4.63 (t, 1 H), 7.08 (s, 1 H), 8.22 (dd, 1 H), 8.28 (s, 1 H), 8.41 (t, 1 H), 8.48 (d, 1 H), 8.74 (s, 1 H) , 10.70 (s, 1 H).Instance 39 N-[6- Methoxy -2-(3- Oxidyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:2.50 g (7.4 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (CAS number: 1799836-45-5) Dissolved in 15 ml of DMF and added 1.63 ml (11.9 mmol) of 2-(2-bromoethyl)-2-methyl-1,3-dioxolane, 3.08 g (22.3 mmol) of carbonic acid with stirring. Potassium and 1.85 g (11.2 mmol) of potassium iodide. The reaction mixture was stirred at 100 ° C for 21 hours. Subsequently, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, the phases separated, filtered and concentrated with a pad. Ethyl acetate was added to the residue and the solid formed was filtered. The filtrate was concentrated and purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). This gave 860 mg of N-{6-methoxy-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2H-indazol-5-yl} -6-(Trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.20 min (UV detector: TIC Smooth), mass measurement 450.00. Step B:855 mg (1.37 mmol) N-{6-methoxy-2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-2H-indazole-5 -yl}-6-(trifluoromethyl)pyridine-2-carboxamide dissolved in 20 ml of dichloromethane, adding 520 mg (2.73 mmol) of p-toluenesulfonic acid monohydrate and stirring the mixture at 25 ° C 67 hours. Another 260 mg (1.36 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 25 ° C for 24 hours. The solid formed was filtered off and washed three times with dichloromethane. A saturated sodium bicarbonate solution was added and the reaction mixture was stirred briefly. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with a saturated sodium chloride solution, filtered (hydrophobic filter) and concentrated. Ethyl acetate was added to the residue and the mixture was stirred briefly. The solid was filtered off with suction and washed three times with ethyl acetate and dried. This gave 392 mg of N-[6-methoxy-2-(3-o-oxybutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide . LC-MS (Method A1): R_t = 1.13 min (UV detector: TIC Smooth), mass measurement 406.00¹ H NMR (400 MHz, DMSO-d6): δ = 2.14 (s, 3 H), 3.15 (t, 2 H), 3.98 (s, 3 H), 4.54 (t, 2 H), 7.13 (s, 1 H), 8.21 (dd, 1 H), 8.28 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.67 (s, 1 H), 10.49 (s, 1 H) .Instance 40 N-[2-(2- Hydroxyethyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:7.00 g (20.8 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 6.60 ml (41.6 mmol) of bromoacetic acid A mixture of benzyl ester and 8.83 ml (41.6 mmol) of N,N-dicyclohexylmethylamine in 100 ml of THF was heated to 70 ° C for 5 hours. Another 3.30 ml (20.8 mmol) of benzyl bromoacetate and 4.42 ml (20.8 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 65 ° C for 20 hours. The precipitated solid was filtered, washed twice with ethyl acetate, washed three times with water and th The filtrate of the reaction mixture was concentrated, ethyl acetate was added and the mixture was stirred for 15 min. The solid was filtered off with suction and washed twice with ethyl acetate and dried. The two batches of solids were combined. This gave 7.08 g of solid [6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid benzyl ester. LC-MS (Method A1): R_t = 1.37 min (UV detector: TIC Smooth), mass measurement 484.00¹ H NMR (400 MHz, DMSO-d6): δ = 3.99 (s, 3 H), 5.21. (s, 2 H), 5.41 (s, 2 H), 7.14 (s, 1 H), 7.31 - 7.42 (m , 5 H), 8.22 (dd, 1 H), 8.35 (s, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.72 (s, 1 H), 10.51 (s, 1 H). Step B:7.08 g (14.6 mmol) of [6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]benzyl acetate The base ester was dissolved in 110 ml of THF/ethanol (10:1), and a total of 553 mg (14.6 mmol) of sodium borohydride was added a little at a time. The mixture was stirred at 25 ° C for 48 hours. Water was added to the reaction mixture and the aqueous phase was extracted once with ethyl acetate. The solid was filtered off with suction and washed twice with ethyl acetate. The filtrate phase was separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and concentrated. The crude product and the solid which had been filtered were combined, 60 ml diethyl ether was added and the mixture was stirred for 20 min. The solid was filtered off with suction, washed three times with diethyl ether and dried. This gave 4.56 g of N-[2-(2-hydroxyethyl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.07 min (UV detector: TIC Smooth), mass measurement 380.00¹ H NMR (400 MHz, DMSO-d6): δ = 3.85 (q, 2 H), 3.98 (s, 3 H), 4.38 (t, 2 H), 4.99 (t, 1 H), 7.14 (s, 1 H), 8.19 - 8.23 (m, 1 H), 8.28 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.69 (s, 1 H), 10.50 (s, 1 H).Instance 41 Under ExpNo UBOT8717-1, BAY 1752003N-[2-(3- Hydroxypropyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:200 mg (0.60 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (CAS number: 1799836-45-5) Dissolved in 4 ml of DMF and added 151 μl (0.89 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran, 247 mg (1.78 mmol) of potassium carbonate and 118 mg (0.71) with stirring. Methyl) potassium iodide. The reaction mixture was stirred at 100 ° C for 19 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was dissolved in 2 mL of dimethyl hydrazine and purified by preparative HPLC. This gave 50 mg of N-{6-methoxy-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2H-indazol-5-yl}-6-( Trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.46 min (UV detector: TIC Smooth), mass measurement 478.00. Step B:50 mg (0.10 mmol) of N-{6-methoxy-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2H-indazol-5-yl}- 6-(Trifluoromethyl)pyridine-2-carboxamide was dissolved in 4 ml of dichloromethane, 10 mg (0.05 mmol) of p-toluenesulfonic acid monohydrate was added and the mixture was stirred at 25 ° C for 72 hours. Another 50 mg (0.25 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 25 ° C for 72 hours. The reaction mixture was mixed with a saturated sodium hydrogencarbonate solution and extracted thrice with ethyl acetate. The organic phase was combined by filtration (hydrophobic filter) and concentrated. The residue was dissolved in 2.5 mL of dimethyl hydrazine and purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 30 mg of N-[2-(3-hydroxypropyl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass measurement 394.00¹ </ RTI> <RTIgt; 7.14 (s, 1H), 8.20 (dd, 1H), 8.28 (s, 1H), 8.37 - 8.43 (m, 1H), 8.44 - 8.49 (m, 1H), 8.69 (s, 1H), 10.50 (s, 1H).Instance 42 N-{2-[(2S)-2,3- Dihydroxypropyl ]-6- Methoxy -2H- Carbazole -5- base }-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:Dissolve 200 mg (595 μmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 5 ml of DMF and Add 120 μl (890 μmol) of (4R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, 247 mg (0.89 mmol) potassium carbonate and 148 mg (with stirring) 892 μmol) potassium iodide. The suspension was stirred at 120 ° C for 21 hours. Another 124 mg (4.85 mmol) potassium carbonate and 74 mg (446 μmol) potassium iodide were added, and the mixture was stirred at 120 ° C for an additional 23 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was taken up in 3 mL of dimethyl hydrazine and purified by preparative HPLC. This gave 81 mg of N-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-6-methoxy-2H-carbazole -5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.27 min (UV detector: TIC Smooth), mass measurement 450.00. Step B:First, 81.3 mg (180 μmol) of N-(2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl} was charged in 4 ml of dichloromethane. -6-Methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide. 51.5 mg (271 μmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 25 ° C for 19 hours. A saturated sodium bicarbonate solution was added to the reaction mixture, and the solid formed was filtered off with suction and washed three times with water and three times with diethyl ether. The solid was dried under reduced pressure. This gave 66.3 mg of N-{2-[(2S)-2,3-dihydroxypropyl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine- 2-Protonamine. LC-MS (Method A1): R_t = 1.02 min (UV detector: TIC Smooth), mass measurement 410.00¹ </ RTI> <RTIgt; ), 8.20 (dd, 1H), 8.24 (s, 1H), 8.36 - 8.43 (m, 1H), 8.44 - 8.48 (m, 1H), 8.68 (s, 1H), 10.49 (s, 1H).Instance 43 6-( Difluoromethyl )-N-[2-(2- Hydroxyethyl )-6- Methoxy -2H- Carbazole -5- base ] Pyridine -2- Formamide Step A:400 mg (1.29 mmol) of (5-amino-6-methoxy-2H-indazol-2-yl)acetic acid benzyl ester (CAS number: 1799835-89-4) and 245 mg (1.41 mmol) 6 -(Difluoromethyl)pyridine-2-carboxylic acid was dissolved in 10 ml of THF, and 197 mg (1.29 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 493 mg (2.57 mmol) was added at 25 °C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 537 μl (3.85 mmol) of triethylamine. After aqueous work-up, filtration and concentration, the residue was taken in diethyl ether and a little water and allowed to stir for 30 min. The solid was filtered off with suction, washed with diethyl ether and dried. This gave 401 mg of benzyl 5-[{-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetate. LC-MS (Method A1): R_t = 1.29 min (UV detector: TIC Smooth), mass measurement 466.00. Step B:128 mg (0.27 mmol) of [5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]benzyl acetate The base ester was dissolved in 4.2 ml of THF/methanol (10:1) and 10 mg (0.27 mmol) of sodium borohydride was added. The mixture was stirred at 25 ° C for 21 hours. Water was added to the reaction mixture and the resulting solid was filtered with suction and washed three times with water and three times with diethyl ether. The crude product was dissolved in 2.5 mL of dimethyl hydrazine and purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 37 mg of 6-(difluoromethyl)-N-[2-(2-hydroxyethyl)-6-methoxy-2H-indazol-5-yl]pyridine-2-carboxamide. LC-MS (Method A1): R_t = 0.98 min (UV detector: TIC Smooth), mass measurement 362.00¹ H NMR (400 MHz, DMSO-d6): δ = 3.85 (q, 2 H), 4.00 (s, 3 H), 4.38 (t, 2 H), 4.95 (t, 1 H), 7.15 (t, 1 H), 7.15 (d, 1 H), 7.94 - 8.02 (m, 1 H), 8.25 - 8.37 (m, 3 H), 8.69 (s, 1 H), 10.55 (s, 1 H).Instance 44 N-[6- chlorine -2-(2- Hydroxy ethane base )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:2.50 g (7.4 mmol) N-(6-chloro-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide, 75 ml THF, 2.33 ml (14.7 mmol) A mixture of benzyl bromoacetate and 3.11 ml (14.7 mmol) of N,N-dicyclohexylmethylamine was stirred at 65 ° C for 27 hours. 2.33 ml (14.7 mmol) of benzyl bromoacetate and 3.11 ml (14.7 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 65 ° C for 67 hours. The precipitated solid was filtered off and the filtrate was extracted twice with ethyl acetate. The combined organic phases were washed with aq. EtOAc EtOAc EtOAc. The residue was purified by flash chromatography (Biotage SNAP cartridge (100 g; KP-Sil), mobile phase: hexane/ethyl acetate). The crude product was then purified by preparative HPLC. This gave 1.08 g of [6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid benzyl ester. LC-MS (Method A1): R_t = 1.46 min (UV detector: TIC Smooth), mass measurement 488.00¹ H NMR (400 MHz, DMSO-d6): δ = 5.22 (s, 2 H), 5.53 (s, 2 H), 7.33 - 7.41 (m, 5 H), 7.95 (s, 1 H), 8.24 (dd , 1 H), 8.42 (d, 1 H), 8.45 - 8.49 (m, 1 H), 8.53 - 8.55 (m, 1 H), 8.66 (s, 1 H), 10.53 (s, 1 H). Step B:185 mg (0.38 mmol) of [6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid benzyl ester Dissolved in 5 ml of THF and added 14 mg (0.38 mmol) of sodium borohydride. The mixture was stirred at 25 ° C for 21.5 hours. Then 500 μl of methanol was added using a pipette, and the mixture was stirred at 25 ° C for 5 hours. Water is added to the reaction mixture. The solid was filtered off with suction, washed twice with water and three portions with diethyl ether and dried under reduced pressure. This gave 144 mg of N-[6-chloro-2-(2-hydroxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. LC-MS (Method A1): R_t = 1.16 min (UV detector: TIC Smooth), mass measurement 384.00¹ </ RTI> <RTIgt; 8.44 (m, 1H), 8.45 - 8.50 (m, 2H), 8.65 (s, 1H), 10.52 (s, 1H).Instance 45 N-{6- chlorine -2-[(2R)-2,3- Dihydroxypropyl ]-2H- Carbazole -5- base }-6-( Trifluoromethyl ) Pyridine -2- Formamide Step A:Dissolve 300 mg (881 μmol) of N-(6-chloro-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 4 ml of DMF with stirring Add 180 μl (1.3 mmol) of (4S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane, 365 mg (2.64 mmol) potassium carbonate and 219 mg (1.32 mmol) ) Potassium iodide. The suspension was stirred at 120 ° C for 17 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. This gave 67.3 mg of N-(6-chloro-2-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2H-indazole-5 -yl)-6-(trifluoromethyl)pyridine-2-carbamide. LC-MS (Method A1): R_t = 1.37 min (UV detector: TIC Smooth), mass measurement 454.00. Step B:67.3 mg (148 μmol) of N-(6-chloro-2-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2H-indole Zyrid-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide was dissolved in 3 ml of dichloromethane, 42.2 mg (222 μmol) of p-toluenesulfonic acid monohydrate was added and the mixture was at 25 Stir at ° C for 24 hours. A saturated sodium bicarbonate solution was added and the reaction mixture was stirred briefly. The solid was filtered off with suction, washed three times with water and three times with diethyl ether and dried overnight. This gave 57 mg of N-{6-chloro-2-[(2R)-2,3-dihydroxypropyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2- Formamide. LC-MS (Method A1): R_t = 1.07 min (UV detector: TIC Smooth), mass measurement 414.00¹ </ RTI> <RTIgt; , 5.10 (br s, 1H), 7.92 (s, 1H), 8.23 (dd, 1H), 8.36 - 8.51 (m, 3H), 8.62 (s, 1H), 10.51 (s, 1H).Instance 46 N-[2-(3- Hydroxyl -3- Methyl butyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 150 mg (446 μmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 4 ml of DMF and 112 mg (669 μmol) of 4-bromo-2-methylbutan-2-ol, 185 mg (1.34 mmol) of potassium carbonate and 111 mg (669 μmol) of potassium iodide were added with stirring. The suspension was stirred at 120 ° C for 5.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was taken up in 2 mL of dimethyl hydrazine and purified by preparative HPLC. The combined product fractions were lyophilized. This gave 41.4 mg of the title compound. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass measurement 422.00¹ </ RTI> <RTIgt; ), 7.15 (s, 1H), 8.22 (dd, 1H), 8.33 (s, 1H), 8.37 - 8.51 (m, 2H), 8.69 (s, 1H), 10.50 (s, 1H).Instance 47 N-[2-(3- Hydroxybutyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide ( Mirror isomer 1) Instance 48 N-[2-(3- Hydroxybutyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide ( Mirror isomer 2) 192 mg (0.47 mmol) of N-[6-methoxy-2-(3-oxobutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2- The methotrexate was dissolved in 5.5 ml of THF/methanol (10:1) and 18 mg (0.47 mmol) of sodium borohydride was added. The mixture was stirred at 25 ° C for 20 hours. Water was added to the reaction mixture and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated. The residue was dissolved in 8 ml of a mixture of ethanol and methanol and purified and purified by preparative chiral HPLC using method P6. The fractions containing the product are lyophilized. This gave 72 mg of the title compound (m.p. 1) and 75 mg of ss. LC-MS (Method A1): R_t = 1.16 min (UV detector: TIC Smooth), mass measurement 408.00¹ H NMR (300 MHz, DMSO-d6): δ = 1.02 - 1.11 (m, 3 H), 1.80 - 2.07 (m, 2 H), 3.48 - 3.63 (m, 1 H), 3.98 (s, 3 H) , 4.41 (t, 2 H), 4.68 (d, 1 H), 7.15 (s, 1 H), 8.22 (dd, 1 H), 8.30 (s, 1 H), 8.37 - 8.44 (m, 1 H) , 8.44 - 8.50 (m, 1 H), 8.68 (s, 1 H), 10.50 (s, 1 H).Instance 49 N-[6- Methoxy -2-(3- Methoxypropyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 300 mg (0.60 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 4 ml of DMF and 121 μl (1.07 mmol) of 1-bromo-3-methoxypropane, 370 mg (2.68 mmol) of potassium carbonate and 178 mg (1.07 mmol) of potassium iodide were added with stirring. The reaction mixture was stirred at 100 &lt;0&gt;C for 17 h, diluted with water andEtOAc. