HK1261874B - New 2-substituted indazoles, methods for producing same, pharmaceutical preparations that contain same, and use of same to produce drugs - Google Patents

Description

Novel 2-substituted indazoles, methods for their preparation, pharmaceutical preparations containing them, and their use in preparing medicaments

The present application relates to novel 2-substituted indazoles, methods for their preparation, the use of the novel substituted indazoles for the treatment and/or prevention of diseases, and their use in the preparation of medicaments for the treatment and/or prevention of diseases, in particular the following diseases: proliferative disorders such as autoimmune disorders; metabolic and inflammatory disorders, for example rheumatoid arthritis, spondyloarthritis (in particular psoriatic spondyloarthritis and Bekhterev's disease), chronic obstructive pulmonary disease (COPD), multiple sclerosis, systemic lupus erythematosus, gout, metabolic syndrome, steatohepatitis, insulin resistance, endometriosis, and inflammation-induced pain or chronic pain; and lymphoma.

The present invention relates to novel 2-substituted indazoles of the general formula (I) that inhibit 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 anti-inflammatory substances. IRAK4 is expressed by many cells and mediates signal transduction of the following receptors: Toll-like receptors (TLRs) (except TLR3), and interleukin (IL)-1β family receptors composed of IL-1R (receptor), IL-18R, IL-33R and IL-36R (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).

IRAK4 knockout mice and human cells from patients with IRAK4 deficiency are unresponsive to stimulation by TLRs (except TLR3) and the IL-1β family (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 their respective receptors leads to the recruitment and binding of MyD88 [myeloid differentiation factor primary response gene (88)] to the receptor. Consequently, MyD88 interacts with IRAK4, leading to the formation of an active complex that interacts with and activates the kinases IRAK1 or IRAK2 (Kollewe, Mackensen et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009). As a result, the NF (nuclear factor) -κB signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway are activated (Wang, Deng et al., Nature, 2001). Activation of both the NF-κB signaling pathway and the MAPK signaling pathway results in processes associated with different immune processes. For example, there is increased expression of various inflammatory signaling molecules and enzymes (such as cytokines, chemokines and COX-2 (cyclooxygenase-2)), as well as enhanced mRNA stability of inflammation-related genes (such as COX-2, IL-6 (interleukin-6), IL-8) (Holtmann, Enninga et al., Journal of Biological Chemistry, 2001; Datta, Novotny et al., The Journal of Immunology, 2004). In addition, these processes can be associated with the proliferation and differentiation of specific cell types (such as monocytes, macrophages, dendritic cells, T cells and B cells) (Wan, Chi et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).

The central role of IRAK4 in the pathology of various inflammatory conditions has been shown by direct comparisons of wild-type (WT) mice with genetically modified animals harboring a kinase-inactive form of IRAK4 (IRAK4 KDKI). 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). Furthermore, it was found that the loss of IRAK4 in animal models protects against viral-induced myocarditis by improving antiviral responses and simultaneously reducing systemic inflammation (Valaperti, Nishii et al., Circulation, 2013). IRAK4 expression has also been shown to correlate with the severity of Vogt-Koyanagi-Harada syndrome (Sun, Yang et al., PLoS ONE, 2014). Furthermore, IRAK4 has been shown to be highly correlated with IFNα (interferon-α) production mediated by immune complexes of plasmacytoid dendritic cells, a key process in the pathogenesis of systemic lupus erythematosus (SLE) (Chiang et al., The Journal of Immunology, 2010). Furthermore, the signaling pathway has been associated with obesity (Ahmad, R., P. Shihab et al., Diabetology & Metabolic Syndrome, 2015).

In addition to IRAK4's key role in innate immunity, there are also suggestions that IRAK4 affects the differentiation of so-called Th17 T cells, members of adaptive immunity. In the absence of IRAK4 kinase activity, fewer IL-17-producing T cells (Th17 T cells) are produced compared to WT mice. Inhibition of IRAK4 enables the prevention and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bechterev's disease), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, chronic inflammatory bowel disorders and viral disorders, such as HIV (human immunodeficiency virus), hepatitis viruses (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).

Due to the central role of IRAK4 in the MyD88-mediated signaling cascade of the TLR (except TLR3) and IL-1 receptor families, inhibition of IRAK4 may be useful in preventing and/or treating disorders mediated by these receptors. Members of the TLR and IL-1 receptor families have been implicated in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitides (e.g., Behcet's disease, granulomatosis with polyangiitis, and granulomatosis with 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's 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 such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa, and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway or the IL-1R family (Schmidt, Mittnacht et al., J Dermatol Sci, 1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad et al., Archives of Dermatology, 2004; Niebuhr, Langnickel et al., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali et al., Am J Clin Dermatol, 2010; Viguier, Guigue et al., Annals of Internal Medicine, 2010; 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., Indian Dermatol Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014).

Pulmonary disorders such as pulmonary fibrosis, COPD, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis, and pulmonary hypertension have also been shown to be associated with various TLR-mediated signaling pathways. The pathogenesis of pulmonary disorders may be infectious-mediated or non-infectious-mediated processes (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004; Jeyaseelan, Chu, et al., Infection and Immunity, 2005; Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013). TLR and IL-1R family members are also involved in the pathogenesis of other inflammatory diseases such as allergies, Behcet's disease, gout, lupus erythematosus, adult-onset Still's disease, pericarditis and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, transplant rejection and graft-versus-host reaction, and therefore, inhibition of IRAK4 is a suitable preventive and/or therapeutic approach here (Liu-Bryan, Scott et al., Arthritis & Rheumatism, 2005; Piggott, Eisenbarth et al., J Clin Inves, 2005; Christensen, Shupe et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., Immunity, 2006; Heimesaat, Fischer, et al., PLoS ONE, 2007; Heimesaat, Nogai, et al., Gut, 2010; Kobori, Yagi, et al., J Gastroenterol, 2010; Schmidt, Raghavan, et al., Nat Immunol, 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang et al., Pharmacology & Therapeutics, 2013; Walsh, Carthy et al., Cytokine & Growth Factor Reviews, 2013; Zhu, Jiang et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013; Vennegaard, Dyring-Andersen et al., Contact Dermatitis, 2014; D'Elia, Brucato et al., Clin Exp Rheumatol, 2015; Jain, Thongprayoon et al., Am J Cardiol., 2015; Li, Zhang et al., Oncol Rep., 2015).

Gynecological conditions mediated by the TLR and IL-1R family, such as adenomyosis, dysmenorrhea, dyspareunia, and endometriosis, especially pain associated with endometriosis and other symptoms associated with endometriosis, such as dysmenorrhea, dyspareunia, dysuria, and dysfecation, may 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 The prophylactic and/or therapeutic use of IRAK4 inhibitors may also have a positive impact 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 disorders already mentioned, IRAK4-mediated TLR processes have also been described in the pathogenesis of ocular disorders, such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration, and uveitis (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, 2012). Science, 2014).

Inhibition of IRAK4 is also a suitable treatment for fibrotic disorders, such as liver fibrosis, myocarditis, primary biliary cirrhosis, and cystic fibrosis (Zhao, Zhao et al., Scand J Gastroenterol, 2011; Benias, Gopal et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu et al., Biochim Biophys Acta., 2015).

Since IRAK4 plays a key role in disorders mediated by the TLR and IL-1R family, IRAK4 inhibitors can be used to treat chronic liver disorders, such as fatty liver hepatitis, especially non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) in a preventive and/or therapeutic manner (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 central role of IRAK4 in TLR-mediated processes, inhibition of IRAK4 can also treat and/or prevent cardiovascular and neurological disorders, such as myocardial reperfusion injury, myocardial infarction, and 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; Christia and 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, 2016). Sciences, 2015), as well as Alzheimer's disease, stroke, traumatic brain 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 Immunology, 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 Neurosci, 2015). Neuroinflammation, 2015).

Since TLR-mediated signaling through IRAK4 and IL-1 receptor family-mediated signaling are involved in itch and pain (including acute, chronic, inflammatory and neuropathic pain), it is envisioned that inhibition of IRAK4 would have therapeutic effects on these indications. Examples of pain include hyperalgesia, allodynia, premenstrual pain, pain associated with endometriosis, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, pain caused by spinal cord injury, pain caused by inflammation, low back pain, cancer pain, chemotherapy-related pain, HIV treatment-induced neuropathy, pain caused by burns, 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., Journal of Neuroinflammation, 2013; Zhao, Zhang et al., Neuroscience, 2013; Liu, Zhang et al., Cell Research, 2014; Park, Stokes et al., Cancer Chemother Pharmacol, 2014; Van der Watt, Wilkinson et al., BMC Infect Dis, 2014; Won, K.A., M.J. Kim et al., J Pain, 2014; Min, Ahmad et al., Photochem Photobiol., 2015; Schrepf, Bradley et al., Brain Behav Immun, 2015; Wong, L., J.D. Done et al., Prostate, 2015).

This also applies to some tumor conditions. Specific lymphomas such as ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma), mantle cell lymphoma and Waldenstrom's disease, as well as chronic lymphocytic leukemia, melanoma, pancreatic tumors and hepatocellular carcinoma are characterized by mutations in MyD88 or changes in MyD88 activity and can be treated with 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 therefore, IRAK4 inhibitors are also suitable for treating ras-dependent tumors (Kfoury, A., K.L. Corf et al., Journal of the National Cancer Institute, 2013). It is also conceivable that inhibition of IRAK4 will have therapeutic effects on breast cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer, and prostate cancer, as these indications are related to signaling pathways (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 such as CAPS (cryopyrin-associated periodic syndromes), including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease), and CONCA (chronic infantile, neurological, cutaneous, and articular syndrome); FMF (familial Mediterranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumor necrosis factor receptor 1-associated periodic syndrome), juvenile idiopathic arthritis Arthritis), adult-onset Still's disease, Behçet's syndrome (Adamantiades-disease), rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca, PAPA syndrome (septic arthritis, pyoderma gangrenosum and acne), Schnitzler's syndrome and Sjögren's syndrome are treated by blocking the IL-1 signaling pathway; therefore, IRAK4 inhibitors are also suitable for the treatment of these diseases (Narayanan, Corrales et al., Cornea, 2008; Brenner, Ruzicka et al., British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of Immunology, 2011; Gul, Tugal-Tutkun et al., Ann Rheum Dis, 2012; Pettersson, Annals of Medicine Petterson, 2012; Ruperto, Brunner et al., New England Journal of Medicine, 2012; 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). IL-33, a ligand of IL-33R, is particularly involved in the pathogenesis of acute renal failure. Therefore, inhibition of IRAK4 is a suitable therapeutic approach for prevention and/or treatment (Akcay, Nguyen et al., Journal of the American Society of Nephrology, 2011). IL-1 receptor family members are associated with myocardial infarction, various lung disorders (e.g., asthma, COPD, idiopathic interstitial pneumonia), allergic rhinitis, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS), and therefore, in these indications, a preventive and/or therapeutic effect is expected to be achieved by inhibiting IRAK4 (Kang, Homer et al., The Journal of Immunology, 2007; Imaoka, Hoshino et al., European Respiratory Journal, 2008; Coullin, Vasseur et al., The Journal of Immunology, 2009; Abbate, Kontos et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke et al., European Respiratory Journal, 2011; Haenuki, Matsushita et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013; Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013; Martínez-González, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Biology, 2014. Immunology, 2014; Lugrin, Parapanov et al., The Journal of Immunology, 2015).

The prior art discloses many IRAK4 inhibitors (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).

US8293923 and US20130274241 disclose IRAK4 inhibitors having a 3-substituted indazole structure, but do not describe 2-substituted indazoles.

WO2013106254 and WO2011153588 disclose 2,3-disubstituted indazole derivatives.

WO2007091107 describes 2-substituted indazole derivatives for treating Duchenne muscular dystrophy. WO2007091107 does not disclose 5,6-disubstituted indazole derivatives.

WO2009024341 describes indazoles as insecticides which have further substituents in the 7-position.

WO2013042137 describes benzothiazole, benzoxazole and benzimidazole as IRAK4 inhibitors, each of which has a morpholine group at position 2, but none of which has a cyclic substituent linked via carbon to position 2. WO2013042137 does not describe indazole.

WO2015104688 also reports bicyclic IRAK4 inhibitors with fused 6- and 5-membered bicyclic heteroaromatic ring systems. These inhibitors are substituted on the 5-membered heteroaromatic ring with a saturated nitrogen-containing heterocycle bonded to the bicyclic system via a nitrogen atom. Indazole is not described as a bicyclic ring system.

WO2015091426 describes indazoles substituted at the 2-position with a carboxamide side chain.

There is no disclosure of compounds having a cyclic substituent directly bonded to the 2-position of indazole.

WO2015104662 discloses 2-substituted indazoles of the following general formula:

Wherein ^R2 is an alkyl or cycloalkyl group. Indazoles with methyl, 2-methoxyethyl, and cyclopentyl groups at the 2-position are clearly described (Examples 1, 4, 7, and 76). WO2015104662 does not describe 2-substituted indazoles with a saturated heterocycle bonded to a carbon atom at the 2-position of the indazole.

WO2015193846 discloses 2-substituted indazoles of the following general formula:

Wherein Z ¹ and Z ² are each an optionally substituted cycloalkyl, aryl or heteroaryl group. ^{R 2} may be hydrogen, halogen, amino, or an optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, arylalkyl or heterocyclylalkyl group in each case. Indazole derivatives in which R ² is a methyl group and Z ¹ and/or Z ² is a heteroaryl group are explicitly described, wherein -NH(C=O)Z ¹ -Z ² -(R ³ ) _n substituents are bonded to the 6-position of the indazole skeleton. Indazole derivatives having -NH(C=O)Z ¹ -Z ² -(R ³ ) _n substituents bonded to the 5-position are not described. In WO2015193846, there are no records of indazole derivatives having a saturated heterocycle bonded to the 2-position via a carbon atom. The problem addressed by the present invention is to provide new compounds as inhibitors of interleukin-1 receptor associated kinase-4 (IRAK4).