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 81 mg of the title compound. LC-MS (Method A1): R_t = 1.28 min (UV detector: TIC Smooth), mass measurement 408.00¹ H NMR (300 MHz, DMSO-d6): δ = 2.05 (five peaks, 2 H), 3.22 (s, 3 H), 3.27 (t, 2 H), 4.04 (s, 3 H), 4.42 (t , 2 H), 7.31 (s, 1 H), 8.01 (s, 1 H), 8.17 - 8.25 (m, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.72 (s , 1 H), 10.43 (s, 1 H).Instance 50 N-[6-(2- Hydroxyethoxy )-2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 40 mg (0.08 mmol) of {[2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl)carbonyl}amino)-2H Ethyl oxazol-6-yl]oxy}acetate was dissolved in 1.1 ml of THF/methanol (10:1) and 6 mg (0.16 mmol) of sodium borohydride was added. The reaction mixture was stirred at 25 ° C for 2 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. This gave 28 mg of the title compound. LC-MS (Method A1): R_t = 1.02 min (UV detector: TIC Smooth), mass 452.00 1H NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.96 - 2.04 (m, 2 H), 3.88 (q , 2 H), 4.19 (t, 2 H), 4.38 - 4.45 (m, 2 H), 4.51 (s, 1 H), 4.87 (t, 1 H), 7.14 (s, 1 H), 8.21 (dd , 1 H), 8.31 (s, 1 H), 8.40 (t, 1 H), 8.46 (d, 1 H), 8.70 (s, 1 H), 10.65 (s, 1 H).Instance 51 N-[6-( Cyclopropylmethoxy )-2-(2- Hydroxyethyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 3.00 g (6.49 mmol) of [6-(cyclopropylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-2 Ethyl acetate was dissolved in 33 ml of THF/methanol (10:1) and 245 mg (6.49 mmol) of sodium borohydride was added. The reaction mixture was stirred at 25 ° C for 3 hours. Another 245 mg (6.49 mmol) of sodium borohydride was added and the mixture was stirred at 25 ° C for another 2 hours. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The crude product was stirred with diethyl ether and the solid was filtered with suction. This gave 1.91 g of the title compound. LC-MS (Method A1): R_t = 1.20 min (UV detector: TIC Smooth), mass measurement 420.00 1H NMR (400 MHz, DMSO-d6): δ = 0.40 - 0.47 (m, 2 H), 0.61 - 0.71 (m, 2 H), 1.35 (br. s., 1 H), 3.85 (q, 2 H), 3.99 - 4.05 (m, 2 H), 4.37 (t, 2 H), 4.94 (t, 1 H), 7.08 (s, 1 H ), 8.21 (dd, 1 H), 8.26 (s, 1 H), 8.40 (t, 1 H), 8.47 (d, 1 H), 8.74 (s, 1 H), 10.69 (s, 1 H).Instance 52 N-[6- Methoxy -2-( Oxetane -3- Methyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 1.00 g (2.97 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 10 ml of DMF and 539 mg (3.57 mmol) of 3-(bromomethyl)oxetane, 1.23 g (8.92 mmol) of potassium carbonate and 592 mg (3.57 mmol) of potassium iodide were added with stirring. The reaction mixture was stirred at 100 ° C for 22.5 hours. Then, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was stirred with EtOAc (EtOAc)EtOAc. This gave 158 mg of the title compound. LC-MS (Method A1): R_t = 1.19 min (UV detector: TIC Smooth), mass measurement 406.00¹ </ RTI> <RTIgt; ), 8.21 (dd, 1H), 8.33 (d, 1H), 8.38 - 8.43 (m, 1H), 8.45 - 8.48 (m, 1H), 8.69 (s, 1H), 10.50 (s, 1H).Instance 53 N-[6- Methoxy -2-(4,4,4- Trifluorobutyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 120 mg (357 μmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 2 ml of DMF and 68 μl (540 μmol) of 3-(bromomethyl)oxetane and 148 mg (1.07 mmol) of potassium carbonate were added with stirring. The reaction mixture was stirred at 50 ° C for 4.5 hours and at 80 ° C for 16 hours. Then, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC. The combined product fractions were lyophilized. This gave 33 mg of the title compound. LC-MS (Method A3): R_t = 1.36 min (UV detector: TIC Smooth), mass measurement 446.00¹ </ RTI> <RTIgt; 8.34 (s, 1H), 8.38 - 8.44 (m, 1H), 8.45 - 8.49 (m, 1H), 8.70 (s, 1H), 10.51 (s, 1H).Instance 54 N-[6- chlorine -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 1.10 g (3.23 mmol) of N-(6-chloro-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 10 ml of DMF with stirring 809 mg (4.84 mmol) of 4-bromo-2-methylbutan-2-ol, 1.34 g (9.69 mmol) of potassium carbonate and 804 mg (4.84 mmol) of potassium iodide were added. The suspension was stirred at 120 ° C for 23 hours. Another 670 mg (4.85 mmol) potassium carbonate and 402 mg (2.42 mmol) potassium iodide were added, and the mixture was stirred at 120 ° C for additional 24 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (mobile phase: hexane/ethyl acetate, EtOAc, EtOAc (EtOAc) The combined product fractions were concentrated, diethyl ether was added and the mixture was stirred 15 min. The solid was filtered off with suction, washed three times with diethyl ether and dried overnight in a dry cabinet. This gave 342 mg of the title compound. LC-MS (Method A1): R_t = 1.17 min (UV detector: TIC Smooth), mass measurement 408.00¹ </ RTI> <RTIgt; ), 8.03 (dd, 1H), 8.28 - 8.39 (m, 2H), 8.52 (s, 1H), 8.63 (s, 1H), 10.59 (s, 1H).Instance 55 N-[6- Methoxy -2-(2- Methoxyethyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 200 mg (0.60 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 4 ml of DMF and 84 μl (0.89 mmol) of 2-bromoethyl methyl ether, 247 mg (1.78 mmol) of potassium carbonate and 118 mg (0.71 mmol) of potassium iodide were added with stirring. The reaction mixture was stirred at 100 &lt;0&gt;C for 19 h, diluted with water andEtOAc. The combined organic phases were filtered through a hydrophobic filter and concentrated. The residue was purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 52 mg of the title compound. LC-MS (Method A1): R_t = 1.28 min (UV detector: TIC Smooth), mass measurement 394.00¹ H-NMR (500MHz, DMSO-d6): δ = 3.24 (s, 3H), 3.81 (t, 2H), 3.99 (s, 3H), 4.51 (t, 2H), 7.15 (s, 1H), 8.21 ( Dd, 1H), 8.28 (s, 1H), 8.38 - 8.43 (m, 1H), 8.45 - 8.48 (m, 1H), 8.69 (s, 1H), 10.50 (s, 1H).Instance 56 N-{2-[2-(2- Hydroxyethoxy ) Ethyl ]-6- Methoxy -2H- Carbazole -5- base }-6-( Trifluoromethyl ) Pyridine -2- Formamide Dissolve 150 mg (446 μmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 2 ml of DMF and 71 μl (670 μmol) of 2-(2-chloroethoxy)ethanol, 185 mg (1.34 mmol) of potassium carbonate and 111 mg (669 μmol) of potassium iodide were added with stirring. The suspension was stirred at 100 ° C for 26 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, filtered and concentrated with a pad. The residue was purified by flash chromatography (EtOAc EtOAc (EtOAc) This gave 38.9 mg of the title compound. LC-MS (Method A1): R_t = 1.08 min (UV detector: TIC Smooth), mass measurement 424.00¹ H-NMR (400MHz, DMSO-d6): δ = 3.40 - 3.50 (m, 4H), 3.90 (t, 2H), 3.99 (s, 3H), 4.51 (t, 2H), 4.62 (t, 1H), 7.16 (s, 1H), 8.22 (d, 1H), 8.32 (s, 1H), 8.38 - 8.45 (m, 1H), 8.45 - 8.50 (m, 1H), 8.70 (s, 1H), 10.51 (s, 1H).Instance 57 {2-[6- Methoxy -5-({[6-( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine )-2H- Carbazole -2- base ] Ethoxy } Ethyl acetate Dissolve 300 mg (0.89 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-methylpyridine-2-carboxamide in 5 ml of DMF and add 377 with stirring. Methyl (1.78 mmol) (2-bromoethoxy)ethyl acetate and 493 mg (3.57 mmol) of potassium carbonate. The reaction mixture was stirred at 25 ° C for 2 hours and at 65 ° C for 21 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, the phases separated, filtered and concentrated with a pad. The residue was purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 96 mg of the title compound. LC-MS (Method A1): R_t = 1.26 min (UV detector: TIC Smooth), mass measurement 466.00¹ </ RTI> <RTIgt; 7.40 (s, 1H), 8.02 (d, 1H), 8.21 (dd, 1H), 8.38 - 8.43 (m, 1H), 8.45 - 8.49 (m, 1H), 8.72 (s, 1H), 10.43 (s, 1H).Instance 58 {[2-(3- Hydroxyl -3- Methyl butyl )-5-({[6-( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine )-2H- Carbazole -6- base ] Oxyl } Acetic acid 50 mg (0.10 mmol) of {[2-(3-hydroxy-3-methylbutyl)-5-({[6-(trifluoromethyl)pyridin-2-yl)carbonyl}amino)-2H Ethyl acetate of carbazole-6-yl]oxy} was dissolved in 1.5 ml of THF, and 12 mg (0.51 mmol) of lithium hydroxide monohydrate and 150 μl of water were added. The reaction mixture was stirred at 25 ° C for 60 minutes. The mixture was acidified to pH = 3 with 1 M hydrochloric acid and the obtained residue was filtered, and washed with water and diethyl ether. This gave 35 mg of the title compound. LC-MS (Method A1): R_t = 1.00 min (UV detector: TIC Smooth), mass measurement 466.00 1H NMR (300 MHz, DMSO-d6): δ = 1.15 (s, 6 H), 1.96 - 2.06 (m, 2 H), 4.38 - 4.47 (m, 2 H), 4.51 (s, 1 H), 4.89 (s, 2 H), 7.13 (s, 1 H), 8.14 - 8.24 (m, 1 H), 8.34 (s, 1 H), 8.36 - 8.45 (m, 1 H), 8.45 - 8.50 (m, 1 H), 8.73 (s, 1 H), 10.57 (s, 1 H).Instance 59 {2-[6- Methoxy -5-({[6-( Trifluoromethyl ) Pyridine -2- base ] Carbonyl } Amine )-2H- Carbazole -2- base ] Ethoxy } Acetic acid 82 mg (0.18 mmol) of {2-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl Ethyloxy}acetate was dissolved in 2 ml of THF and a solution of 300 μl of ethanol, 73 mg (1.76 mmol) of lithium hydroxide monohydrate in 300 μl of water was added, and the mixture was stirred at 50 ° C for 17 hours. The mixture was diluted with water and acidified to pH 3 using a 10% strength citric