The present invention provides compounds of general formula (I), and diastereomers, enantiomers, metabolites, salts, solvates or solvates of their salts

in

R ¹ is halogen, cyano, C(═O)OH, C(═O)OR ^a , C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , C(═O)R ^d , hydroxy or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl groups may optionally be mono- or polysubstituted, identically or differently, by:

hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N( ^Ra )R ^b , C ₁ -C ₆ -alkoxy or C ₃ -C ₇ -cycloalkoxy optionally substituted by mono- to hexafluoro, 4- to 7-membered heterocycloalkyl optionally mono- to tri-substituted by the same or different R ^c ,

or C ₁ -C ₆ -alkoxy, where the C ₁ -C ₆ -alkoxy radical may optionally be mono- or polysubstituted, identically or differently, by:

hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N( ^Ra )R ^b , C ₃ -C ₇ -cycloalkyl optionally substituted by mono- to tetrafluoro, C ₁ -C ₆ -alkoxy optionally substituted by mono- to pentafluoro, C ₃ -C ₇ -cycloalkoxy optionally substituted by mono- to tetrafluoro, 4- to 7-membered heterocycloalkyl optionally mono- or polysubstituted identically or differently by R ^c ,

or C ₃ -C ₇ -cycloalkoxy or 4- to 7-membered heterocycloalkoxy, wherein C ₃ -C ₇ -cycloalkoxy and 4- to 7-membered heterocycloalkoxy may be optionally mono- or polysubstituted, identically or differently, by hydroxy, fluorine, cyano, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy;

^Ra is C1- _{C6 -} alkyl, C3- _C7 -cycloalkyl, 4- to 7 _- membered heterocycloalkyl, wherein _C1 - _C6 -alkyl, _C3 - _C7 -cycloalkyl and 4- to 7-membered heterocycloalkyl may be optionally mono- or polysubstituted, identically or differently, by fluorine, hydroxy, cyano, _C1 - _C4 -alkyl, _C1 - _C4 -alkoxy or _C3 - _C7 -cycloalkyl;

R ^b is C ₁ -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl;

or ^Ra and ^Rb together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may be optionally mono- or disubstituted, identically or differently, by hydroxy, halogen, cyano or C1- _C6 - _alkyl ;

R ^c is hydroxy, fluorine, chlorine, cyano, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy;

R ^d is hydrogen, C ₃ -C ₇ -cycloalkyl or C ₁ -C ₆ -alkyl which may be optionally substituted by hydroxy;

^R2 is a 5-membered heteroaryl group which is monosubstituted by ^R4 and monosubstituted by ^R5 , or

^R2 is a 6-membered heteroaryl group, which is monosubstituted by ^R4 and monosubstituted or disubstituted identically or differently by ^R5 ;

R ³ is a group selected from the following:

Where * represents the site of attachment of the group to the rest of the molecule;

^R4 is hydrogen, halogen, hydroxy, C(=O)OH, cyano, _NH2 , ^NHRa , N( ^Ra ) ^Rb , C(=O) ^Ra , N(H)C(=O) ^Ra , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , S(=O) ^Ra , S(= ^O ) _2Ra , S(=O) _2NH2 , S(=O) _2NHRa ^or S(= _O ) _2N ( ^Ra ) ^Rb ,

or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may be optionally substituted by 1 to 5 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, bromo, chloro, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₇ -cycloalkoxy, trifluoromethoxy,

or C ₁ -C ₆ -alkoxy, wherein

C ₁ -C ₆ -alkoxy may be optionally substituted by 1 to 5 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₇ -cycloalkoxy, trifluoromethoxy,

or C ₃ -C ₇ -cycloalkyl or C ₃ -C ₇ -cycloalkoxy, wherein

C ₃ -C ₇ -cycloalkyl and C ₃ -C ₇ -cycloalkoxy may be optionally substituted by 1 to 4 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^d , C(═O)OH, C ₁ -C ₆ -alkyl or C ₁ -C ₄ -alkoxy,

or is 4-7 membered heterocycloalkyl, which may be optionally substituted by 1 to 4 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chloro, bromo, cyano, NH ₂ , NHR ^a , N( ^Ra )R ^b , C(═O)R ^d , C(═O)OH, C ₁ -C ₆ -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or C ₁ -C ₄ -alkoxy,

or phenyl or 5-membered or 6-membered heteroaryl, wherein

Phenyl and 5-membered or 6-membered heteroaryl may be optionally mono- to disubstituted, identically or differently, by fluorine, chlorine, bromine, hydroxy, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₄ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(═O)R ^a , C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₁ -C ₄ -alkyl, wherein C ₁ -C ₄ -alkyl may be optionally mono- to trisubstituted by fluorine;

R ⁵ is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may be optionally substituted by 1 to 5 fluorine atoms,

R ^6f is hydrogen, fluorine, C(═O)OH, C(═O)NH ₂ , trifluoromethyl, hydroxymethyl, methoxymethyl, cyano or C ₁ -C ₆ -alkyl;

R ^6g is hydrogen, fluorine or C ₁ -C ₆ -alkyl, or

R ^6f and R ^6g together with the carbon atom to which they are attached form C ₃ -C ₇ -cycloalkyl, or

R ^6f and R ^6g together are an oxo group;

R ^6h is hydrogen, trifluoromethyl or C ₁ -C ₆ -alkyl;

R ⁶ⁱ is hydrogen or C ₁ -C ₆ -alkyl, or

R ^6h and R ⁶ⁱ together represent an oxo group;

R ^6j is hydrogen, fluorine, NH ₂ , N(H)R ^a , N(R ^a )R ^b , C ₁ -C ₆ -alkyl, hydroxy, cyano, C ₁ -C ₄ -alkoxy, C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , hydroxymethyl, dimethylaminomethyl, or trifluoromethyl;

R ^6k is hydrogen, fluorine or C ₁ -C ₆ -alkyl, or

R ^6j and R ^6k together with the carbon atom form a C ₃ -C ₇ -cycloalkyl group;

R ⁶¹ is hydrogen or methyl;

R ^6m is hydrogen or methyl;

G is -CH ₂ - or -CH ₂ CH ₂ -;

n in formula R ^3a is 0, 1 or 2,

n in formula R ^3b is 1 or 2,

n in formula R ^3c is 0 or 1,

z is a group selected from NR ⁷ , O, S, S(═O), S(═O) ₂ , and S(═O)(═NH);

R ⁷ is hydrogen, C(=O)R ^e , C(=O)OR ^a , C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(=O) ₂ N(R ^a )H, S(=O) ₂ N(R ^a )R ^b , S(=O) ₂ NHC(=O)CH ₃ , S(=O) ₂ NHC(=O)CH ₂ CH ₃ or C ₁ -C ₆ -alkyl, where

C ₁ -C ₆ -alkyl may optionally be mono- to pentasubstituted by fluorine atoms and mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^a , C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , morpholin-4-yl, 4-methylpiperazin-1-yl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy or C ₃ -C ₇ -cycloalkoxy;

or C ₃ -C ₇ -cycloalkyl, which may be optionally mono- to tetra-substituted by fluorine atoms and may be optionally mono- to di-substituted, identically or differently, by hydroxy, methyl, ethyl, trifluoromethyl or cyano groups;

or is a 4- to 7-membered heterocycloalkyl radical, which is linked to the remainder of the molecule via a carbon atom, or is a 4- to 7-membered heterocycloalkyl-C ₁ -C ₄ -alkyl radical, which may be optionally mono- to hexa-substituted by fluorine atoms and mono- to tri-substituted, identically or differently, by the following radicals: hydroxy, chlorine, bromine, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl;

R ^e is C ₁ -C ₆ -alkyl, wherein C ₁ -C ₆ -alkyl may be optionally mono- to trisubstituted, identically or differently, by hydroxy, fluorine, chlorine, cyano, C(═O)R ^a , C(═O)OH, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₃ -C ₇ -cycloalkoxy, or

R ^e is C ₃ -C ₇ -cycloalkyl, wherein C ₃ -C ₇ -cycloalkyl may be optionally mono- to tetra-substituted by fluorine and may be optionally mono-substituted by hydroxy.

One embodiment of the present invention includes compounds of formula (I), and diastereomers, enantiomers, metabolites, salts, solvates, or solvates of their salts.

in

R ¹ is halogen, cyano, C(═O)OH, C(═O)OR ^a , C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , C(═O)R ^d , hydroxy or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl groups may optionally be mono- or polysubstituted, identically or differently, by:

hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N( ^Ra )R ^b , C ₁ -C ₆ -alkoxy or C ₃ -C ₇ -cycloalkoxy optionally substituted by mono- to hexafluoro, 4- to 7-membered heterocycloalkyl optionally mono- to tri-substituted by the same or different R ^c ,

or C ₁ -C ₆ -alkoxy, where the C ₁ -C ₆ -alkoxy radical may optionally be mono- or polysubstituted, identically or differently, by:

hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N( ^Ra )R ^b , C ₃ -C ₇ -cycloalkyl optionally substituted by mono- to tetrafluoro, C ₁ -C ₆ -alkoxy optionally substituted by mono- to pentafluoro, C ₃ -C ₇ -cycloalkoxy optionally substituted by mono- to tetrafluoro, 4- to 7-membered heterocycloalkyl optionally mono- or polysubstituted identically or differently by R ^c ,

or C ₃ -C ₇ -cycloalkoxy or 4- to 7-membered heterocycloalkoxy, wherein C ₃ -C ₇ -cycloalkoxy and 4- to 7-membered heterocycloalkoxy may be optionally mono- or polysubstituted, identically or differently, by hydroxy, fluorine, cyano, C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy;

^Ra is C1- _{C6 -} alkyl, C3- _C7 -cycloalkyl, 4- to 7 _- membered heterocycloalkyl, wherein _C1 - _C6 -alkyl, _C3 - _C7 -cycloalkyl and 4- to 7-membered heterocycloalkyl may be optionally mono- or polysubstituted, identically or differently, by fluorine, hydroxy, cyano, _C1 - _C4 -alkyl, _C1 - _C4 -alkoxy or _C3 - _C7 -cycloalkyl;

R ^b is C ₁ -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl;

or ^Ra and ^Rb together with the nitrogen atom form a 5- or 6-membered heterocyclic ring which may be optionally mono- or disubstituted, identically or differently, by hydroxy, halogen, cyano or C1- _C6 - _alkyl ;

R ^c is hydroxy, fluorine, chlorine, cyano, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkoxy;

R ^d is hydrogen, C ₃ -C ₇ -cycloalkyl or C ₁ -C ₆ -alkyl which may be optionally substituted by hydroxy;

^R2 is a 5-membered heteroaryl group which is monosubstituted by ^R4 and monosubstituted by ^R5 , or

^R2 is a 6-membered heteroaryl group, which is monosubstituted by ^R4 and monosubstituted or disubstituted identically or differently by ^R5 ;

R ³ is a group selected from the following:

Where * represents the site of attachment of the group to the rest of the molecule;

^R4 is hydrogen, halogen, hydroxy, C(=O)OH, cyano, _NH2 , ^NHRa , N( ^Ra ) ^Rb , C(=O) ^Ra , N(H)C(=O) ^Ra , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , S(=O) ^Ra , S(= ^O ) _2Ra , S(=O) _2NH2 , S(=O) _2NHRa ^or S(= _O ) _2N ( ^Ra ) ^Rb ,

or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may be optionally substituted by 1 to 5 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, bromo, chloro, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₇ -cycloalkoxy, trifluoromethoxy,

or C ₁ -C ₆ -alkoxy, wherein

C ₁ -C ₆ -alkoxy may be optionally substituted by 1 to 5 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₇ -cycloalkoxy, trifluoromethoxy,

or C ₃ -C ₇ -cycloalkyl or C ₃ -C ₇ -cycloalkoxy, wherein

C ₃ -C ₇ -cycloalkyl and C ₃ -C ₇ -cycloalkoxy may be optionally substituted by 1 to 4 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^d , C(═O)OH, C ₁ -C ₆ -alkyl or C ₁ -C ₄ -alkoxy,

or is 4-7 membered heterocycloalkyl, which may be optionally substituted by 1 to 4 fluorine atoms and may be optionally mono- or disubstituted, identically or differently, by hydroxy, chloro, bromo, cyano, NH ₂ , NHR ^a , N( ^Ra )R ^b , C(═O)R ^d , C(═O)OH, C ₁ -C ₆ -alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or C ₁ -C ₄ -alkoxy,

or phenyl or 5-membered or 6-membered heteroaryl, wherein

Phenyl and 5-membered or 6-membered heteroaryl may be optionally mono- to disubstituted, identically or differently, by fluorine, chlorine, bromine, hydroxy, cyano, C(═O)OH, S(═O) ₂ -C ₁ -C ₄ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(═O)R ^a , C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₁ -C ₄ -alkyl, wherein C ₁ -C ₄ -alkyl may be optionally mono- to trisubstituted by fluorine;

R ⁵ is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may be optionally substituted by 1 to 5 fluorine atoms,

R ^6f is hydrogen, fluorine, C(═O)OH, C(═O)NH ₂ , trifluoromethyl, hydroxymethyl, methoxymethyl, cyano or C ₁ -C ₆ -alkyl;

R ^6g is hydrogen, fluorine or C ₁ -C ₆ -alkyl, or

R ^6f and R ^6g together with the carbon atom to which they are attached form C ₃ -C ₇ -cycloalkyl, or

R ^6f and R ^6g together are an oxo group;

R ^6h is hydrogen, trifluoromethyl or C ₁ -C ₆ -alkyl;

R ⁶ⁱ is hydrogen or C ₁ -C ₆ -alkyl, or

R ^6h and R ⁶ⁱ together represent an oxo group;

R ^6j is hydrogen, fluorine, NH ₂ , N(H)R ^a , N(R ^a )R ^b , C ₁ -C ₆ -alkyl, hydroxy, cyano, C ₁ -C ₄ -alkoxy, C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , hydroxymethyl, dimethylaminomethyl, or trifluoromethyl;

R ^6k is hydrogen, fluorine or C ₁ -C ₆ -alkyl, or

R ^6j and R ^6k together with the carbon atom form a C ₃ -C ₇ -cycloalkyl group;

R ⁶¹ is hydrogen or methyl;

R ^6m is hydrogen or methyl;

G is -CH ₂ - or -CH ₂ CH ₂ -;

n in formula R ^3a is 0, 1 or 2,

n in formula R ^3b is 1 or 2,

n in formula R ^3c is 0 or 1,

z is a group selected from NR ⁷ , O, S, S(═O), S(═O) ₂ , and S(═O)(═NH);

R ⁷ is hydrogen, C(=O)R ^e , C(=O)OR ^a , C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(=O) ₂ N(R ^a )H, S(=O) ₂ N(R ^a )R ^b , S(=O) ₂ NHC(=O)CH ₃ , S(=O) ₂ NHC(=O)CH ₂ CH ₃ or C ₁ -C ₆ -alkyl, where

C ₁ -C ₆ -alkyl may optionally be mono- to penta-substituted by fluorine atoms, or

C ₁ -C ₆ -alkyl may be optionally mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^a , C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , morpholin-4-yl, 4-methylpiperazin-1-yl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy or C ₃ -C ₇ -cycloalkoxy, or

C ₁ -C ₆ -alkyl may optionally be mono- to pentasubstituted by fluorine atoms and mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^a , C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , morpholin-4-yl, 4-methylpiperazin-1-yl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy or C ₃ -C ₇ -cycloalkoxy;

or C ₃ -C ₇ -cycloalkyl, which may be optionally mono- to tetra-substituted by fluorine atoms and may be optionally mono- to di-substituted, identically or differently, by hydroxy, methyl, ethyl, trifluoromethyl or cyano groups;

or is a 4- to 7-membered heterocycloalkyl radical, which is linked to the remainder of the molecule via a carbon atom, or is a 4- to 7-membered heterocycloalkyl-C ₁ -C ₄ -alkyl radical, which may be optionally mono- to hexa-substituted by fluorine atoms and mono- to tri-substituted, identically or differently, by the following radicals: hydroxy, chlorine, bromine, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl;

R ^e is C ₁ -C ₆ -alkyl, wherein C ₁ -C ₆ -alkyl may be optionally mono- to trisubstituted, identically or differently, by hydroxy, fluorine, chlorine, cyano, C(═O)R ^a , C(═O)OH, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy, trifluoromethoxy or C ₃ -C ₇ -cycloalkoxy, or

R ^e is C ₃ -C ₇ -cycloalkyl, wherein C ₃ -C ₇ -cycloalkyl may be optionally mono- to tetra-substituted by fluorine and may be optionally mono-substituted by hydroxy.