acid solution. The aqueous phase was extracted three times with ethyl acetate and the combined organics were filtered th Diethyl ether was added to the residue, and the mixture was stirred for 10 min, filtered, washed with diethyl ether and dried under reduced pressure. The residue was purified by preparative HPLC. The fractions containing the product are lyophilized. This gave 49 mg of the title compound. LC-MS (Method A1): R_t = 1.09 min (UV detector: TIC Smooth), mass measurement 438.00¹ H NMR (300 MHz, DMSO-d6): δ = 3.94 - 4.02 (m, 7 H), 4.53 (t, 2 H), 7.15 (s, 1 H), 8.21 (dd, 1 H), 8.33 (s , 1 H), 8.36 - 8.44 (m, 1 H), 8.44 - 8.49 (m, 1 H), 8.69 (s, 1 H), 10.50 (s, 1 H).Instance 60 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6-( Pentafluoroethyl ) Pyridine -2- Formamide 100 mg (0.38 mmol) 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 137 mg (0.57 mmol) 6-( A mixture of pentafluoroethyl)pyridine-2-carboxylic acid (CAS 1283717-85-0), 80 μl (0.57 mmol) of triethylamine and 217 mg (0.57 mmol) of HATU in 2 ml of DMF was stirred overnight at RT. The mixture was purified by preparative HPLC to give 150 mg of the title compound. LC-MS (Method A2): R_t = 1.32 min (UV detector: TIC Smooth), mass measurement 486.17¹ H-NMR (400MHz, DMSO-d₆ ): δ = 1.14 (s, 6H), 1.47 (t, 3H), 1.97 – 2.05 (m, 2H), 4.15 – 4.24 (q, 2H), 4.37 - 4.48 (m, 2H), 4.52 (s, 1H ), 7.11 (s, 1H), 8.23 - 8.27 (m, 1H), 8.31 (s, 1H), 8.39 – 8.51 (m, 2H), 8.73 (s, 1H), 10.60 (s, 1H).Instance 61 6-(1,1- Difluoroethyl )-N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ] Pyridine -2- Formamide 100 mg (0.38 mmol) 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 106 mg (0.57 mmol) 6-( A mixture of 1,1-difluoroethyl)pyridine-2-carboxylic acid, 80 μl (0.57 mmol) of triethylamine and 217 mg (0.57 mmol) of HATU in 2 ml of DMF was stirred overnight at RT. The mixture was purified by preparative HPLC to give the title compound. LC-MS (Method A2): R_t = 1.23 min (UV detector: TIC Smooth), mass measurement 432.20.¹ H-NMR (400MHz, DMSO-d₆ ): δ = 1.15 (s, 6 H), 1.51 (t, 3H), 1.96 – 2.05 (m, 2H), 2.15 (t, 3H), 4.15 – 4.26 (m, 2 H), 4.37 - 4.45 (m , 2H), 4.52 (s, 1H), 7.11 (s, 1H), 7.97 - 8.04 (m, 1H), 8.24 – 8.37 (m, 3H), 8.72 (s, 1H), 10.70 (s, 1H).Instance 62 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-6,7- Dihydrogen -4H- Pyrazole [5,1-c][1,4] Oxazine -2- Formamide 100 mg 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 67 mg 6,7-dihydro-4H-pyrazole And a mixture of [5,1-c][1,4]oxazine-2-carboxylic acid, 0.19 ml N-ethyl-N-isopropylpropan-2-amine and 165 mg HATU in 2 ml THF at RT Stir for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc EtOAc. The mixture was purified by preparative HPLC to give 124 mg of the title compound. LC-MS (Method A1): R_t = 0.93 min (UV detector: TIC Smooth), mass measurement 413.61.¹ H-NMR (400MHz, DMSO-d₆ ): δ = 1.14 (s, 6H), 1.46 (t, 3H), 1.96 - 2.04 (m, 2H), 4.07 - 4.14 (m, 2H), 4.16 - 4.28 (m, 4H), 4.36 - 4.44 (m , 2H), 4.51 (br s, 1H), 4.84 (s, 2H), 6.59 (s, 1H), 7.08 (s, 1H), 8.25 (s, 1H), 8.55 (s, 1H), 9.46 (s , 1H).Instance 63 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-1- Ethyl -1H- Pyrazole -3- Formamide 100 mg 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 56 mg 1-ethyl-1H-pyrazole-3 A mixture of formic acid, 0.19 ml of N-ethyl-N-isopropylpropan-2-amine and 165 mg of HATU in 2 ml of THF was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc EtOAc. The mixture was purified by preparative HPLC to give 114 mg of the title compound. LC-MS (Method A1): R_t = 1.02 min (UV detector: TIC Smooth), mass measurement 385.21.¹ H-NMR (400MHz, DMSO-d₆ ): δ = 1.14 (s, 6H), 1.42 - 1.51 (m, 6H), 1.97 - 2.03 (m, 2H), 4.15 - 4.28 (m, 4H), 4.36 - 4.43 (m, 2H), 4.51 (s , 1H), 6.75 (d, 1H), 7.07 (s, 1H), 7.93 (d, 1H), 8.25 (s, 1H), 8.54 (s, 1H), 9.57 (s, 1H).Instance 64 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ]-1- Isopropyl -1H- Pyrazole -3- Formamide 100 mg 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 61 mg 1-isopropyl-1H-pyrazole- A mixture of 3-carboxylic acid, 0.19 ml of N-ethyl-N-isopropylpropan-2-amine and 165 mg of HATU in 2 ml of THF was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc EtOAc. The mixture was purified by preparative HPLC to give 127 mg of the title compound. LC-MS (Method A1): R_t = 1.10 min (UV detector: TIC Smooth) with a mass measurement of 399.23.¹ H-NMR (400MHz, DMSO-d₆ ): δ [ppm] = 1.14 (s, 6H), 1.44 - 1.53 (m, 9H), 1.97 - 2.03 (m, 2H), 4.18 (q, 2H), 4.36 - 4.44 (m, 2H), 4.51 ( s, 1H), 4.62 (spt, 1H), 6.74 (d, 1H), 7.07 (s, 1H), 7.96 (d, 1H), 8.25 (s, 1H), 8.54 (s, 1H), 9.65 (s , 1H).Instance 65 N-[6- Ethoxy -2-(3- Hydroxyl -3- Methyl butyl )-2H- Carbazole -5- base ] Pyrazole [1,5-a] Pyrimidine -3- Formamide 100 mg 4-(5-Amino-6-ethoxy-2H-indazol-2-yl)-2-methylbutan-2-ol, 65 mg 1-pyrazolo[1,5-a A mixture of pyrimidine-3-carboxylic acid, 0.19 ml of N-ethyl-N-isopropylpropan-2-amine and 165 mg of HATU in 2 ml of THF was stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc EtOAc. The mixture was purified by preparative HPLC to give 57 mg of the title compound. LC-MS (Method A1): R_t = 0.89 min (UV detector: TIC Smooth), mass measurement 408.19¹ </ RTI> <RTIgt; ), 4.51 (br s, 1H), 7.05 (s, 1H), 7.34 (dd, 1H), 8.25 (s, 1H), 8.71 (s, 2H), 8.86 (dd, 1H), 9.38 (dd, 1H) ), 10.64 (s, 1H).Instance 66 N-[6- Methoxy -2-( Tetrahydrofuran -3- Methyl )-2H- Carbazole -5- base ]-6-( Trifluoromethyl ) Pyridine -2- Formamide 400 mg of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (CAS number: 1799836-45-5) as crude product A mixture of 310 mg of 3-(bromomethyl)tetrahydrofuran and 519 mg of potassium carbonate in 5.0 ml of DMF was stirred at 100 ° C for 5 hours and at 80 ° C for 21 hours. Water was then added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, filtered and concentrated with a sep. Purification by preparative HPLC gave 120 mg of the title compound.¹ H-NMR (400MHz, DMSO-d₆ ): δ = 1.59 - 1.72 (m, 1H), 1.88 - 2.00 (m, 1H), 2.79 - 2.92 (m, 1H), 3.49 - 3.57 (m, 1H), 3.60 - 3.73 (m, 2H), 3.79 (td, 1H), 3.99 (s, 3H), 4.35 (d, 2H), 7.17 (s, 1H), 8.22 (d, 1H), 8.34 - 8.49 (m, 3H), 8.69 (s, 1H), 10.51 (s, 1H).Instance 67 N-[2-(3- Hydroxyl -3- Methyl butyl )-6- Methoxy -2H- Carbazole -5- base ]-6-( Pyrrolidine -1- base ) Pyridine -2- Formamide 277 mg of potassium carbonate and 125 mg of potassium iodide were added to 169 mg of N-(6-methoxy-1H-indazol-5-yl)-6-(pyrrolidin-1-yl)pyridine-2-carboxamide and 126 mg of 4-bromo-2-methylbutan-2-ol in a mixture of 2.7 ml of DMF, and the mixture was heated at 100 ° C for 22 hours. 42 mg of 4-bromo-2-methylbutan-2-ol and 327 mg of cesium carbonate were added and the mixture was stirred at 100 ° C for 6 hours. The mixture was filtered off with suction, the residue was purified eluting eluting This gave 49 mg of the title compound.¹ </ RTI> <RTIgt; - 4.45 (m, 2H), 4.52 (s, 1H), 6.73 (d, 1H), 7.09 (s, 1H), 7.33 (d, 1H), 7.67 - 7.75 (m, 1H), 8.26 (s, 1H ), 8.65 (s, 1H), 10.92 (s, 1H).Evaluation of physiological efficacy IRAK4 Kinase analysis The IRAK4-inhibitory activity of the substance of the invention was measured in an Irak4 TR-FRET assay (TR-FRET = time-resolved fluorescence resonance energy transfer) as set forth below. Use from baculovirus-infected insect cells (Hi5, BTI-TN-5B1-4, cell line purchased from Invitrogen, Cat. No. B855-02) and purified from affinity chromatography by N-terminal GST (Beth A recombinant fusion protein of the peptide S-transferase) and human Irak4 is used as an enzyme. The substrate used for the kinase reaction is biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminal in the form of a guanamine), which is commercially available, for example, from Biosyntan GmbH (Berlin-Buch). For this analysis, 11 different concentrations ranging from 20 μM to 0.073 nM were prepared from the test substance in 2 mM solution in DMSO. 50 nl of each solution was pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) and 2 μl of Irak4 was added to the assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl2, 1.0 mM Dithiothreitol, 30 μM activated sodium orthovanadate, 0.1% (w/v) bovine gamma-immunoglobulin (BGG) 0.04% (v/v) nonidet-P40 (Sigma)] solution, and The mixture was incubated for 15 minutes to allow the material to pre-adhere to the enzyme prior to the kinase reaction. Then by adding 3 μl adenosine triphosphate (ATP, 1.67 mM = final concentration in 5 