The new IRAK4 inhibitors are particularly suitable for the treatment and prevention of proliferative, metabolic and inflammatory disorders characterized by an overreactive immune system. Inflammatory skin disorders, cardiovascular disorders, lung disorders, eye disorders, neurological disorders, pain disorders and cancer should be mentioned in particular in this context.

In addition, new IRAK4 inhibitors are suitable for treatment and prevention

Autoimmune and inflammatory conditions, especially rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, spondyloarthritis, and gout,

Metabolic disorders, especially liver disorders such as fatty liver, and

Gynecological conditions, particularly endometriosis and endometriosis-related pain, as well as other endometriosis-related symptoms such as dysmenorrhea, dyspareunia, dysuria, and dysuria.

For the synthetic intermediates and working examples of the present invention described below, any compound specifically indicated in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition obtained by the respective preparation and/or purification process. Therefore, unless otherwise indicated in more detail, for such salts, the supplementary names and structural formulae (e.g., "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF ₃ COOH", "x Na ⁺ ") are not to be understood in a stoichiometric sense, but are merely descriptive symbols with respect to the salt-forming components present therein.

This also applies correspondingly if synthetic intermediates or working examples or salts thereof are obtained by the preparation and/or purification processes described in the form of solvates (eg hydrates) of unknown stoichiometric composition.

The compounds of the present invention are compounds of formula (I) and salts, solvates and solvates of salts thereof, compounds encompassed by formula (I) and of the following formulae and salts, solvates and solvates of salts thereof, and compounds encompassed by formula (I) and mentioned below as working examples and salts, solvates and solvates of salts thereof, with the proviso that the compounds encompassed by formula (I) and mentioned below are not already salts, solvates and solvates of salts thereof.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. However, the invention also comprises salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolating or purifying the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic 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 according to the invention also include salts with customary bases, such as, for example and preferably, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the present invention, solvates are described as those forms of the compounds of the invention which form solid or liquid complexes by coordination with solvent molecules. Hydrates are a special form of solvates which coordinate with water.

Depending on their structure, the compounds of the invention may exist in different stereoisomeric forms, i.e. in the form of configurational isomers or, if appropriate, as conformers (enantiomers and/or diastereomers, including atropisomers). The present invention therefore encompasses enantiomers and diastereomers and their respective mixtures. Stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers by known methods; for this purpose, preferably chromatography is used, in particular HPLC chromatography on an achiral or chiral phase.

If the compounds according to the invention can exist in tautomeric forms, the invention encompasses all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of the present invention. In this article, isotopic variants of the compounds of the present invention are understood to mean compounds in which at least one atom in the compounds of the present invention is replaced by another atom having the same atomic number but an atomic mass different from the atomic mass usually or mainly present in nature. Examples of isotopes that can be included in the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I, and 131I. Specific isotopic variants of the compounds of the present invention, such as variants in which one or more radioactive isotopes have been incorporated, can be useful, for example, for studying the mechanism of action or the distribution of the active ingredient in vivo; compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose due to their relatively easy preparability and detectability. In addition, due to the higher metabolic stability of the compound, the incorporation of an isotope (e.g., deuterium) can produce special therapeutic benefits, such as extending the half-life in vivo or reducing the required active dose; therefore, in some cases, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example, by the methods further described below and in the working examples, using the corresponding isotopic modifications of the respective reagents and/or starting compounds.

The present invention further provides all possible crystalline forms and polymorphic forms of the compounds of the invention, where the polymorphs may be present as single polymorphs or as mixtures of a plurality of polymorphs within the entire concentration range.

In addition, the present invention also includes prodrugs of the compounds of the present invention. In this article, the term "prodrug" refers to a compound that may or may not be biologically active, but reacts during its residence in the body (e.g., by metabolic or hydrolytic processes) to give the compounds of the present invention.

In the context of the present invention, unless otherwise stated, substituents have the following meanings:

In the context of the present invention, alkyl is a straight or branched chain alkyl group with a specified specific number of carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 2-methylbutyl, 3-methylbutyl and 2,2-dimethylpropyl. Particularly preferred are methyl, ethyl and isopropyl.

In the context of the present invention, cycloalkyl is a monocyclic saturated alkyl radical having the specified number of carbon atoms in each case. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preference is given to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Particular preference is given to cyclopropyl.

In the context of the present invention, alkoxy is a straight-chain or branched alkoxy group with a specified specific number of carbon atoms. Preferably, it has 1 to 6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy. Particularly preferred are straight-chain or branched alkoxy groups with 1 to 4 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy. Methoxy and ethoxy are very particularly preferred.

Halogen in the context of the present invention is fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred. Fluorine is particularly preferred.

A hydroxyl group in the context of the present invention is OH.

Heterocycloalkyl

The term "4- to 7-membered heterocycloalkyl" refers to a monocyclic saturated heterocycle having a total of 4 to 7 ring atoms, wherein one or two ring carbon atoms are replaced by the same or different heteroatoms selected from N, O and S; the heterocycloalkyl group can be attached to the rest of the molecule via any one carbon atom or, if present, a nitrogen atom.

The heterocycloalkyl group may, although this is not intended to be limiting, be, for example, a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinyl; or a 7-membered ring, such as azepanyl, 1,4-diazepanyl or 1,4-oxazepanyl.

A 4- to 6-membered heterocycloalkyl group is preferred.

Particularly preferred are oxetanyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

Heterocycloalkoxy

The term "4- to 7-membered heterocycloalkoxy group" refers to a monocyclic saturated heterocycloalkoxy group having a total of 4 to 7 ring atoms, wherein one or two ring carbon atoms are replaced by the same or different heteroatoms selected from N, O and S. The heterocycloalkoxy group can be attached to the oxygen atom that attaches the heterocycloalkoxy group to the rest of the molecule via any carbon atom. Preferred heteroatoms in the ring are nitrogen atoms or oxygen atoms.

Preferred are 4- to 6-membered heterocycloalkoxy groups. Examples include oxetan-3-yloxy, azetidin-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, and piperidin-4-yloxy.

Preferred are oxetan-3-yloxy and tetrahydrofuran-3-yloxy.

Heteroaryl

The term "heteroaryl" is understood to mean a monovalent monocyclic aromatic ring system having 5 or 6 ring atoms and containing at least one ring heteroatom and optionally one, two or three further ring heteroatoms selected from N, O and S, and which is linked to the remainder of the molecule via a ring carbon atom or, if valence permits, via a ring nitrogen atom.

Examples of 5-membered heteroaryl groups ("5-membered heteroaryl") include thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl. Examples of 6-membered heteroaryl groups ("6-membered heteroaryl") include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

Generally, unless otherwise indicated, heteroaryl groups include all possible isomeric forms, such as tautomers and positional isomers related to the point of attachment of the rest of the molecule. For example, the term "pyridyl" includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl. Another illustrative example is the term "thiazolyl," which includes 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, and 1,3-thiazol-2-yl. The examples are cited to illustrate the definitions and should not be construed as limiting the terms mentioned.

Preferred 5-membered heteroaryl groups are oxazolyl, thiazolyl and pyrazolyl. Particularly preferred are pyrazol-3-yl, 1,3-thiazol-4-yl and 1,3-thiazol-2-yl. Very particularly preferred are pyrazol-3-yl and 1,3-thiazol-4-yl.

Preferred 6-membered heteroaryl groups are pyridinyl. Pyridin-2-yl and pyridin-4-yl are particularly preferred. Pyridin-2-yl is very particularly preferred.

The symbol * above a bond indicates the site of attachment in the molecule.

When a group in the compounds of the invention is substituted, the group may be monosubstituted or polysubstituted, unless otherwise indicated. In the context of the present invention, all groups that occur more than once are defined independently of one another. Preferably, the group is substituted by one, two or three identical or different substituents.

When ^R7 is _C1 - _C6 -alkyl, which may optionally be mono- to pentasubstituted by fluorine atoms and mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(=O) ^Ra , C(=O)OH, C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , S(=O) ₂ - _C1 - _C6 -alkyl, _NH2 , ^NHRa , N( ^Ra ) ^Rb , morpholin-4-yl, 4-methylpiperazin-1-yl, _C3 - _C7 -cycloalkyl, _C1 - _C4 -alkoxy or _C3 - _C7 -cycloalkyloxy, the substitution of _C1 - _C6 -alkyl is to be understood as follows:

When R ⁷ is C ₁ -C ₆ -alkyl,

C ₁ -C ₆ -alkyl may be unsubstituted or mono- to penta-substituted by fluorine atoms, or

C ₁ -C ₆ -alkyl may be unsubstituted or mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^a , C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , morpholin-4-yl, 4-methylpiperazin-1-yl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy or C ₃ -C ₇ -cycloalkoxy, or

C ₁ -C ₆ -Alkyl can be unsubstituted or mono- to pentasubstituted by fluorine atoms and mono- to disubstituted, identically or differently, by hydroxy, chlorine, bromine, cyano, C(═O)R ^a , C(═O)OH, C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , morpholin-4-yl, 4-methylpiperazin-1-yl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₄ -alkoxy or C ₃ -C ₇ -cycloalkoxy.

A preferred embodiment of the present invention is a compound of formula (I), wherein

R ¹ is a C ₁ -C ₃ -alkyl group substituted by a hydroxy group. Particular preference is given to hydroxymethyl, 1-hydroxyethyl and 2-hydroxyprop-2-yl. Very particular preference is given to 2-hydroxyprop-2-yl.

Other preferred embodiments of the present invention are compounds in which ^R is a C ₁ -C ₆ -alkoxy group which may be optionally substituted by a C ₃ -C ₇ -cycloalkyl group. In this context, preference is given to C ₁ -C ₄ -alkoxy groups or cyclopropylmethoxy groups. Particular preference is given to cyclopropylmethoxy, ethoxy and methoxy. Very particular preference is given to cyclopropylmethoxy and methoxy.

In a further preferred embodiment of the present invention, R ¹ is a 2,2,2-trifluoroethoxy group or a 2,2-difluoroethoxy group.

In other preferred embodiments of the present invention, R ¹ is C(═O)NH ₂ .

In other preferred embodiments of the present invention, R ¹ is C(═O)OH.

In a further preferred embodiment of the invention, R ¹ is a C(═O)(C ₁ -C ₄ -alkyl)- group, particularly preferably C(═O)CH ₃ .

A preferred embodiment of the present invention is a compound in which R ² is a pyridin-2-yl group substituted in the 6-position by a C ₁ -C ₆ -alkyl group, wherein the C ₁ -C ₆ -alkyl group may optionally be substituted by up to 5 fluorine atoms. Alternatively, R ² is a pyridin-2-yl group substituted in the 6-position by a cyano group, a chloro group, a cyclopropyl group, a cyclopropylmethyl group, an NH ₂ , an NH(C ₁ -C ₄ -alkyl group), an N(C ₁ -C ₄ -alkyl group) ₂ , a C ₁ -C ₄ -alkoxy group, a 2,2,2-trifluoroethoxy group, a 2-hydroxypropan-2-yl group, a morpholin-4-yl group, a 4-methylpiperazin-1-yl group or a piperazin-1-yl group.

As R ² , particular preference is given to a pyridin-2-yl group substituted in the 6-position by trifluoromethyl, difluoromethyl, methyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, ethyl, isopropyl, tert-butyl, cyano, chloro, cyclopropyl, cyclopropylmethyl, NH ₂ , NH(C ₁ -C ₄ -alkyl), N(C ₁ -C ₄ -alkyl) ₂ , C ₁ -C ₄ -alkoxy, 2,2,2-trifluoroethoxy, 2-hydroxyprop-2-yl, morpholin-4-yl, 4-methylpiperazin-1-yl or piperazin-1-yl. Most preferably, ^R2 is 6-(trifluoromethyl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(1,1-difluoroethyl)pyridin-2-yl, 6-aminopyridin-2-yl and 6-(2-hydroxypropan-2-yl)pyridin-2-yl. Among them, 6-(trifluoromethyl)pyridin-2-yl is preferred.

Furthermore, R ² is preferably an optionally substituted 1,3-thiazol-2-yl group, especially an optionally substituted 1,3-thiazol-2-yl group or 1,3-thiazol-4-yl group. Particularly preferred are 4-cyclopropyl-1,3-thiazol-2-yl and 1,3-thiazol-2-yl, wherein the 1,3-thiazol-2-yl group is substituted at the 4-position by a C ₁ -C ₆ -alkyl group, and the C ₁ -C ₆ -alkyl group may be optionally substituted by 1 to 5 fluorine atoms. Also particularly preferred are 2-cyclopropyl-1,3-thiazol-4-yl and 1,3-thiazol-4-yl, wherein the 1,3-thiazol-4-yl group is substituted at the 2-position by a C ₁ -C ₆ -alkyl group, and the C ₁ -C ₆ -alkyl group may be optionally substituted by 1 to 5 fluorine atoms.

As R ² , 4-methyl-1,3-thiazol-2-yl, 2-methyl-1,3-thiazol-4-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl or 2-(trifluoromethyl)-1,3-thiazol-4-yl are particularly preferred, and 4-(trifluoromethyl)-1,3-thiazol-2-yl is very particularly preferred.

Another preferred embodiment for R ² is a pyrazole group, especially pyrazol-3-yl. Particularly preferred is 1-(C ₁ -C ₆ -alkyl)-1H-pyrazol-3-yl, where the C ₁ -C ₆ -alkyl substituent may contain 1 to 5 fluorine atoms. Also particularly preferred are 1-cyclopropyl-1H-pyrazol-3-yl and 1-cyclopropylmethyl-1H-pyrazol-3-yl. Very particularly preferred are 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl, and 1-(difluoromethyl)-1H-pyrazol-3-yl. Of these, 1-(difluoromethyl)-1H-pyrazol-3-yl is particularly preferred.

Preferred embodiments for R ³ include tetrahydro-2H-pyran-4-yl, 2,6-dimethyltetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, (3R)-tetrahydrofuran-3-yl, and 5,5-dimethyltetrahydrofuran-3-yl. Particularly preferred are tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, and (3R)-tetrahydrofuran-3-yl.

Other preferred embodiments of ^R are 1-oxotetrahydro-2H-thiopyran-4-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, 1-oxotetrahydrothiophen-3-yl, 1,1-dioxotetrahydrothiophen-3-yl, (3S)-1,1-dioxotetrahydrothiophen-3-yl and (3R)-1,1-dioxotetrahydrothiophen-3-yl. Particularly preferred are 1,1-dioxotetrahydro-2H-thiopyran-4-yl, 1,1-dioxotetrahydrothiophen-3-yl, (3S)-1,1-dioxotetrahydrothiophen-3-yl and (3R)-1,1-dioxotetrahydrothiophen-3-yl.

Other preferred embodiments of R ³ are tetrahydro-2H-thiopyran-4-yl and tetrahydrothiophen-3-yl.

In the case of another preferred embodiment, R ³ is a group

in

z is nitrogen;

R ^6f is hydrogen or methyl, preferably hydrogen;

R ^6g is hydrogen or methyl, preferably hydrogen;

R ^6h is hydrogen or methyl, preferably hydrogen;

R ⁶ⁱ is hydrogen or methyl, preferably hydrogen;

R ^6j is hydrogen or methyl, preferably hydrogen;

R ^6k is hydrogen or methyl, preferably hydrogen;

R ⁶¹ is hydrogen or methyl, preferably hydrogen;

R ^6m is hydrogen or methyl, preferably hydrogen;

R7 ^is hydrogen, C(=O) _CH2OH , C(=O)C( _CH3 ) _2OH , S(=O) _{2NH2 ,} S(=O) _2NHC (=O) _CH3 , _C1 - _C4 -alkyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl, 2-(dimethylamino)ethyl, 2-aminoethyl, 2-(diethylamino)ethyl, 2-(methylamino)ethyl, 3-(dimethylamino)propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-methoxyethyl, oxetan-3-yl, oxetan-3-ylmethyl, tetrahydrofuran-3-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, azetidin-3-yl, 1-methylazetidin-3-yl, azetidin-3-yl, azetidin-3-ylmethyl, 1-methylazetidin-3-ylmethyl;

R ⁷ is preferably hydrogen, C(═O)CH ₂ OH, S(═O) ₂ NH ₂ , S(═O) ₂ NHC(═O)CH ₃ , methyl, ethyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, oxetan-3-yl, 1-methylpiperidin-4-yl;

R ⁷ is most preferably hydrogen, methyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, oxetan-3-yl or 1-methylpiperidin-4-yl;

n has the definition n=0, 1, preferably n=1.

In another embodiment, R ³ is a group

in

z is nitrogen;

R ^6h , R ⁶ⁱ , R ^6l , and R ^6m are hydrogen;

G has the definition -CH ₂ CH ₂ - or -CH ₂ -, and is preferably -CH ₂ -;

n is defined as n=1, 2, preferably n=1;

^R7 is hydrogen, C(=O) _{CH2OH ,} S(=O) _2NH2 , S(=O) _2NHC (=O) _CH3 , methyl, ethyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, oxetan-3-yl, 1-methylpiperidin-4-yl, preferably hydrogen or methyl.

In another embodiment, R ³ is a group

in

z is nitrogen;

R ^6j , R ^6k , R ^6l , and R ^6m are hydrogen;

G has the definition -CH ₂ CH ₂ -;

n has the definition n=1;

^R7 is hydrogen, C(=O) _{CH2OH ,} S(=O) _2NH2 , S(=O) _2NHC (=O) _CH3 , methyl, ethyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, oxetan-3-yl, 1-methylpiperidin-4-yl, preferably hydrogen or methyl.

Preferred embodiments for R ⁴ are cyclopropyl, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkyl substituted by 1 to 5 fluorine atoms. Particular preference is given to methyl, ethyl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, difluoromethyl and trifluoromethyl. Very particular preference is given to trifluoromethyl.

Preferred embodiments for R ⁵ are hydrogen, fluorine, chlorine, cyano, methoxy, C ₁ -C ₆ -alkyl, and C ₁ -C ₆ -alkyl substituted by 1 to 5 fluorine atoms. Particular preference is given to hydrogen, fluorine, chlorine, cyano, methyl, ethyl, and trifluoromethyl. Very particular preference is given to hydrogen, fluorine, and methyl. Particular preference is given to hydrogen.

Preferred embodiments for ^Ra are C1- _{C6 -} alkyl, cyclopropyl, cyclopropylmethyl, oxetan-3-yl, azetidin-3-yl, 1-methylazetidin-3-yl, tetrahydrofuran-3-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 2,2,2-trifluoroethyl, and 2-hydroxyethyl. _C1 - _C4 -alkyl is particularly preferred. Methyl is very particularly preferred.

Preferred embodiments for R ^b are C ₁ -C ₄ -alkyl and cyclopropyl, with methyl and ethyl being particularly preferred.

As for R ^c , preferred embodiments are hydroxy, fluorine, methyl, ethyl, methoxy and ethoxy, with fluorine and methyl being particularly preferred.

Preferred embodiments for R ^d are cyclopropyl and C ₁ -C ₆ -alkyl which may be optionally mono- or disubstituted by hydroxy. Particularly preferred are C ₁ -C ₄ -alkyl which may be optionally mono-substituted by hydroxy. Most preferably, R ^d is methyl or hydroxymethyl.

For ^Re , a preferred embodiment is _C1 - _C6 -alkyl which may be optionally mono- or di-substituted by hydroxy. Particularly preferred is _C1 - _C4 -alkyl which is mono-substituted by hydroxy. Most preferably, ^Re is hydroxymethyl.

Also preferred are compounds of formula (I) wherein

R ¹ is fluorine, chlorine, cyano, C(═O)OH, C(═O)OR ^a , C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , hydroxy or C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may be optionally substituted by hydroxy,

or C ₁ -C ₆ -alkoxy, wherein the C ₁ -C ₆ -alkoxy group may be optionally mono- to tri-substituted by fluorine and optionally substituted by hydroxy, optionally mono- to difluoro-substituted C ₃ -C ₆ -cycloalkyl, or optionally mono- to difluoro-substituted oxetane or tetrahydrofuran,

or C ₃ -C ₆ -cycloalkoxy, oxetan-3-yloxy or tetrahydrofuran-3-yloxy;

R ^a is C ₁ -C ₆ -alkyl;

R ^b is C ₁ -C ₆ -alkyl;

R ² is a group selected from the following general formulae II to VII, IX and X, wherein R ² is optionally monosubstituted by R ⁵ , and

* represents the point of attachment of the group to the rest of the molecule, and

R ⁴ in Formula II and III

is hydrogen, C(═O) ^Ra or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may optionally be mono- to tri-substituted by fluorine and mono-substituted by hydroxy or mono-substituted by cyclopropyl,

or C ₃ -C ₆ -cycloalkyl,

or is pyridyl, which is optionally mono- or disubstituted, identically or differently, by fluorine, chlorine or C ₁ -C ₄ -alkyl, and

R ⁴ in Formulas IV to VII

is hydrogen, fluorine, chlorine, hydroxy, cyano, C(═O)R ^a , NH ₂ , NHR ^a , N(R ^a )R ^b or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl is optionally mono- to tri-substituted by fluorine and optionally mono-substituted by hydroxy or cyclopropyl,

or is C ₁ -C ₆ -alkoxy, which may be optionally mono- to tetra-substituted by fluorine,

or is C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkoxy or pyridyl, where the pyridyl radicals may be optionally mono- or disubstituted, identically or differently, by fluorine, chlorine or C ₁ -C ₄ -alkyl, and

R ⁴ in Formula IX and X

is hydrogen, cyano, NH ₂ , NHC ₁ -C ₄ -alkyl, N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), cyclopropyl or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may be optionally mono- or tri-substituted by fluorine and may be optionally mono-substituted by hydroxy or cyclopropyl,

or pyridyl, which is optionally mono- or disubstituted identically or differently by fluorine, chlorine or C ₁ -C ₄ -alkyl

or morpholin-1-yl, 4-methylpiperazin-1-yl, piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl;

R ⁵ is hydrogen, fluorine, chlorine, cyano, C ₁ -C ₄ -alkyl;

R ³ is an R ^3a group

Where * represents the site of attachment of the group to the rest of the molecule;

R ^6f is hydrogen or C ₁ -C ₄ -alkyl;

R ^6g is hydrogen or C ₁ -C ₄ -alkyl:

R ^6h is hydrogen or C ₁ -C ₄ -alkyl;

R ⁶ⁱ is hydrogen or C ₁ -C ₄ -alkyl;

or R ^6h and R ⁶ⁱ together represent an oxo group;

R ^6j is hydrogen or methyl;

R ^6k is hydrogen or methyl;

R ⁶¹ is hydrogen;

R ^6m is hydrogen;

n is 0 or 1;

z is a group selected from the group consisting of NR ⁷ , O, S, S(═O), S(═O) ₂ , and S(═O)(═NH);

R7 ^is hydrogen, C(=O) ^Re , S(=O) _2Ra , S(=O) ^2NH2 , S(=O) _{2N (} ^Ra )H, S(=O) _2N ( ^Ra ) ^Rb , S( ₌ O) _2NHC (=O) _CH3 , S(=O) _2NHC (=O) _{CH2CH3 or C1} - _C6 -alkyl, wherein

C ₁ -C ₆ -alkyl may be optionally mono- to tri-substituted by fluorine and may be optionally mono- to di-substituted by hydroxy and may be optionally substituted by N(R ^a )R ^b , cyclopropyl, methoxy or ethoxy,

or C ₃ -C ₆ -cycloalkyl or oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, 1-methylazetidin-3-yl, 1-methylpyrrolidin-3-yl, 1-methylpiperidin-4-yl;

R ^e is C ₁ -C ₃ -alkyl, wherein the C ₁ -C ₃ -alkyl may be optionally substituted by hydroxy;

or R ³ is an R ^3b group

wherein G is -CH ₂ -;

n is 1;

R ^6h , R ⁶ⁱ , R ^6m , and R ^6l are hydrogen;

^R7 is hydrogen, C(=O) _{CH2OH ,} S(=O) _2NH2 , S(=O) _2NHC (=O) _CH3 , methyl, ethyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, oxetan-3-yl, or 1-methylpiperidin-4-yl.

Particularly preferred are compounds of formula (I) wherein

R ¹ is chlorine, C(═O)OH, C(═O)OMe, C(═O)NH ₂ , hydroxy, C ₁ -C ₃ -alkyl substituted by a hydroxy group, unsubstituted C ₁ -C ₃ -alkoxy or cyclopropylmethoxy,

R ² is a group selected from the following general formula III, VI, VII, VIII, IX or X

and

* represents the point of attachment of the group to the rest of the molecule, and

R ⁴ in Formula III

is hydrogen or C ₁ -C ₄ -alkyl, whereby C ₁ -C ₄ -alkyl may be optionally substituted by up to 3 fluorine atoms or monosubstituted by hydroxy,

or is pyridin-4-yl, and

R ⁴ in Formulas VI, VII and VIII

is hydrogen, cyano, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -alkyl, where C ₁ -C ₄ -alkyl may be optionally substituted by up to 3 fluorine atoms or monosubstituted by hydroxy,

or is pyridin-4-yl, and

R ⁴ in Formula IX and X

is hydrogen, cyano, NH ₂ , NHC ₁ -C ₄ -alkyl, N(C ₁ -C ₄ -alkyl)(C ₁ -C ₄ -alkyl), cyclopropyl or C ₁ -C ₄ -alkyl, where C ₁ -C ₄ -alkyl may be optionally substituted by up to 3 fluorine atoms or monosubstituted by hydroxy,

or pyridinyl, morpholin-1-yl, 4-methylpiperazin-1-yl or piperazin-1-yl;

^R3 is tetrahydro-2H-pyran-4-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, 1-imino- ¹ -oxohexahydro-1λ4-thiopyran-4-yl, 5-oxopyrrolidin-3-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, (3R)-tetrahydrofuran-3-yl, (3S)-tetrahydrothiophen-3-yl, 1,1-dioxotetrahydrothiophen-3-yl, (3S)-1,1-dioxotetrahydrothiophen-3-yl, (3R)-1,1-dioxotetrahydrothiophen-3-yl or tetrahydro-2H-thiopyran-4-yl, or

R ³ is an R ^3d group

Where * represents the site of attachment of the group to the rest of the molecule;

^R7 is hydrogen, C(=O) _{CH2OH ,} S(=O) _2NH2 , S(=O) _2NHC (=O) _CH3 , methyl, ethyl, 2,2,2-trifluoroethyl, 2-(dimethylamino)ethyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, or oxetan-3-yl, 1-methylpiperidin-4-yl.