μl assay volume: 1 mM) and peptide substrate (0.83 μM = final concentration in 5 μl assay volume: 0.5 μM) The kinase reaction was started by analyzing the solution in the buffer, and the resulting mixture was incubated at 22 ° C for a reaction time of 45 minutes. The concentration of Irak4 was adjusted according to the individual activities of the enzyme and was set such that the analysis was carried out in a linear range. Typical concentrations are on the order of about 0.2 nM. By adding 5 μl of TR-FRET detection reagent [0.1 μM streptavidin-XL665 (Cisbio Bioassays; France, Cat. No. 610SAXLG)] and 1.5 nM anti-phosphoric acid antibody [Merck Millipore, "STK Antibody", catalog number 35-002] and 0.6 nM LANCE EU-W1024-labeled anti-mouse IgG antibody (Perkin-Elmer, product number AD0077; alternatively, anti-chick compound resistance from Cisbio Bioassays can be used The mouse-IgG antibody was stopped in a solution of EDTA aqueous solution (100 mM EDTA in 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES (pH 7.5)). The resulting mixture was incubated at 22 ° C for 1 hour to allow formation of a complex of biotinylated phosphorylated substrate and detection reagent. The amount of phosphorylated host was then assessed by measuring the resonance energy transfer of the ruthenium chelate labeled anti-mouse-IgG antibody to streptavidin-XL665. To this end, fluorescence emission at 620 nm and 665 nm was measured after excitation at 350 nm in a TR-FRET measuring instrument (eg, Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer)). The ratio of emission at 665 nm and 622 nm is taken as a measure of the amount of phosphorylation. The data was normalized (enzyme reaction without test substance = 0% inhibition; all other analytical components but no enzyme = 100% inhibition). Typically, 11 different concentrations (20 μM, 5.7 μM, 1.6 μM, 0.47 μM, 0.13 μM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25) in the range of 20 μM to 0.073 nM on the same microtiter plate. The test substance was tested under nM and 0.073 nM). A dilution series (2 mM to 7.3 nM in 100% DMSO) was prepared by serial dilution prior to analysis. Calculate IC by 4 parameter fitting₅₀ value.table 1 : IC of an example compound in IRAK4 kinase assay₅₀ value THP-1 In cells TNF-α secretion By means of this test, the ability of a substance to inhibit the secretion of TNF-α (tumor necrosis factor alpha) in THP-1 cells (human mononuclear acute leukemia cell line) can be tested. TNF-α is involved in the interleukins of the inflammatory process. In this test, TNF-α secretion was triggered by utilization with bacterial lipopolysaccharide (LPS). THP-1 cells were maintained in continuous suspension cell culture [no L-Glutamax (GE Healthcare, Cat. No. E15-039) and supplemented with fetal bovine serum (FCS) 10% (Invitrogen, Cat. No. 10082-147), 1% L - RPMI of branide (Sigma, Cat. No. G7513), 1% penicillin/streptomycin (PAA, Cat. No. P11-010) and 50 μM 2-mercaptoethanol (Gibco, Cat. No. 31350-010) 1460 medium] and should not exceed 1 × 10⁶ Cell concentration of cells/ml. The analysis was carried out in a cell culture medium (RPMI 1460 medium supplemented with L-glutamic acid, penicillin, streptomycin and 2-mercaptoethanol). THP-1 cells at 2.5×10⁵ The cell density of the cells/well was seeded in a 96-well plate. The compounds of the invention were subjected to serial dilutions in a constant volume of 100% DMSO and used in this assay at 8 different concentrations ranging from 10 μM to 3 nM such that the final DMSO concentration was 0.4% DMSO. Cells were pre-incubated with these for 30 minutes prior to actual stimulation. To induce interleukin secretion, cells were stimulated with 1 μg/ml LPS (Sigma, E. coli 0127: B8, Cat. No. L4516) for 6 hours. As a neutral control, cells were treated with 1 μg/ml LPS and 0.04% DMSO, and as inhibitor controls, cells were only treated with 0.04% DMSO. Cell viability was determined using CellTiter-Glo Luminescence Analysis (Promega, Cat. No. G7571 (G755/G756A)) according to the manufacturer's instructions. The amount of TNF-α secreted in the cell culture supernatant was determined using a human pro-inflammatory 9-Plex tissue culture kit (MSD, Cat. No. K15007B) according to the manufacturer's instructions. The activity of the substance is expressed as the ratio between the neutral and inhibitor controls (expressed as a percentage). Calculate the IC using a 4-parameter fit₅₀ value.table 2 : Example Compounds for the secretion of TNF-α in THP-1 cells and having no effect on cell viability₅₀ value Working examples of pharmaceutical compositions The compounds of the invention can be converted into the following pharmaceutical preparations:Lozenge : composition : 100 mg of the compound of Example 11 or the compound of Example 12, 50 mg of lactose (monohydrate), 50 mg of maize starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate. The tablet weight is 212 mg. It has a diameter of 8 mm and a radius of curvature of 12 mm.produce: A mixture of the compound of the present invention, lactose and starch was granulated using a 5% aqueous solution of PVP (w/w). The granules were dried and then mixed with magnesium stearate for 5 minutes. This mixture was compressed using a conventional tablet press (see above for the format of the tablet). The pressing force used for pressing is 15 kN.Suspension for oral administration composition : 1000 mg of the compound of Example 11 or the compound of Example 12, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum, from FMC, Pennsylvania, USA) and 99 g of water. A 10 ml oral suspension corresponds to a single dose of 100 mg of a compound of the invention.produce: Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. Add water while stirring. The mixture was stirred for about 6 hours until the Rhodigel had finished expanding.For oral administration of solutions: composition 500 mg of the compound of Example 11 or the compound of Example 12, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. The 20 g oral solution corresponds to a single dose of 100 mg of the compound of the invention.produce The compound of the invention is suspended in a mixture of polyethylene glycol and polysorbate with stirring. This stirring operation is continued until the compound of the present invention is completely dissolved.

Claims (17)

a compound of the formula (I), Wherein R ¹ represents chloro or OR ⁴ , and R ² represents C ₁ -C ₈ -alkyl, which may optionally be mono- or polysubstituted, respectively, via the same or different substituents selected from the group consisting of: 1 to 5 a fluorine atom, 1 to 3 hydroxyl groups, oxetanyl group, tetrahydrofuranyl group, pyranyl group, pendant oxy group, and C ₁ -C ₆ -alkoxy group, wherein the C ₁ -C ₆ -alkoxy group may be fluorine-containing Or mono-substituted to trisubstituted by hydroxyl group or via C(=O)OH, C(=O)Me, C(=O)Et, C(=O)NH ₂ ; R ³ represents a group selected from the group consisting of: Wherein R ⁵ represents hydrogen, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may optionally be monosubstituted by cyclopropyl, cyano and hydroxy to three Substituting wherein each substituent may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; R ⁶ represents hydrogen, fluorine or methyl, or R ³ represents a group selected from the group consisting of: Wherein R ⁷ represents hydrogen, C ₃ -C ₆ -cycloalkyl, cyano, NH ₂ , NH(C ₁ -C ₆ -alkyl), N(C ₁ -C ₆ -alkyl) ₂ , pyrrolidine- 1-yl, hexahydropyridin-1-yl, morpholin-4-yl, 4-methylhexahydropyrazin-1-yl or a C ₁ -C ₆ -alkyl group, wherein C ₁ -C ₆ -alkane The group may be mono-substituted to trisubstituted by cyclopropyl, cyano and hydroxy, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted through a fluorine atom; R ⁸ , R ⁹ , R ¹⁰ represent hydrogen, A Base or fluorine, or R ³ represents Wherein R ¹¹ represents a C ₃ -C ₆ -cycloalkyl group or a C ₁ -C ₆ -alkyl group, wherein the C ₁ -C ₆ -alkyl group may be monosubstituted to trisubstituted by a cyclopropyl group, a cyano group and a hydroxy group, wherein Each substituent may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; and R ¹² represents hydrogen, fluorine or C ₁ -C ₆ -alkyl; or R ³ represents 6,7-dihydro-4H-pyridyl Zoxa[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2 -yl or 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl or represents pyrazolo[1,5-a]pyrimidin-3-yl, pyrrole [ 