Also preferred are compounds of formula (I) wherein

R ¹ is chlorine, C(=O)NH ₂ , 2-hydroxypropan-2-yl, methoxy, cyclopropylmethoxy,

R2 is ^6- (trifluoromethyl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-(1,1-difluoroethyl)pyridin-2-yl, 6-(morpholin-4-yl)pyridin-2-yl, 2-methyl-1,3-thiazol-4-yl, 6-aminopyridin-2-yl, 2-isopropylpyrimidin-4-yl, 6-(2-hydroxypropan-2-yl)-pyridin-2-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl or 1-(difluoromethyl)-1H-pyrazol-3-yl,

^R3 is tetrahydro-2H-pyran-4-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, 1-imino- ¹ -oxohexahydro-1λ4-thiopyran-4-yl, 5-oxopyrrolidin-3-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, (3R)-tetrahydrofuran-3-yl, 1,1-dioxotetrahydrothiophen-3-yl, (3S)-1,1-dioxotetrahydrothiophen-3-yl or (3R)-1,1-dioxotetrahydrothiophen-3-yl,

or

^R3 is piperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-methylpiperidin-4-yl, 1-glycoloylpiperidin-4-yl, 1'-methyl-1,4'-bipiperidin-4-yl, 1-(acetylsulfamoyl)piperidin-4-yl, [2-(dimethylamino)ethyl]piperidin-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(2-hydroxyethyl)piperidin-4-yl, 1-(3-hydroxy-3-methylbutyl)piperidin-4-yl.

Likewise very particular preference is given to compounds of the formula (I) in which

R ¹ is C(=O)NH ₂ , 2-hydroxypropan-2-yl or methoxy,

R2 ^is 6-(trifluoromethyl)pyridin-2-yl, 6-(difluoromethyl)pyridin-2-yl, 6-aminopyridin-2-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 1-(difluoromethyl)-1H-pyrazol-3-yl,

^R3 is tetrahydro-2H-pyran-4-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, (3R)-tetrahydrofuran-3-yl or (3S)-1,1-dioxotetrahydrothiophen-3-yl

or

^R3 is piperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-methylpiperidin-4-yl, 1-hydroxyacetylpiperidin-4-yl, 1'-methyl-1,4'-bipiperidin-4-yl, 1-(acetylsulfamoyl)piperidin-4-yl, [2-(dimethylamino)ethyl]piperidin-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(2-hydroxyethyl)piperidin-4-yl or 1-(3-hydroxy-3-methylbutyl)piperidin-4-yl.

According to the invention, the following compounds are very particularly preferred:

(1) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(2) N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(3) N-{6-methoxy-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(4) N-[6-methoxy-2-(1-methylpiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(5) N-[2-(1-hydroxyacetylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(6) N-[6-methoxy-2-(1'-methyl-1,4'-bipiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(7) N-[6-methoxy-2-(1-sulfamoylpiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(8) N-{2-[1-(acetylsulfamoyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(9) N-(2-{1-[2-(dimethylamino)ethyl]piperidin-4-yl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

(10) N-{6-methoxy-2-[1-(oxetan-3-yl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(11) N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(12) N-[6-methoxy-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(13) N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(14) rel-N-{2-[(1R, 4R, 5S)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(15) rel-N-{2-[(1R, 4R, 5R)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(16) N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-hydroxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(17) N-[6-(cyclopropylmethoxy)-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(18) rel-N-{6-methoxy-2-[(1R, 4R, 5S)-2-methyl-2-azabicyclo[2.2.1]hept-5-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(19) rel-N-{6-methoxy-2-[(1R, 4R, 5R)-2-methyl-2-azabicyclo[2.2.1]hept-5-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(20) N-[2-(1-Imino-1-oxohexahydro-1λ ⁴ -thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Isomer 1)

(21) N-[2-(1-Imino-1-oxohexahydro-1λ ⁴ -thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Isomer 2)

(22) N-[6-methoxy-2-(5-oxopyrrolidin-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(23) 6-(Difluoromethyl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

(24) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(morpholin-4-yl)pyridine-2-carboxamide

(25) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-2-methyl-1,3-thiazole-4-carboxamide

(26) 6-amino-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

(27) 2-Isopropyl-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyrimidine-4-carboxamide

(28) 6-(2-Hydroxypropan-2-yl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

(29) N-[6-methoxy-2-(tetrahydrofuran-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(30) N-[6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(31) N-[6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide

(32) N-[6-chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(2-hydroxypropan-2-yl)pyridine-2-carboxamide

(33) 2-(tetrahydro-2H-pyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

(34) N-[6-(2-Hydroxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(35) Methyl 2-[(3S)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

(36) N-{6-(2-hydroxypropan-2-yl)-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(37) Methyl 2-[(3R)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

(38) N-{6-(2-hydroxypropan-2-yl)-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(39) Methyl 2-[(3S)-tetrahydrothiophen-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

(40) N-{6-(2-hydroxypropan-2-yl)-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(41) N-{2-[(3S)-1,1-dioxotetrahydrothiophen-3-yl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(42) 2-(tetrahydro-2H-thiopyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

(43) N-[6-(2-Hydroxypropan-2-yl)-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(44) N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(45) 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

(46) N-[6-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(47) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide

(48) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-3-(pyridin-4-yl)-1,2,4-oxadiazole-5-carboxamide

(49) N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-3-methyl-1,2,4-oxadiazole-5-carboxamide

(50) N-[6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide

(51) 1-(Difluoromethyl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide

(52) N-{2-[1-(3-hydroxy-3-methylbutyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

(53) 2-(Piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

(54) 2-(Piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid

(55) Methyl 2-(1-methylpiperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate

(56) 2-[1-(3-hydroxy-3-methylbutyl)piperidin-4-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

(57) 2-(1-methylpiperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

(58) N-{6-methoxy-2-[1-(2-methoxyethyl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

The following compounds are particularly preferred:

(34) N-[6-(2-Hydroxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(44) N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

(46) N-[6-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

The compounds of the present invention act as IRAK4 kinase inhibitors and possess an unexpectedly useful spectrum of pharmacological activity.

In addition to the subjects mentioned above, the present invention therefore also provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases in humans and animals.

Particularly preferred are the treatment and/or prevention of gynecological disorders, inflammatory skin disorders, cardiovascular disorders, lung disorders, eye disorders, autoimmune disorders, pain disorders, metabolic disorders, gout, liver disorders, metabolic syndrome, insulin resistance and cancer using the IRAK4 inhibitors of the present invention.

The compounds of the present invention are suitable for preventing and/or treating various disorders and disease-related conditions, in particular disorders mediated by TLRs (other than TLR3) and/or the IL-1 receptor family and/or disorders whose pathology is directly mediated by IRAK4. IRAK4-related disorders include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondyloarthritis, and arthritis.

The compounds of the present invention may also be used to prevent and/or treat conditions mediated by MyD88 and TLRs (except TLR3). These include multiple sclerosis, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bechterev's disease), metabolic syndrome (including insulin resistance, diabetes), osteoarthritis, Gren's syndrome, giant cell arteritis, sepsis, polymyositis and dermatomyositis, skin conditions such as psoriasis, atopic dermatitis, alopecia areata, acne inversa and acne vulgaris, lung conditions such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension.

Due to their mechanism of action, the compounds of the present invention are suitable for the prevention and/or treatment of TLR-mediated disorders: Behcet's disease, gout, endometriosis and pain associated with endometriosis, as well as other symptoms associated with endometriosis, such as dysmenorrhea, dyspareunia, dysuria, and dysfecia. Furthermore, the compounds of the present invention are suitable for the prevention and/or treatment of transplant rejection, lupus erythematosus, adult-onset Still's disease, and chronic inflammatory bowel disorders, such as ulcerative colitis and Crohn's disease.

In addition to the disorders already listed, the use of the compounds according to the invention is also suitable for the treatment and/or prevention of the following disorders: ocular disorders such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis; cardiovascular disorders such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension; and neurological disorders such as Alzheimer's disease, stroke and Parkinson's disease.

The mechanism of action of the compounds of the present invention also enables the prevention and/or treatment of liver disorders mediated by the TLR and IL-1 receptor families, in particular NAFLD, NASH, ASH, liver fibrosis and cirrhosis.

The compounds of the present invention also provide for the prevention and/or treatment of pruritus and pain, particularly acute, chronic, inflammatory and neuropathic pain.

Due to their mechanism of action, the compounds according to the invention are suitable for the prophylaxis and/or treatment of tumor disorders such as lymphomas, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer and Ras-dependent tumors.

Furthermore, the compounds of the present invention are suitable for the treatment and/or prevention of conditions mediated by the IL-1 receptor family. These conditions include: CAPS (cold pyrin-associated periodic syndromes), including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wells syndrome), NOMID (neonatal multisystem inflammatory disease) and CONCA (chronic infantile neurocutaneous arthritis) syndrome; FMF (familial Mediterranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumor necrosis factor receptor 1-associated periodic syndromes), juvenile idiopathic arthritis, adult-onset Still's disease, Behçet's syndrome, rheumatoid arthritis, psoriasis, arthritis, Bechterev's disease, osteoarthritis, keratoconjunctivitis sicca, and Sjögren's syndrome, multiple sclerosis, lupus erythematosus, alopecia areata, type 1 diabetes, type 2 diabetes and post-myocardial infarction syndrome. The following conditions are associated with dysregulation of the IL-1 receptor family and are amenable to therapeutic and/or prophylactic use of the compounds of the present invention: pulmonary conditions such as asthma, COPD, idiopathic interstitial pneumonias and ARDS; gynecological conditions such as endometriosis and pain associated with endometriosis and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria and dysfecation; chronic inflammatory bowel conditions such as Crohn's disease and ulcerative colitis.

The compounds of the present invention are also useful for treating and/or preventing neurological disorders mediated by the IL-1 receptor family, such as stroke, Alzheimer's disease, and craniocerebral trauma, as well as skin disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata, and allergic contact dermatitis.

Furthermore, the compounds according to the invention are suitable for the treatment and/or prevention of pain conditions, in particular acute, chronic, inflammatory and neuropathic pain. This preferably includes hyperalgesia, allodynia, pain from arthritis (e.g. osteoarthritis, rheumatoid arthritis and spondyloarthritis), premenstrual pain, pain associated with endometriosis, postoperative pain, pain from interstitial cystitis, CRPS (Complex Regional Pain Syndrome), trigeminal neuralgia, pain from prostatitis, pain caused by spinal cord injury, pain caused by inflammation, low back pain, cancer pain, pain associated with chemotherapy, neuropathies caused by HIV treatment, pain caused by burns and chronic pain.

The present invention further provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one compound according to the invention.

In the context of the present invention, the term "treatment" or "treating" includes inhibiting, delaying, checking, alleviating, relieving, limiting, reducing, stopping, resisting or curing a disease, condition, disorder, injury or health problem, or the development, course or progression of said state and/or the symptoms of said state. The term "therapy" is understood herein to be synonymous with the term "treatment".

In the context of the present invention, the terms "prevention," "prophylaxis," and "preclusion" are used synonymously and refer to avoiding or reducing the risk of contracting, experiencing, suffering, or having a disease, condition, disorder, injury, or health problem, or the development or progression of such a condition and/or the symptoms of such a condition.

A disease, condition, disorder, injury or health problem may be partially or completely treated or prevented.

The compounds according to the invention can be used alone or, if necessary, in combination with other active ingredients. The present invention also provides medicaments comprising at least one compound according to the invention and one or more other active ingredients, in particular for the treatment and/or prevention of the above-mentioned conditions. Preferred examples of suitable active ingredient combinations include:

Typically, they include active ingredients such as antibacterial substances (e.g. penicillin, vancomycin, ciprofloxacin), antiviral substances (e.g. aciclovir, oseltamivir) and antifungal substances (e.g. naftifin, nystatin); as well as gamma globulin compounds, immunomodulatory compounds and immunosuppressive compounds, such as cyclosporin, TNF antagonists (e.g. etanercept, infliximab), IL-1 inhibitors (e.g. anakinra), ra), canakinumab, rilonacept), phosphodiesterase inhibitors (e.g., apremilast), Jak/STAT inhibitors (e.g., tofacitinib, baricitinib, GLPG0634), leflunomid, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin, mycophenolate mofetil, mofetil), interferon, steroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine, and sulfasalazine; acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).

For tumor treatment, the following should be mentioned: immunotherapy (e.g., aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod), interferon-alpha, interferon-beta, interferon-gamma a), ipilimumab, lenalidomid, lenograstim, mifamurtid, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermin, teceleukin, tocilizumab), antiproliferative substances (such as, but not limited to, amsacrine, arglabin, arsenic trioxide, trioxide), asparaginase, bleomycin, busulfan, dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, obinutuzumab, ofatumumab, tositumomab), aromatase estradiol, polyestradiol phosphate, raloxifen), progestagens (e.g., medroxyprogesterone, megestrol), topoisomerase I inhibitors (e.g., irinotecan, topotecan), topoisomerase II inhibitors (e.g., amrubicin, daunorubicin, elliptinium acetate), acetate), etoposide, idarubicin, mitoxantrone, teniposide), microtubule-active substances (e.g., cabazitaxel, eribulin, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine), telomerase inhibitors (e.g., imetelstat), alkylating substances and histone deacetylase inhibitors (e.g., bendamustine, carmustine, chlormethine, dacarbazine, estramustine, ifosfamid, lolimus), lomustine, mitobronitol, mitolactol, nimustine, prednimustine, procarbazine, ranimustine, streptozotocine, temozolomide, thiotepa, treosulfan, trofosfamid, vorinostat, romidepsin, panobinostat); substances that affect cell differentiation processes such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptide mimetics, non-peptide mimetics, and tetracyclines such as marimastat, BAY 12-9566, BMS-275291, clodronate, prinomastat, doxycycline), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus, zotarolimus), antimetabolites (e.g., clofarabine, doxifluridine, methotrexate, 5-fluorouracil, cladribine, cytarabine, fludarabine, mercaptopurine, pemetrexed, raltitrexed), ed), tegafur, tioguanine), platinum compounds (e.g., carboplatin, cisplatin, cisplatinum, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin); antiangiogenic compounds (e.g., bevacizumab), antiandrogenic compounds (e.g., bevacizumab, enzalutamide, flutamide, nilutamide, bicalutamide, cyproterone acetate, cyproterone acetate); acetate), proteasome inhibitors (e.g., bortezomib, carfilzomib, oprozomib, ONYX0914), gonadotropin-releasing hormone agonists and antagonists (e.g., abarelix, buserelin, deslorelin, ganirelix, goserelin, histrelin, triptorelin, degarelix, leuprorel in)), methionine aminopeptidase inhibitors (e.g., bengamide derivatives, TNP-470, PPI-2458), heparanase inhibitors (e.g., SST0001, PI-88); inhibitors of genetically modified Ras proteins (e.g., farnesyl transferase inhibitors such as lonafarnib, tipifarnib), HSP90 inhibitors (e.g., geldamycin derivatives such as 17-allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17-DMAG, retaspimycin hydrochloride (retaspimycin hydrochloride), IPI-493, AUY922, BIIB028, STA-9090, KW-2478), kinesin spindle protein inhibitors (e.g., SB715992, SB743921, pentamidine/chlorpromazine), MEK (mitogen-activated protein kinase) inhibitors (e.g., trametinib, BAY86-9766 (refametinib), AZD6244), kinase inhibitors (e.g., sorafenib, regorafenib, lapatinib, sutent, dasatinib, cetuximab), BMS-908662, GSK2118436, AMG 706, erlotinib, gefitinib, imatinib, nilotinib, pazopanib, roniciclib, sunitinib, vandetanib, vemurafenib), hedgehog signaling inhibitors (e.g., cyclopamine, vismodegib), BTK (Bruton's tyrosine kinase) inhibitors (e.g., ibrutinib), JAK/pan-JAK (Janus kinase) inhibitors (e.g., SB-1578, baricitinib, tofacitinib, pacritinib, momelotinib, ruxolitinib, VX-509, AZD-1480, TG-101348), PI3K inhibitors (e.g., 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 (e.g., fostamatinib, Excellair, PRT-062607), p53 gene therapy, bisphosphonates (e.g., etidonate, clodronate, tiludronate, pamidronate, alendronic acid, ibandronate, risedronate, zoledronate). Examples of active ingredients for combination include the following: rituximab, cyclophosphamide, doxorubicin, doxorubicin combined with oestrone, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 131I-chTNT, abiraterone, aclarubicin, alitretinoin, bisantren, calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, crisantaspase, darbepoetin alfa alfa), decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitiostanol, epoetinalfa, filgrastim, fotemustin, gallium nitrate, gemcitabin, glutoxim, histamine dihydrochloride, hydroxycarbamide, improsulfan, ixabepilon, lanreotid, lentinan, levamisol, lisurid, lonidamin, masoprocol, methyltestosterone, methoxsalen, methyl aminolevulinate aminolevulinate), miltefosin, mitoguazon, mitomycin, mitotan, nelarabin, nimotuzumab, nitracrin, omeprazol, palifermin, panitumumab, pegaspargase, PEG epoetin beta (methoxy-PEG epoetin beta), pegfilgrastim, pegylated interferon alpha-2b (peg interferonalfa-2b), pentazocin, pentostatin, perfosfamid, pirarubicin, plicamycin, poliglusam, porfimer-sodium, pralatrexate, quinagolid, razoxan, sizofiran, sobuzoxan, sodium glycidazole glycididazole), tamibaroten, tegafur, and a combination of gimeracil and oteracil, testosterone, tetrofosmin, thalidomide, thymalfasin, trabectedin, tretinoin, trilostan, tryptophan, ubenimex, vapreotid, yttrium-90 glass microbeads, zinostatin, and zinostatin stimalamer.

For tumor treatment, combination therapy is also suitable: non-drug therapy, such as chemotherapy (e.g., azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunin, zorubicin), radiotherapy (e.g., I-125 seeds, palladium-103 seeds, radium-223 chloride) or phototherapy (e.g., temoporfin, talaporfin), accompanied by drug treatment with the IRAK4 inhibitor of the present invention; or, after completion of non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy, supplementary drug treatment with the IRAK4 inhibitor of the present invention.

In addition to those active ingredients mentioned above, the IRAK4 inhibitors of the present invention may also be combined with the following active ingredients:

Active ingredients for the treatment of Alzheimer's disease, such as acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamin, tacrine), NMDA (N-methyl-D-aspartate) receptor antagonists (e.g., memantine); L-DOPA/carbidopa (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease, COMT (catechol-O-methyltransferase) inhibitors (e.g., enolepezil), entacapone), dopamine agonists (e.g., ropinrol, pramipexol, bromocriptin), MAO-B (monoaminooxidase-B) inhibitors (e.g., selegiline), anticholinergics (e.g., trihexyphenidyl), and NMDA antagonists (e.g., amantadin); beta-interferon (IFN-β) (e.g., IFN-β) for the treatment of multiple sclerosis β-1b, IFN β-1a and IFN β-1b), glatiramer acetate, immunoglobulins, natalizumab, fingolimod, and immunosuppressants such as mitoxantrone, azathioprine, and cyclophosphamide; substances for the treatment of pulmonary disorders, such as beta-2 sympathomimetics (e.g., salbutamol), anticholinergics (e.g., glycopyrronium), methylxanthines (e.g., theophylline), leukotriene receptor antagonists (e.g., montelukast), PDE-4 (phosphodiesterase type 4) inhibitors (e.g., roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, preparations containing cortisol; substances for the treatment of osteoarthritis, such as nonsteroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, methotrexate and biological agents (eg rituximab, abatacept) used for B-cell and T-cell therapy should be mentioned for rheumatoid disorders such as rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis. Neurotrophic substances such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoamine oxidase) inhibitors (e.g. selegiline), interferons and anticonvulsants (e.g. gabapentin); active ingredients for the treatment of cardiovascular disorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g. benazepril), angiotensin receptor blockers (e.g. losartan, valsartan), diuretics (e.g. hydrochlorothiazide), calcium channel blockers (e.g. nifedipine), statins (e.g. simvastatin, fluvastatin) antidiabetic agents, such as metformin, glinides (e.g., nateglinide), DPP-4 (dipeptidyl peptidase-4) inhibitors (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT2 (sodium/glucose co-transporter 2) inhibitors/gliflozins (e.g., dapagliflozin, empagliflozin), incretin mimetics (the hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1), 1) (GLP-1) analogs/agonists) (e.g., exenatide, liraglutide, lixisenatide), α-glucosidase inhibitors (e.g., acarbose, miglitol, voglibiose) and sulfonylureas (e.g., glibenclamide, tolbutamide), insulin sensitizers (e.g., pioglitazone) and insulin therapy (e.g., NPH insulin, insulin lispro), substances used to treat hypoglycemia, treat diabetes, and metabolic syndrome. Lipid-lowering drugs, such as fibrates (e.g., bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (e.g., niacin/laropiprant), ezetimib, statins (e.g., simvastatin, fluvastatin), anion exchangers (e.g., colestyramine, colestipol, colesevelam). Active ingredients for the treatment of chronic inflammatory bowel disorders such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotics (Mutaflor, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics such as ciprofloxacin and metronidazole, antidiarrheal drugs such as loperamide, or laxatives (bisacodyl). Immunosuppressants used to treat lupus erythematosus, such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide, for example, but not limited to, calcineurin inhibitors (e.g., tacrolimus and ciclosporin), cell division inhibitors (e.g., azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus, or sirolimus), rapamycin, basiliximab, daclizumab, anti-CD3 antibodies, anti-T lymphocyte globulin/antilymphocyte globulin for organ transplantation. Vitamin D3 analogs for skin conditions such as calcipotriol, tacalcitol, or calcitriol, salicylic acid, urea, ciclosporine, methotrexate, efalizumab.

Mention should also be made of medicaments for the treatment and/or prevention of the aforementioned disorders, which comprise at least one compound according to the invention and one or more further active ingredients, in particular EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinergic receptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKR1C3 inhibitors (aldoketoreductase family 1 member C3 inhibitors).

The compounds of the present invention can act systemically and/or locally. For this reason, they can be administered in an applicable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal or conjunctival route, via ear, or as implant or stent administration.

The compounds of the present invention can be administered in administration forms suitable for these administration routes.

Suitable administration forms for oral administration are administration forms which act according to the prior art and release the compound according to the invention rapidly and/or in a modified manner, containing the compound according to the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a coating resistant to gastric juices or a coating which delays dissolution or an insoluble coating which controls the release of the compound according to the invention), tablets or films/oblates which disintegrate rapidly in the mouth, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by avoiding an absorption step (e.g., by intravenous, intraarterial, intracardiac, intraspinal, or intralumbar routes) or by including absorption (e.g., by intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal routes). Suitable administration forms for parenteral administration include injections and infusions in the form of solutions, suspensions, emulsions, lyophilized formulations, or sterile powders.

For other routes of administration, suitable examples are inhaled medicines (including powder inhalers, nasal sprays), nasal drops, solutions or sprays; tablets, films/papers or capsules for tongue, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration is preferred, especially oral administration.

The compounds according to the invention can be converted into the administration forms mentioned. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. These include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxide), and flavorings and/or flavoring agents.

The invention also provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

In general, it has been found advantageous to administer an amount of about 0.001 to 1 mg/kg body weight, preferably about 0.01 to 0.5 mg/kg body weight, in the case of parenteral administration to achieve effective results. In the case of oral administration, the dosage is about 0.01 to 100 mg/kg body weight, preferably about 0.01 to 20 mg/kg body weight and most preferably 0.1 to 10 mg/kg body weight.

However, in some cases, it may be necessary to deviate from the amounts stated, in particular by adjusting the dose to body weight, route of administration, individual response to the active ingredient, the nature of the formulation and the time or interval of administration. Thus, in some cases, less than the above-mentioned minimum amount may be sufficient, while in other cases the upper limit mentioned must be exceeded. In the case of administration of larger amounts, it may be advisable to divide these doses into several individual doses over the day.

The following working examples illustrate the invention. The invention is not limited to the examples described.

Unless otherwise stated, percentages in the following tests and examples are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for liquid/liquid solutions are in each case based on volume.

Preparation of the compounds of the present invention

The preparation of the compounds of the present invention is illustrated by the following synthetic schemes.

Starting materials for the synthesis of some of the compounds of the invention are carboxylic acids ^R2 - _CO2H (wherein ^R2 is as defined in formula (I)), which are commercially available or can be prepared by or in analogy to routes known from the literature (see, for example, European Journal of Organic Chemistry 2003, 8, 1559-1568; Chemical and Pharmaceutical Bulletin, 1990, 38, 9, 2446-2458; Synthetic Communications 2012, 42, 658-666; Tetrahedron, 2004, 60, 51, 11869-11874). Some carboxylic acids ^R2 - _CO2H (wherein ^R2 is as defined in formula (I)) can be prepared starting from carboxylic acid esters by hydrolysis (see, for example, the reaction of ethyl 6-(hydroxymethyl)pyridine-2-carboxylate with aqueous sodium hydroxide solution in methanol, WO2004113281) or - in the case of tert-butyl esters - by reaction with acids such as hydrogen chloride or trifluoroacetic acid (see, for example, Dalton Transactions, 2014, 43, 19, 7176-7190). The carboxylic acids ^R2 - _CO2H can also be used in the reaction in the form of their alkali metal salts. Carboxylic acid esters as starting materials for preparing carboxylic acids ^R2- _CO2H can be prepared from halogenated units ^R2 -I, ^R2 -Br or ^R2 -Cl (wherein ^R2 is as defined in formula (I)) by reacting under carbon monoxide atmosphere, optionally under high pressure, in the presence of a phosphine ligand (e.g. 1,3-bis(diphenylphosphino)propane), a palladium compound (e.g. palladium(II) acetate) and a base (e.g. triethylamine) in a solvent (e.g. dimethyl sulfoxide) with addition of ethanol or methanol (for preparation methods, see, e.g. WO2012112743; WO2005082866; Chemical Communications (Cambridge, England), 2003, 15, 1948-1949; WO200661715). The starting materials ^R2 -I, ^R2 -Br or ^R2- Cl are commercially available or can be prepared by routes known from the literature. Exemplary preparation methods are described in detail in WO2012061926; European Journal of Organic Chemistry, 2002, 2, 327-330; Synthesis, 2004, 10, 1619-1624; Journal of the American Chemical Society, 2013, 135, 32, 12122-12134; Bioorganic and Medicinal Chemistry Letters, 2014, 24, 16, 4039-4043; US2007185058; and WO2009117421.

Some azide compounds (intermediate 2) required for the synthesis of the compounds of the present invention can be prepared according to Synthesis Scheme 1. Starting from a suitable aldehyde known in the literature (exemplary synthesis method: Synthesis, 2009, 12, 2040-2060; Journal of Fluorine Chemistry, 1995, 70, 39-44) or commercially available, intermediate 1 can be prepared by nitration. Herein, nitration methods known to those skilled in the art can be used (exemplary synthesis method: WO2013174744; Journal of Medicinal Chemistry, 2013, 56, 4343-4356). Nitric acid or potassium nitrate is preferably used in concentrated sulfuric acid. Then, intermediate 1 can be converted into intermediate 2 using an azide (e.g., sodium azide) in a solvent (e.g., dimethyl sulfoxide).

Hal is fluorine or chlorine, preferably fluorine.

The substituent R ¹ has the meaning given in the general formula (I).

Synthesis Scheme 1

Starting from the appropriate azide compound (intermediate 2), indazole (intermediate 3) can be prepared by reaction with a primary amine (Synthetic Scheme 2). Useful methods for this purpose include, for example, those from Chemical Communications 2011, 47, 10133-10135 and RSC Adv., 2014, 4, 34232-34236. Alternatively, however, related methods such as those described in Organic Process Research and Development, 2011, 15, 4, 831-840; Chemistry of Heterocyclic Compounds, 2001, 37, 504-505 and Organic Letters, 2011, 13, 3542-3545 can also be used. Intermediate 2 is preferably reacted with an amine R ³ —NH ₂ (wherein R ³ is as defined in formula (I)) in the presence of activated molecular sieves in a solvent such as dichloromethane. Alternatively, trimethoxymethane (CAS 149-73-5) and toluene can also be used as solvents.