2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2,3-b]pyrazine-7- 5-Aminopyrazolo[1,5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, 2 -Aminopyrrolo[1,2-b]pyridazin-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl; R ⁴ represents a saturated 4- to 7-membered heterocyclic ring Or a C ₃ -C ₇ -cycloalkyl group, wherein the saturated heterocyclic group and the C ₃ -C ₇ -cycloalkyl group are optionally mono- or polysubstituted by the same or different substituents from the group consisting of: C ₁ -C ₆ -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl , C(=O)OH, C ₁ -C ₆ -alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, chloro, cyano, hydroxy, NH ₂ , NHR ^a And N(R ^a )R ^b , or C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may be mono- or polysubstituted by the same or different substituents from the group consisting of: Fluorine, chlorine, cyano, hydroxy, C(=O)OC ₁ -C ₆ -alkyl, C(=O)OH, C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , SC ₁ -C ₆ -alkyl, S(=O) ₂ -C ₁ -C ₆ -alkyl, S(=O) ₂ NH ₂ , C ₁ - C ₆ -alkoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, tetra An azole and a 4- to 7-membered saturated heterocyclic group, wherein the C ₃ -C ₇ -cycloalkyl group, the heteroaryl group and the 4 to 7 membered saturated heterocyclic group may be optionally substituted by the same or different groups from the group consisting of Substituted to tetrasubstituted: fluorine, C ₁ -C ₄ -alkyl, hydroxy, C(=O)OH, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy , trifluoromethoxy, cyclopropyl, cyclopropylmethyl, methyl sulfonic ^{_{acyl, NH 2, NHR a, N}} (R a) R b; R a representative of C ₁ -C ₆ - alkyl C ₃ -C ₇ - cycloalkyl, wherein C ₁ -C ₆ - alkyl and C ₃ -C ₇ - cycloalkyl group optionally substituted by the same or a different group of consisting of mono- or poly-substituted by the group consisting of the following: Fluorine, hydroxy, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy and C ₃ -C ₇ -cycloalkyl; R ^b represents C ₁ -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl; and solvates thereof and their non-image isomers, mirror image isomers, metabolites, salts, solvates or salts thereof. A compound of formula (I), wherein R ¹ represents chloro or OR ⁴ , and R ² represents C ₁ -C ₆ -alkyl, which may optionally be substituted, independently of each other, by the same or different substituents selected from the group consisting of Mono- or poly-substituted: 1 to 3 fluorine atoms, 1 to 2 hydroxyl groups, oxetanyl groups, tetrahydrofuranyl groups, and C ₁ -C ₃ -alkoxy groups, wherein the C ₁ -C ₃ -alkoxy group It may be substituted by a hydroxyl group or by C(=O)OH, C(=O)Me, C(=O)Et; or R ² represents a 3-sided oxybutyl group; R ³ represents a group selected from the group consisting of: Wherein R ⁵ represents hydrogen, cyclopropyl or C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may optionally be mono-substituted to trisubstituted with cyclopropyl, cyano and hydroxy, wherein each substitution The group may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; and R ⁶ represents hydrogen; or R ³ represents a group Wherein R ⁷ represents hydrogen, cyclopropyl, cyano, NH ₂ , NH(C1-C ₆ -alkyl), N(C ₁ -C ₆ -alkyl) ₂ , pyrrolidin-1-yl, hexahydropyridine -1-yl, morpholin-4-yl, 4-methylhexahydropyrazin-1-yl or represents C ₁ -C ₆ -alkyl, wherein C ₁ -C ₆ -alkyl may optionally be cyclopropyl , cyano and hydroxy, mono- to tri-substituted, wherein each substituent may occur only once, or may be mono-substituted to penta-substituted through a fluorine atom; and R ⁸ , R ⁹ , R ¹⁰ represent hydrogen or R ³ represents a group Wherein R ¹¹ represents a C ₃ -C ₆ -cycloalkyl group or a C ₁ -C ₆ -alkyl group, wherein the C ₁ -C ₆ -alkyl group may be monosubstituted to trisubstituted by a cyclopropyl group, a cyano group and a hydroxy group, wherein Each substituent may occur only once, or may be mono-substituted to penta-substituted with a fluorine atom; and R ¹² represents hydrogen or R ³ represents 6,7-dihydro-4H-pyrazolo[5,1-c][1, 4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl or 4,5,6,7-tetra Hydropyrazolo[1,5-a]pyrazin-2-yl, or represents pyrazolo[1,5-a]pyrimidin-3-yl, pyrrolo[2,1-f][1,2, 4] Triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno[2,3-b]pyrazin-7-yl, 5-aminopyrazolo[1 , 5-a]pyrimidin-3-yl, 2-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, 2-aminopyrrolo[1,2-b Pyridazine-7-yl, 2-aminothieno[2,3-b]pyrazin-7-yl; R ⁴ represents cyclopropyl, hexahydropyridin-4-yl, 1-methylhexahydropyridine 4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, azetidin-3-yl, 1-methylazetidin-3-yl, oxetane- 3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl, wherein oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H- Thiopyran-4-yl optionally substituted by mono or di-substituted by methyl, or represents C ₁ -C ₆ - alkyl, wherein C ₁ -C ₆ - alkyl optionally substituted by the following: hydroxy, C (= O) OMe , C(=O)OEt, C(=O)OH, C(=O)NH ₂ , SMe, SEt, S(=O) ₂ Me, S(=O) ₂ Et, methoxy, ethoxy , N(CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or represents three a solvent such as fluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; and its non-image, isomer, metabolite, metabolite, salt, solvate or salt thereof Compound. A compound of the formula (I) according to claim 2, wherein R ¹ represents chloro or OR ⁴ ; R ² represents C ₂ -C ₅ -alkyl, which is 1 to 2 hydroxy or oxetan-3-yl Or substituted with tetrahydrofuran-3-yl or via the group OCH ₂ C(=O)OH, OCH ₂ C(=O)OMe, OCH ₂ CH ₂ OH or via C ₁ -C ₃ -alkoxy, where C ₁ -C ₃ -alkoxy may be substituted by hydroxy or by C(=O)OH, C(=O)Me, C(=O)Et; or R ² represents 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl or 3-sided oxybutyl; R ³ represents 1-(C ₁ -C ₆ -alkyl)-1H-pyrazol-3-yl, wherein the C ₁ -C _{The 6} -alkyl substituent may optionally be mono-substituted with a cyclopropyl group, monosubstituted to penta-substituted with a fluorine atom and optionally substituted by a hydroxy group, or represented by 2-cyclopropyl-1,3-thiazol-4-yl or 2 -(C ₁ -C ₆ -alkyl)-1,3-thiazol-4-yl, wherein the C ₁ -C ₆ -alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted by fluorine atom to five Substituting and optionally monosubstituted by a hydroxy group, or representing 4-(C ₁ -C ₆ -alkyl)-1,3-thiazol-2-yl, wherein the C ₁ -C ₆ -alkyl substituent may optionally be cyclic Propyl monosubstituted, monosubstituted to pentasubstituted by fluorine atom and optionally substituted by hydroxy group Or represents 2-propyl-1,3-oxazol-4-yl or 2- (C ₁ -C ₆ - alkyl) -1,3-oxazol-4-yl, wherein the C ₁ -C ₆ - an alkyl substituent may optionally be monosubstituted by cyclopropyl, monosubstituted to pentasubstituted by fluorine atom and optionally substituted by hydroxy, or represented by 2-(C ₁ -C ₆ -alkyl)-1,3- An oxazol-5-yl group, wherein the C ₁ -C ₆ -alkyl substituent is optionally monosubstituted by a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom, and optionally substituted by a hydroxy group, or represents 6-(C ₁ a -C ₆ -alkyl)pyridin-2-yl group, wherein the C ₁ -C ₆ -alkyl substituent may optionally be monosubstituted by a cyclopropyl group, monosubstituted to pentasubstituted with a fluorine atom, and optionally monosubstituted by a hydroxy group, Or represents 6-aminopyridin-2-yl, 6-((C ₁ -C ₄ -alkyl)amino)pyridin-2-yl, 6-(di-(C ₁ -C ₄ -alkyl)amine Pyridin-2-yl, 6-(pyrrolidin-1-yl)pyridin-2-yl, 6-(hexahydropyridin-1-yl)pyridin-2-yl, 6-(morpholin-4-yl Pyridin-2-yl, 6-(4-methylhexahydropyrazin-1-yl)pyridin-2-yl, or 6,7-dihydro-4H-pyrazolo[5,1-c] [1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl or 4,5,6, 7-tetrahydropyrazolo[1,5-a] Pyrazin-2-yl, or pyrazolo[1,5-a]pyrimidin-3-yl, pyrrolo[2,1-f][1,2,4]triazin-7-yl, pyrrolo[ 1,2-b]pyridazin-7-yl, thieno[2,3-b]pyrazin-7-yl, 5-aminopyrazolo[1,5-a]pyrimidin-3-yl, 2 -aminopyrrolo[2,1-f][1,2,4]triazin-7-yl, 2-aminopyrrolo[1,2-b]pyridazin-7-yl, 2-amino group Thieno[2,3-b]pyrazin-7-yl; R ⁴ represents C ₁ -C ₄ -alkyl, or represents oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H- Pyran-4-yl or represents 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl or represents CH ₂ C(=O)OMe, CH ₂ C (=O)OEt, CH ₂ C(=O)OH, CH ₂ CH ₂ SMe, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl)propyl, 2-methoxy Ethyl, 2-ethoxyethyl, CH ₂ CH ₂ N(CH ₃ ) ₂ , cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, oxetan-3-ylmethyl, tetrahydrofuran -3-ylmethyl, tetrahydro-2H-pyran-4-ylmethyl or represents trifluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl; R ⁵ represents Hydrogen or fluorine; and its non-image isomers, mirror image isomers, metabolites, salts, solvates or salts thereof Solvate. A compound of the formula (I) according to claim 3, wherein R ¹ represents chlorine or OR ⁴ ; R ² represents 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methyl Butyl, 4-hydroxybutyl, 4-hydroxypentyl, 2,3-dihydroxypropyl, 2,3-dihydroxy-2-methylpropyl, 2-hydroxypropyl, oxetane-3 -ylmethyl, oxetan-3-ylethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-3-ylethyl, 3-sided oxybutyl, 3-methoxy-3-methyl Butyl, 3-methoxypropyl, 2-methoxyethyl, 4,4,4-trifluorobutyl, 3,3,3-trifluoropropyl, 2-(2-hydroxyethoxy) Ethyl, CH ₂ CH ₂ OCH ₂ C(=O)OH, CH ₂ CH ₂ OCH ₂ C(=O)OEt; R ³ represents 1-(difluoromethyl)-1H-pyrazol-3-yl , 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3 -yl, 1-isopropyl-1H-pyrazol-3-yl, 1-propyl-1H-pyrazol-3-yl, 1-tert-butyl-1H-pyrazol-3-yl, 1- Isobutyl-1H-pyrazol-3-yl, 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-4-yl, 2-B -1,3-thiazol-4-yl, 2-propyl-1,3-thiazol-4-yl, 2-isopropyl-1,3-thiazol-4-yl, 2- Third butyl-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-thiazol-4-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl, 4-ethyl-1,3-thiazol-2-yl, 4-isopropyl-1,3-thiazol-2-yl, 4-third Butyl-1,3-thiazol-2-yl, 4-cyclopropyl-1,3-thiazol-2-yl, 2-methyl-1,3-oxazol-4-yl, 2-(trifluoro Methyl)-1,3-oxazol-4-yl, 2-ethyl-1,3-oxazol-4-yl, 2-(1,1-difluoroethyl)-1,3-oxazole 4-yl, 2-(2,2,2-trifluoroethyl)-1,3-oxazol-4-yl, 2-isopropyl-1,3-oxazol-4-yl, 2- Third butyl-1,3-oxazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-(cyclopropylmethyl)-1,3-oxazole- 4-yl, 2-methyl-1,3-oxazol-5-yl, 2-ethyl-1,3-oxazol-5-yl, 2-isopropyl-1,3-oxazolyl-5 -yl, 6-methylpyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-ethylpyridin-2-yl 6-(1,1-Difluoroethyl)pyridin-2-yl, 6-(pentafluoroethyl)pyridin-2-yl, 6-(2,2,2-trifluoroethyl)pyridine-2 -yl,6-propylpyridin-2-yl, 6-isopropylpyridin-2-yl, 6-(2-hydroxypropan-2-yl)pyridin-2-yl, 6-tert-butylpyridine- 2-based, 6-cyclopropylpyridin-2-yl 6-Aminopyridin-2-yl, 6-(methylamino)pyridin-2-yl, 6-(ethylamino)pyridin-2-yl, 6-(dimethylamino)pyridine-2 -yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyridyl Zizo[1,5-a]pyrazin-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5 -a]pyrimidin-3-yl, pyrrolo[2,1-f][1,2,4]triazin-7-yl, pyrrolo[1,2-b]pyridazin-7-yl, thieno [2,3-b]pyrazin-7-yl; R ⁴ represents methyl, ethyl, isopropyl, propyl, cyclopropylmethyl, oxetan-3-yl, oxetane- 3-ylmethyl, tetrahydrofuran-3-yl, 2-hydroxyethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-(methylsulfonate Ethyl, 3-(methylsulfonyl)propyl, 2-(methylthio)ethyl, CH ₂ C(=O)OEt, CH ₂ C(=O)OH; R ⁵ represents hydrogen And solvates thereof, which are non-image isomers, mirror image isomers, metabolites, salts, solvates or salts thereof. A compound of the formula (I) according to claim 4, wherein R ¹ represents chlorine or OR ⁴ ; R ² represents 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methyl Butyl, 2,3-dihydroxypropyl, oxetan-3-ylmethyl, tetrahydrofuran-3-ylmethyl, 3-sided oxybutyl, 3-methoxy-3-methylbutyl , 3-methoxypropyl, 2-methoxyethyl, 4,4,4-trifluorobutyl, 2-(2-hydroxyethoxy)ethyl, CH ₂ CH ₂ OCH ₂ C ( =O)OH, CH ₂ CH ₂ OCH ₂ C(=O)OEt; R ³ represents 1-(difluoromethyl)-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazole-3 -yl, 1-isopropyl-1H-pyrazol-3-yl, 2-(trifluoromethyl)-1,3-oxazol-4-yl, 2-(trifluoromethyl)-1,3 -thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-methyl-1,3-oxazol-5-yl, 2-methyl-1,3-thiazole 4-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 6-(1,1-difluoroethyl)pyridin-2-yl, 6-(2-hydroxypropyl- 2-yl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(pentafluoroethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridine-2- 6,6-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 6-aminopyridin-2-yl, pyrazolo[1,5 -a] pyrimidin-3-yl; R ⁴ generations Methyl, ethyl, isopropyl, cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl, tetrahydrofuran-3-yl, 2-hydroxyethyl, trifluoro Methyl, 3-(methylsulfonyl)propyl, 2-(methylthio)ethyl, CH ₂ C(=O)OEt, CH ₂ C(=O)OH; a solvate of a substance, a mirror image isomer, a metabolite, a salt, a solvate or a salt thereof. A compound of the formula (I) according to claim 5, wherein R ¹ represents OR ⁴ ; R ² represents 3-hydroxy-3-methylbutyl; and R ³ represents 1-(difluoromethyl)-1H-pyrazole- 3-yl, 1-ethyl-1H-pyrazol-3-yl, 2-(trifluoromethyl)-1,3-oxazol-4-yl, 2-(trifluoromethyl)-1,3 -thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-methyl-1,3-oxazol-5-yl, 2-methyl-1,3-thiazole 4-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 6-(1,1-difluoroethyl)pyridin-2-yl, 6-(2-hydroxypropyl- 2-yl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-aminopyridin-2-yl, pyrazole And [1,5-a]pyrimidin-3-yl; R ⁴ represents methyl, ethyl, isopropyl, cyclopropylmethyl, oxetan-3-yl, oxetan-3-yl A solvate of a methyl group, a 2-hydroxyethyl group; and a non-image thereof, a mirror image isomer, a metabolite, a salt, a solvate or a salt thereof. A compound of the formula (I) according to claim 5 which is 1-(difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indole Zyrid-5-yl]-1H-pyrazole-3-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indazol-5-yl] -2-(trifluoromethyl)-1,3-oxazole-4-carboxamide 6-(difluoromethyl)-N-[2-(3-hydroxypropyl)-6-methoxy- 2H-carbazol-5-yl]pyridine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]- 4-(Trifluoromethyl)-1,3-thiazol-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5 -yl]-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H- Oxazol-5-yl]-2-methyl-1,3-oxazol-5-carboxamide 1-(difluoromethyl)-N-[6-ethoxy-2-(3-hydroxy- 3-methylbutyl)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl) -2H-carbazol-5-yl]-2-methyl-1,3-thiazole-4-carboxamide 2-cyclopropyl-N-[6-ethoxy-2-(3-hydroxy- 3-methylbutyl)-2H-indazol-5-yl]-1,3-oxazole-4-carboxamide 6-amino-N-[6-ethoxy-2-(3-hydroxyl) -3-methylbutyl)-2H-indazol-5-yl]pyridine-2-carboxamide N-[6- Oxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3 -hydroxy-3-methylbutyl)-6-(oxetan-3-yloxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidine Amine N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-yloxy)-2H-indazol-5-yl]-2-(trifluoromethyl) -1,3-1,3-thiazol-4-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-yloxy)-2H-indole Zyrid-5-yl]-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide 1-(difluoromethyl)-N-[2-(3-hydroxy-3-methyl Butyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide 6-(difluoromethyl)-N -[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]pyridine-2-carboxamide N -2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-5-yl-2-methyl-1,3- Oxazole-5-carbamamine N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-5-yl- 6-(Trifluoromethyl)pyridine-2-carboxamide 6-amino-N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy ]]-2H-carbazole-5-ylpyridine-2-carboxamidine N-[6-Chloro-2-(3-methoxy-3-methylbutyl)-2H-indazol-5-yl]-6-(2-hydroxypropan-2-yl)pyridine-2- Methionamine N-[6-chloro-2-(3-methoxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-methyl Indoleamine N-[6-isopropoxy-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N -[6-Isopropoxy-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 6-(two Fluoromethyl)-N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]pyridine-2-carboxamide N-[6- (cyclopropylmethoxy)-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6 -(cyclopropylmethoxy)-2-(2-methoxyethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[ 6-(cyclopropylmethoxy)-2-(oxetan-3-ylmethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamidine Amine N-[2-(3-hydroxy-3-methylbutyl)-6-(trifluoromethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2 -Procarbamide 2-cyclopropyl-N-[6-methoxy-2-(3-methoxypropyl)-2H-indazol-5-yl]-1,3-oxazole-4- Methionamine N-[6-chloro-2-(3-hydroxy-3-methyl) -2H-carbazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide N-[2-(2-hydroxyethyl)-6-isopropoxy-2H- Oxazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxypropyl)-6-isopropoxy-2H-indazole-5- -6-(trifluoromethyl)pyridine-2-carboxamide N-2-(3-hydroxy-3-methylbutyl)-6-[3-(methylsulfonyl)propoxy -2H-carbazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide N-2-(3-hydroxy-3-methylbutyl)-6-[2-(A Ethylthio)ethoxy]-2H-indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide [2-(3-hydroxy-3-methylbutyl)-5 -([6-(Trifluoromethyl)pyridin-2-yl]carbonylamino)-2H-indazol-6-yl]oxyacetic acid ethyl N-[2-(3-hydroxy-3-methyl Butyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6- (cyclopropylmethoxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N -[6-(cyclopropylmethoxy)-2-(3-hydroxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N- [6-Methoxy-2-(3-o-oxybutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-( 2-hydroxyethyl - 6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxypropyl)-6-methoxy -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-2-[(2S)-2,3-dihydroxypropyl]-6-methoxy -2H-indazole-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide 6-(difluoromethyl)-N-[2-(2-hydroxyethyl)-6- Methoxy-2H-indazol-5-yl]pyridine-2-carboxamide N-[6-chloro-2-(2-hydroxyethyl)-2H-indazol-5-yl]-6-( Trifluoromethyl)pyridine-2-carboxamide N-6-chloro-2-[(2R)-2,3-dihydroxypropyl]-2H-indazol-5-yl-6-(trifluoromethyl) Pyridyl-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl Pyridine-2-carboxamide N-[2-(3-hydroxybutyl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-methyl Indoleamine N-[2-(3-hydroxybutyl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6 -Methoxy-2-(3-methoxypropyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(2- Hydroxyethoxy)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6 -(cyclopropylmethoxy)-2-(2-hydroxyl -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-methoxy-2-(oxetan-3-ylmethyl) -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-methoxy-2-(4,4,4-trifluorobutyl) -2H-carbazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-chloro-2-(3-hydroxy-3-methylbutyl)-2H- Oxazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-methoxy-2-(2-methoxyethyl)-2H-indazole-5 -yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-2-[2-(2-hydroxyethoxy)ethyl]-6-methoxy-2H-indazole-5 -yl-6-(trifluoromethyl)pyridine-2-carboxamide 2-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonylamino)- Ethyl 2H-carbazol-2-yl]ethoxyacetate [2-(3-hydroxy-3-methylbutyl)-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl) Amino)-2H-indazol-6-yl]oxyacetic acid 2-[6-methoxy-5-([6-(trifluoromethyl)pyridin-2-yl]carbonylamino)-2H- Oxazol-2-yl]ethoxyacetic acid N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6-(pentafluoro Ethyl)pyridine-2-carboxamide 6-(1,1-difluoroethyl)-N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indole Oxazol-5-yl]pyridine- 2-Protonamine N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-6,7-dihydro-4H-pyrazole And [5,1-c][1,4]oxazine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-carbazole- 5-yl]-1-ethyl-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5 -yl]-1-isopropyl-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5 -yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide N-[6-methoxy-2-(tetrahydrofuran-3-ylmethyl)-2H-indazol-5-yl] -6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indazol-5-yl]- 6-(pyrrolidin-1-yl)pyridine-2-carboxamide. A compound of the formula (I) according to claim 6 which is 1-(difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H- Oxazol-5-yl]-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-carbazole-5-yl ]-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide 1-(difluoromethyl)-N-[6-ethoxy-2-(3-hydroxy-3-methyl) Benzyl)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H -carbazol-5-yl]-2-methyl-1,3-thiazole-4-carboxamide 2-cyclopropyl-N-[6-ethoxy-2-(3-hydroxy-3-methyl Butyl)-2H-carbazol-5-yl]-1,3-oxazole-4-carboxamide 6-amino-N-[6-ethoxy-2-(3-hydroxy-3- Methylbutyl)-2H-indazol-5-yl]pyridine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-carbazole -5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-yl) Oxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-( Oxetidin-3-yloxy)-2H-indazol-5-yl]-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide 1-(difluoromethyl) -N-[2-(3-hydroxy-3-methylbutyl)-6-(oxa) Cyclobut-3-ylmethoxy)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide 6-(difluoromethyl)-N-[2-(3-hydroxy- 3-methylbutyl)-6-(oxetan-3-ylmethoxy)-2H-indazol-5-yl]pyridine-2-carboxamide N-2-(3-hydroxy-3 -Methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazol-5-yl-2-methyl-1,3-oxazol-5-carboxamide N -2-(3-Hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazole-5-yl-6-(trifluoromethyl)pyridine 2-carbamamine 6-amino-N-2-(3-hydroxy-3-methylbutyl)-6-[(3S)-tetrahydrofuran-3-yloxy]-2H-indazole-5 -ylpyridine-2-carboxamide 6-(difluoromethyl)-N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-carbazole-5-yl Pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-(oxetan-3-ylmethoxy)-2H-indazole-5-yl -6-(Trifluoromethyl)pyridine-2-carboxamide N-[2-(3-hydroxy-3-methylbutyl)-6-methoxy-2H-indazol-5-yl] -6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(2-hydroxyethoxy)-2-(3-hydroxy-3-methylbutyl)-2H-carbazole- 5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 6-(1,1-difluoroethyl)-N-[6-ethoxy-2-(3-hydroxy-3) -methylbutyl)-2H-carbazole-5-yl Pyridine-2-carboxamide N-[6-ethoxy-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl]-1-ethyl-1H-pyridyl Oxazole-3-carboxamide. A compound of the formula (I) according to any one of claims 1 to 8 for use in the treatment and/or prevention of a disease. A compound of the formula (I) according to any one of claims 1 to 8 for use in a method for the treatment and/or prevention of a neoplastic disorder, a dermatological disorder, a gynecological disorder, a cardiovascular disorder , pulmonary disorders, ophthalmic disorders, neurological disorders, metabolic disorders, liver disorders, inflammatory conditions, autoimmune disorders and pain. A compound of the formula (I) according to any one of claims 1 to 8 for use in a method for the treatment and/or prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis , COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome, spondylarthritis and rheumatoid arthritis, endometriosis and endometriosis-related pain and other endometriosis Symptoms associated with symptoms (such as dysmenorrhea, painful intercourse, difficulty urinating, and difficulty in defecation). A compound of the formula (I) according to any one of claims 1 to 8, which is a method for the treatment and/or prevention of pain, which comprises acute, chronic, inflammatory and neuropathic pain, preferably hyperesthesia, touch Pain, arthritis pain (eg osteoarthritis, rheumatoid arthritis and spinal arthritis), premenstrual pain, endometriosis-related pain, post-operative pain, interstitial cystitis pain, CRPS (complex Sexual regional pain syndrome), trigeminal neuralgia, prostatitis pain, pain caused by spinal cord injury, inflammation-induced pain, lumbar pain, cancer pain, chemotherapy-related pain, HIV-induced neuropathy, burn-induced pain And chronic pain. Use of a compound of formula (I) according to any one of claims 1 to 8 for the preparation of a medicament. The use of claim 13, wherein the agent is for treating and/or preventing a neoplastic disorder, a dermatological disorder, a gynecological disorder, a cardiovascular disorder, a pulmonary disorder, an ophthalmic disorder, a neurological disorder, a metabolic disorder, a liver disorder , inflammatory conditions, autoimmune disorders and pain. The use of claim 13 or 14, for the treatment and/or prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome , spondylitis and rheumatoid arthritis, endometriosis and endometriosis-related pain and other endometriosis-related symptoms (such as dysmenorrhea, painful intercourse, dysuria, and feces) difficult). The use of claim 13 or 14, for the treatment and/or prevention of pain, including acute, chronic, inflammatory and neuropathic pain, preferably hyperesthesia, touch pain, arthritic pain (eg osteoarthritis, Rheumatoid arthritis and spondyloarthritis), premenstrual pain, endometriosis-related pain, postoperative pain, interstitial cystitis pain, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostate Inflammation pain, pain caused by spinal cord injury, inflammation-induced pain, lumbar pain, cancer pain, chemotherapy-related pain, HIV-induced neuropathy, burn-induced pain, and chronic pain. An agent comprising a combination of a compound of formula (I) according to any one of claims 1 to 8 with an inert, non-toxic pharmaceutically suitable excipient.