If necessary, the amine R ³ —NH ₂ used may have a functional group that may be protected in advance with a protecting group. This protecting group can be removed after the reaction or in a subsequent step of synthesizing the compounds of the present invention (for introduction and removal of suitable protecting groups, see also PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, ISBN: 9780471697541).

The substituents R ¹ and R ³ have the meanings given in the general formula (I).

Synthesis Scheme 2

Alternatively, intermediate 3 can also be prepared starting from intermediate 7 (see Synthesis Scheme 3). For this purpose, useful reactions are those with chlorine compounds (R ³ -Cl), bromine compounds (R ³ -Br), iodine compounds (R ³ -I), mesylate (R ³ -OMs) or 4-methylbenzenesulfonate (R ³ -OTs). The halide compounds or 4-methylbenzenesulfonate used are commercially available or can be prepared analogously to routes known from the literature (for the preparation of 4-methylbenzenesulfonate, one example is the reaction of a suitable alcohol with 4-methylbenzenesulfonyl chloride in the presence of triethylamine or pyridine; see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12, 4277-4294). Optionally, when using chlorine compounds or bromine compounds, an alkali metal iodide, such as potassium iodide or sodium iodide, can also be added. The base used can be, for example, potassium carbonate, cesium carbonate or sodium hydride. Useful solvents include, for example, 1-methylpyrrolidone, DMF, DMSO, or THF. If desired, the halogen compound or 4-methylbenzenesulfonate used can have a functional group that can be protected in advance with a blocking group (see also PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, ISBN: 9780471697541). For example, if a halogen compound or 4-methylbenzenesulfonic acid alkyl ester with one or more hydroxyl groups is used, these hydroxyl groups can be optionally protected with tert-butyl (dimethyl) silyl groups well known to those skilled in the art or similar silicon-containing blocking groups. Alternatively, the hydroxyl groups can be protected with tetrahydro-2H-pyrans (THP) groups or acetyl or benzoyl groups. The blocking group used can then be removed after the synthesis of intermediate 3 or removed as the final stage of releasing the compounds of this invention. For example, if a tert-butyl (dimethylsilyl) group is used as a blocking group, it can be removed, for example, in a solvent such as THF, using tetrabutylammonium fluoride. The THP protecting group can be removed, for example, using 4-methylbenzenesulfonic acid (optionally in the form of the monohydrate).The acetyl group or the benzoyl group can be removed by treatment with aqueous sodium hydroxide solution.

Alternatively, intermediate 3 can be prepared by the Mitsunobu reaction of intermediate 7 with an alcohol compound (R ³ -OH) (see, for example, KCK Swamy et al., Chem. Rev. 2009, 109, 2551-2651). Various phosphines (such as triphenylphosphine, tributylphosphine, or 1,2-diphenylphosphinoethane) can be used with diisopropyl azodicarboxylate (CAS 2446-83-5) or other diazene derivatives mentioned in the literature (KCK Swamy et al., Chem. Rev. 2009, 109, 2551-2651). Triphenylphosphine and diisopropyl azodicarboxylate are preferably used. If the alcohol compound (R ³ —OH) carries a functional group, then - as in the above-mentioned reaction with the halogen compound - known protecting group strategies can be used (further instructions can be found in PGM Wuts, TW Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, ISBN: 9780471697541).

The substituents R ¹ and R ³ have the meanings given in the general formula (I).

Synthesis Scheme 3

Selected intermediates 7 can be obtained by nitration of the appropriate 6-substituted indazole (see Synthesis Scheme 4). Useful methods for this purpose are nitration methods known to those skilled in the art, for example using nitric acid and concentrated sulfuric acid. Some intermediates 7 are known from the literature or are commercially available or can be synthesized analogously to routes known from the literature (see, for example, Bioorganic and Medicinal Chemistry, 2004, 12, 2115-2137).

The substituent R ¹ has the meaning given in the general formula (I).

Synthesis Scheme 4

Starting from intermediate 3, intermediate 4 (see synthesis scheme 5) can be prepared by reducing nitro. For example, nitro can be reduced with palladium carbon under hydrogen atmosphere (see, for example, WO2013174744 about 6-isopropoxy-5-nitro-1H-indazole being reduced to 6-isopropoxy-1H-indazole-5-amine), or by using iron and ammonium chloride reduction in water or ethanol (see also, for example, Journal of the Chemical Society, 1955,2412-2419), or by using tin (II) chloride reduction (CAS7772-99-8) (see, for example, Bioorganic and Medicinal Chemistry, 2004,12,2115-2137). Preferably, iron and ammonium chloride are used in water and ethanol and palladium carbon is used under hydrogen atmosphere.

The substituents R ¹ and R ³ have the meanings given in the general formula (I).

Synthesis Scheme 5

Starting from intermediate 4, compounds of the general formula (I) according to the present invention can be prepared (see Synthesis Scheme 6). For this purpose, various coupling agents known from the literature can be used (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 3 - Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12 - Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606). For example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-1H-benzotriazole hydrate (HOBt, WO2012107475; Bioorg. Med. Chem. Lett., 2008, 18, 2093), (1H-benzotriazol-1-yloxy)(dimethylamino)-N,N-dimethylmethaniminium tetrafluoroborate (TBTU, CAS 125700-67-6), (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, CAS 125700-67-6) can be used. The coupling agents used are 1H-imidazol-1-ylmethanone (CDI), 148893-10-1, propanephosphonic anhydride (in ethyl acetate or DMF, CAS 68957-94-8), or di-1H-imidazol-1-ylmethanone (CDI), with a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine being added to the reaction mixture. Preferred coupling agents are HATU, N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (EDC, CAS 1892-57-5), 1H-benzotriazol-1-ol hydrate (1:1) (HOBt, CAS 123333-53-9), and TBTU. The preferred base is N-ethyl-N-isopropylpropan-2-amine. Preferred solvents are THF or DMF.

Compounds of general formula (I) are prepared from intermediate 4. The substituents R ¹ , R ² and R ³ have the definitions given for general formula (I).

Synthesis Scheme 6

Starting from 6-substituted indazoles known from the literature or commercially available, selected intermediates 6 can be prepared by Mitsunobu reaction with alcohols ( ^R3 -OH) or by alkylation with appropriate halide reagents ^R3 -Cl, ^R3 -Br, ^R3 -I, or mesylates (R3 ^- OMs) or 4-methylbenzenesulfonates (R3 ^- OTs) (see Synthetic Scheme 7). Useful methods for Mitsunobu reaction and alkylation are described in Synthetic Scheme 3. For the synthesis of intermediates 3 starting from intermediates 6, nitration methods as described in Synthetic Scheme 4 can be used.

Another preparation method of intermediate 3: Substituents R ¹ and R ³ have the definitions given in the general formula (I).

Synthesis Scheme 7

Alternatively, compounds of general formula (I) can be obtained starting from intermediates 5. To this end, intermediates 5 can be reacted with halogen compounds R3 ^- I, ^R3 -Br, ^R3 -Cl, mesylate (R3 ^- OMs) or 4-methylbenzenesulfonate (R3 ^- OTs) as described in Synthesis Scheme 3. Intermediates 5 can be prepared from the corresponding 5-aminoindazoles by amide synthesis with carboxylic acids ^R2 - _CO2H in the presence of a coupling agent, as described in Synthesis Scheme 6. Suitable 5-aminoindazoles are commercially available or can be prepared by routes known from the literature.

Compounds of general formula (I) are prepared from intermediate 5. The substituents R ¹ , R ² and R ³ have the definitions given for general formula (I).

Synthesis Scheme 8

If R ¹ in formula (I) is defined as -CO ₂ Me (see formula (I)-a), this CO ₂ Me group can be converted into alternative functional groups known to those skilled in the art. More specifically, by reaction with methylmagnesium bromide, compounds of formula (I) in which R ¹ = -C(OH)(CH ₃ ) ₂ can be obtained. In addition, compounds of formula (I) in which R ¹ = -CO ₂ NH ₂ can be prepared by reaction with ammonia.

The substituents R ² and R ³ have the meanings given in the general formula (I).

If R ³ has a suitable functional group, these functional groups can be derivatized by methods known to those skilled in the art (see, for example, Science of Synthesis, Georg Thieme Verlag). For example, secondary amines can be alkylated (see, for example, alkylation of 1- (piperidin-4-yl) -1H- indazole with 1- bromo -2- (2- methoxyethoxy) ethane in WO2007142584 or alkylation of pyrazole-piperidine derivatives with 2- bromoethanol in US2015133422) or in a reductive amination manner (see, for example, WO20148992 about reductive amination with oxetane -3- ketone or US2002156081 about reductive amination of piperidine derivatives with acetaldehyde) converted into tertiary amino groups. For reductive amination, sodium triacetoxyborohydride is preferably used in the presence of acetic acid. For alkylation, potassium carbonate is preferably used as a base. Additionally, secondary amines can be reacted with carboxylic acids in an amide coupling (e.g., by using conditions as in Scheme 6).

For example, if the functional group is a sulfide group, it can be oxidized to sulfoxide or sulfone group by methods known in the literature. If the group is a sulfoxide group, it can be oxidized to sulfone group or sulfoximine (sulphoximine) group (see Angewandte Chemie, 2013, 125, 9570) equally. For oxidation step, for example 3-chloroperbenzoic acid (CAS 937-14-4) can be used (in this regard, also see for example US201094000 about 2- (methylsulfanyl) ethyl -1H- pyrazole derivatives are oxidized to 2- (methylsulfinyl) ethyl -1H- pyrazole derivatives, and another 2- (methylsulfanyl) ethyl -1H- pyrazole derivative is oxidized to 2- (methylsulfonyl) ethyl -1H- pyrazole derivatives). If the functional group is a keto group, it can be reduced to an alcohol group by reduction methods known to those skilled in the art (see, for example, Chemische Berichte, 1980, 113, 1907-1920 with regard to the use of sodium borohydride).

Synthesis of Example Compounds

Abbreviations and descriptions

The term sodium chloride solution always means a saturated aqueous sodium chloride solution.

The chemical names of the intermediates and examples were generated using ACD/LABS (Batch version 12.01) software.

method

In some cases, compounds of the invention and their precursors and/or intermediates were analyzed by LC-MS.

LC-MS method (analytical):

Method A:

MS instrument: Waters ZMD mass spectrometer; HPLC instrument: Agilent 1100; column: Phenomenex Luna C18 (2) 3.0 micron 30 mm × 4.6 mm; mobile phase A: water 0.1% formic acid, mobile phase B: acetonitrile 0.1% formic acid; gradient: 0.0 min 95% A → 0.5 min 95% A → 4.5 min 5% A → 5.5 min 5% A; flow rate: 2.0 ml/min; UV detection: 190-450 nM.

Method B:

MS instrument: Waters Micromass ZQ2000; HPLC instrument: Waters Acquity UPLC system; column: Acquity UPLC BEH C18 1.7 μm 100 mm × 2.1 mm; mobile phase A: water 0.1% formic acid, mobile phase B: acetonitrile 0.1% formic acid; gradient: 0.0 min 95% A→0.4 min 95% A→6.0 min 5% A→6.8 min 5% A; flow rate: 0.4 ml/min; UV detection: PDA.

Method C: UPLC (MeCN-HCOOH):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; eluent A: water + 0.1 volume % formic acid (99%), eluent 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 volume: 2 μl; DAD scan: 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z; ELSD.

Method D: UPLC (MeCN-NH ₃ ):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; eluent A: water + 0.2 volume% ammonia (32%), eluent 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 volume: 2 μl; DAD scan: 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z; ELSD.

In some cases, compounds of the invention and their precursors and/or intermediates were purified by the following exemplary preparative HPLC methods.

LC-MS method (preparative):

Method E:

MS instrument: Agilent 1260 Infinity Purification System. Agilent 6100 Series Single Quadruple LC/MS; Column: XSEELECT CSH Prep C18 5 μm OBD, 30 × 150 mm; Mobile phase A: 0.1% formic acid in water, Mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 10% to 95% over 22 min, centered on a specific focused gradient; Flow rate: 60 ml/min. Sample: 20-60 mg/ml solution in DMSO (optionally with formic acid and water) was injected.

Method F:

MS instrument: Agilent 1260 Infinity Purification System. Agilent 6100 Series Single Quadruple LC/MS; Column: XBridge Prep C18 5 μm OBD, 30 × 150 mm; Mobile phase A: 0.1% ammonia in water, Mobile phase B: 0.1% ammonia in acetonitrile; Gradient: 10% to 95% over 22 min, centered on a specific focused gradient; Flow rate: 60 ml/min. Sample: 20-60 mg/ml solution in DMSO (optionally with formic acid and water) was injected.

Method G:

System: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBridge C18 5μm 100×30mm; eluent A: water + 0.1% by volume formic acid, eluent B: acetonitrile; gradient: 0-8min 10-100% B, 8-10min 100% B; flow rate: 50ml/min; temperature: room temperature; solution: maximum 250mg/maximum 2.5ml DMSO or DMF; injection volume: 1×2.5ml; detection: DAD scan range 210-400nm; MS ESI+, ESI-, scan range 160-1000m/z.

Method H:

Waters automated purification system: pump 254, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD3100; column: XBridge C18 5μm 100×30mm; eluent A: water + 0.2% by volume ammonia (32%), eluent B: methanol; gradient: 0-8min 30-70% B; flow rate: 50ml/min; temperature: room temperature; detection: DAD scanning range 210-400nm; MSESI+, ESI-, scanning range 160-1000m/z; ELSD.

In some cases, mixtures of materials were purified by silica gel column chromatography.

To prepare some of the compounds of the present invention and their precursors and/or intermediates, column chromatography purification ("flash chromatography") was performed on silica gel using equipment available from Biotage. This was accomplished using columns available from Biotage, such as "SNAP Cartridge, KP_SIL" columns of varying sizes and "Interchim Puriflash Silica HP 15UM flash column" columns of varying sizes available from Interchim.

Starting compound

Intermediate V2-1

Methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate

2.00g (9.26mmol) 2-(6-bromopyridin-2-yl) propan-2-ol (CAS 638218-78-7) is dissolved in 20ml methanol and 20ml DMSO. Subsequently, 250mg 1,3-bis(diphenylphosphino)propane, 130mg palladium acetate (II) and 3ml triethylamine are added. The reaction mixture is purged with carbon monoxide three times at room temperature, and stirred for 30min under a carbon monoxide atmosphere of 13bar. The carbon monoxide atmosphere is removed by applying a vacuum, and the mixture is stirred for 24h at 100 ℃ under a carbon monoxide atmosphere of 14bar. The autoclave is decompressed, water is added into the reaction mixture, the reaction mixture is extracted with ethyl acetate three times, washed with saturated sodium bicarbonate aqueous solution and sodium chloride solution, filtered and concentrated by a hydrophobic filter. Obtain 1.60g crude product.

UPLC-MS (Method C): _Rt = 0.76 min (UV detector: TIC), mass measured 195.00.

Intermediate V3-1

Potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate

First, 1.60 g of the crude product of Intermediate 0-1 was added to 15 ml of methanol, 0.74 g of potassium hydroxide was added, and the mixture was stirred for 16.5 h at 50° C. After concentration, 2.1 g of a residue was obtained, which was used without further purification.

UPLC-MS (Method C): _Rt = 0.47 min (UV detector: TIC), mass measured 181.00.

Intermediate 1A

2-Fluoro-4-methoxy-5-nitrobenzaldehyde

To 21 ml of cooled sulfuric acid was added 3 g (19.5 mmol) of 2-fluoro-4-methoxybenzaldehyde [CAS: 331-64-6] and the solution was kept cooled at a temperature between -25°C and -15°C. 1.83 g of 70% nitrating acid was added dropwise and the mixture was stirred between -25°C and -15°C for 45 minutes. The mixture was added to ice water (100 ml) and allowed to stand for 30 minutes. The solid was filtered off and washed with water. The solid was dissolved in dichloromethane, the solution was washed with sodium bicarbonate solution and concentrated. After purification by flash chromatography (Biotage Isolera, 100 g silica gel column, cyclohexane/ethyl acetate gradient), 2.73 g (13.7 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 3.19 min; m/z = 200 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ = 4.06 (s, 3H), 6.87 (d, 1H), 8.45 (d, 1H), 10.22 (s, 1H)

Intermediate 1B

4-Chloro-2-fluoro-5-nitrobenzaldehyde

To a solution of 2.81 g of potassium nitrate in 21 ml of sulfuric acid cooled to 0°C was added 4.0 g of 4-chloro-2-fluorobenzaldehyde, and the mixture was stirred at 0°C for 0.5 h and at room temperature for 1 h. The mixture was added to ice water and extracted twice with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution, removed, and concentrated. 5.1 g of the title compound was obtained.

¹ H-NMR (300MHz, CDCl3): δ=7.47 (d, 1H), 8.46 (d, 1H), 10.31 (s, 1H)

Intermediate 2A

2-Azido-4-methoxy-5-nitrobenzaldehyde

To a solution of 2.73 g (13.7 mmol) of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (Intermediate 1A) in 50 ml of dimethyl sulfoxide was added 1.78 g (27 mmol) of sodium azide, and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with 500 ml of ethyl acetate, washed three times with water and sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. 2.91 g (13.1 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 3.41 min; no ionization (M+H)+

¹ H-NMR (300MHz, CDCl ₃ ): δ = 4.09 (s, 3H), 6.80 (s, 1H), 8.46 (s, 1H), 10.20 (s, 1H)

Intermediate 2B

2-Azido-4-chloro-5-nitrobenzaldehyde

Analogously to the preparation of Intermediate 1B, 5.1 g of 4-chloro-2-fluoro-5-nitrobenzaldehyde (Intermediate 1B) were reacted with 1.63 g of sodium azide in 80 ml of DMSO within 1 h. 5.35 g of the title compound were obtained.

¹ H-NMR (300MHz, CDCl3): δ=7.43 (s, 1H), 8.46 (s, 1H), 10.28 (s, 1H)

Intermediate 3A

6-Methoxy-5-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole

To a solution of 2.4 g (10.8 mmol) of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A) in 70 ml of dichloromethane was added 1.12 ml (10.8 mmol) of tetrahydro-2H-pyran-4-amine [38041-19-9] and 5 g of activated 4 angstrom molecular sieves. The reaction was stirred at room temperature for 3 h. The solution was filtered through celite, the celite was washed with dichloromethane, and the solvent was removed under reduced pressure. The crude product was dissolved in 50 ml of dry toluene and heated at 120° C. for 1 h. The mixture was allowed to reach room temperature, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Biotage Isolera, cyclohexane/ethyl acetate). 2.22 g (8.0 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 3.15 min; m/z = 278 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=2.19-2.29(m, 4H), 3.55-3.66(m, 2H), 3.97(s, 3H), 4.11-4.22(m, 2H), 4.56-4.68(m, 1H), 7.12(s, 1H), 8.08(s, 1H), 8.21(s, 1H)

Intermediate 3B

tert-Butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

To a solution of 2.65 g (11.9 mmol) of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A) in 50 ml of dichloromethane was added a solution of 2.38 g (11.9 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate [87120-72-7] in 20 ml of dichloromethane and 5 g of activated molecular sieves (4 angstroms). The mixture was then stirred at room temperature for 3.5 hours. A solution of 0.79 g (4.0 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate in 20 ml of dichloromethane and 5 g of activated molecular sieves (4 angstroms) were then added, and the mixture was stirred at room temperature for 19 hours. The solution was filtered through celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure, dissolved in 50 ml of anhydrous toluene, and the mixture was heated at 120°C for 1 hour. The mixture was allowed to reach room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (Biotage Isolera, 100 g silica gel column, cyclohexane/ethyl acetate) to give 4.25 g (11.3 mmol) of the title compound.

LC-MS (Method A): Rt = 3.93 min; m/z = 399 (M+Na) +

¹ H-NMR (300MHz, CDCl3): δ=1.49 (s, 9H), 2.08 (ddd, 2H), 2.24 (d, 2H), 2.95 (dd, 2H), 3.97(s, 3H), 4.33(d, 2H), 4.47-4.59(m, 1H), 7.11(s, 1H), 8.06(s, 1H), 8.21(s, 1H)

Intermediate 3C

2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-5-nitro-2H-indazole

2.5 g (13.5 mmol) of tetrahydro-2H-thiopyran-4-amine 1,1-dioxide [116529-31-8] was dissolved in 100 ml of dichloromethane. 3.0 g (13.5 mmol) of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A) and 12 g of activated 4 angstrom molecular sieves were then added. The mixture was stirred at room temperature under argon for 18 h, then filtered through celite and the celite was washed with dichloromethane. The filtrate was concentrated under reduced pressure, 60 ml of anhydrous toluene was added, and the mixture was heated at 120° C. for 1.5 h. The reaction was cooled to room temperature, and the solvent was concentrated under reduced pressure. 4.39 g (13.5 mmol) of the title compound was obtained.

LC-MS (Method A): Rt = 3.04 min; m/z = 326 (M+H) +

¹ H-NMR (300MHz, DMSO-d6): δ=2.41-2.48 (m, 2H), 2.53-2.67 (m, 2H), 3.27 (s, 2H), 3.38 -3.51(m, 2H), 3.91(s, 3H), 4.90-5.02(m, 1H), 7.31(s, 1H), 8.39(s, 1H), 8.67(s, 1H)

Intermediate 3D

6-Methoxy-5-nitro-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole

To 0.949 g (4.3 mmol) of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A) in 75 ml of dichloromethane was added 0.5 g (4.3 mmol) of tetrahydro-2H-thiopyran-4-amine [21926-00-1] and 2 g of activated 4 angstrom molecular sieves. The mixture was then stirred at room temperature for 72 hours. An additional 75 mg (0.64 mmol) of tetrahydro-2H-thiopyran-4-amine [21926-00-1] and 2 g of activated 4 angstrom molecular sieves were added, and the mixture was stirred at room temperature for 4 hours. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, 20 ml of anhydrous toluene was added, and the mixture was heated at 120°C for 1.5 hours. The reaction was cooled to room temperature, and the solvent was removed under reduced pressure. After purification of the residue (Biotage Isolera (100 g silica gel column), cyclohexane/ethyl acetate gradient), 0.938 g (3.2 mmol) of the title compound are obtained.

LC-MS (Method A): Rt = 3.64 min; m/z = 294 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=2.23-2.38(m, 2H), 2.51-2.60(m, 2H), 2.81-2.94(m, 4H), 3.97(s, 3H), 4.34-4.46(m, 1H), 7.11(s, 1H), 8.06(s, 1H), 8.21(s, 1H)

Intermediate 3E

6-Methoxy-5-nitro-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazole (isomer mixture)

To a solution of 850 mg (2.9 mmol) of 6-methoxy-5-nitro-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole (Intermediate 3D) in 51 ml of 2:1 tetrahydrofuran/water at 0°C was added 445 mg (0.724 mmol) of oxone, and the reaction was stirred for 0.5 h. Two 445 mg (0.724 mmol) portions of oxone were added over 1 h. 0.5 g of sodium metabisulfite was then added, and the reaction was partitioned between water and ethyl acetate. The organic phase was removed, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification (Biotage Isolera, 50 g silica gel column, dichloromethane/methanol) yielded 710 mg (2.3 mmol) of the title compound.

LC-MS (Method A): Rt = 2.76 & 2.83 min; m/z = 310 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=2.29-2.43(m, 2H), 2.71-3.03(m, 4H), 3.28(d, 1H) 3.40-3.48(m, 1H) ), 3.96-4.03(m, 3H), 4.57-4.77(m, 1H), 7.10(s, 1H), 8.09-8.22(m, 2H)

Intermediate 3F

rel-(1S,4S,5R)-5-(6-methoxy-5-nitro-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Intermediate 3G

rel-(1S,4S,5S)-5-(6-methoxy-5-nitro-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

To a solution of 314 mg (1.4 mmol) of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A) in 20 ml of dichloromethane was added a solution of 330 mg (1.55 mmol) of tert-butyl 5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate [207405-62-7] in 10 ml of dichloromethane and 0.773 ml (7.0 mmol) of trimethoxymethane [149-73-5], and the mixture was stirred at room temperature for 24 hours. 30 ml of anhydrous toluene was added to the mixture, the dichloromethane was partially evaporated, and the solution was heated at 120° C. for 1 hour. The mixture was allowed to reach room temperature, the solvent was removed under reduced pressure and purification was carried out by silica gel column chromatography (Biotage Isolera (50 g silica gel column), cyclohexane/ethyl acetate) to give 193 mg (0.5 mmol) of intermediate 3F and 336 mg (0.87 mmol) of intermediate 3G.

LC-MS (Method A): Rt = 4.03 min; m/z = 389 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=1.48 (s, 9H), 1.78 (dd, 1H), 2.31-2.52 (m, 3H), 2.89-2.93 (m, 1H), 3.18 (dd , 1H), 3.38(dd, 1H), 3.95(s, 3H), 4.42(d, 1H), 4.67(dd, 1H), 7.10(s, 1H), 8.08(s, 1H), 8.18(s, 1H). (Intermediate 3F)

LC-MS (Method A): Rt = 3.88 min; m/z = 333 (M-tBu+H)+

¹ H-NMR (300 MHz, CDCl 3 ): δ=1.47 (d, 9H), 1.80-1.94 (m, 2H), 2.34-2.57 (m, 2H), 2.78 (dd, 1H), 3.13-3.23 (m, 2H), 3.96 (s, 3H), 4.39 (d, 1H), 5.07-5.14 (m, 1H), 7.08 (s, 1H), 8.05 (d, 1H), 8.19 (s, 1H) (Intermediate 3G)

Intermediate 3H

6-Chloro-5-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole

To a solution of 2.5 g (11.0 mmol) of 2-azido-4-chloro-5-nitrobenzaldehyde (intermediate 2B) and 1.1 ml of 4-aminotetrahydro-2H-pyran in 50 ml of dichloromethane was added 6 ml (55 mmol) of trimethoxymethane (CAS 149-73-5), and the mixture was stirred at room temperature for 17 h. 50 ml of anhydrous toluene was added, the solvent was partially evaporated, and the residue was heated at 120 ° C for 1 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (Biotage Isolera, cyclohexane/ethyl acetate). 2.06 g of the title compound was obtained as a yellow solid.

¹ H-NMR (300MHz, CDCl3): δ=2.20-2.30 (m, 4H), 3.56-3.66 (m, 2H), 4.14-4.23 (m, 2H), 4.62-4.75 (m, 1H), 7.85 (s, 1H), 8.19 (s, 1H), 8.34 (s, 1H).

Intermediate 3I

6-Chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-nitro-2H-indazole

2.13 g of tetrahydro-2H-thiopyran-4-amine 1,1-dioxide hydrochloride (1:1) was dissolved in a mixture of water and methanol and purified by SCX column (eluent: 2 M ammonia in methanol). The resulting amine was dissolved in 50 ml of dichloromethane, and this solution was added to 2-azido-4-chloro-5-nitrobenzaldehyde (Intermediate 2B) in 50 ml of dichloromethane. The mixture was stirred at room temperature for 17 h, 50 ml of anhydrous toluene was added, and the solvent was partially evaporated. The mixture was then heated at 120° C. for 1.5 h and allowed to reach room temperature. The solid was filtered off and washed with ether. 3 g of the title compound were obtained.

¹ H-NMR (300MHz, DMSO-d6): δ=2.42-2.45(m, 2H), 2.53-2.69(m, 2H), 3.20-3.28(m, 2H), 3.40-3.53(m, 2H), 4.99-5.11(m, 1H), 8.08(s, 1H), 8.67(s, 1H), 8.87(d, 1H)

Intermediate 3J

4-(6-Methoxy-5-nitro-2H-indazol-2-yl)pyrrolidin-2-one

Analogously to the preparation of Intermediate 3I, 122 mg (0.9 mmol) of 4-aminopyrrolidin-2-one hydrochloride (1:1) was reacted with 0.2 g of 2-azido-4-methoxy-5-nitrobenzaldehyde (Intermediate 2A). 200 mg of the title compound were obtained as a yellow solid.

¹ H-NMR (300MHz, DMSO): δ = 2.65 (dd, 1H), 2.89 (dd, 1H), 3.48-3.53 (m, 1H), 3.86 (dd, 1H), 3 .91(s, 3H), 5.46-5.55(m, 1H), 7.31-7.32(m, 1H), 7.87(s, 1H), 8.41(s, 1H), 8.66(d, 1H)

Intermediate 3K

5-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylic acid methyl ester

Preparation method a), nitration:

To an ice-cold solution of 985 mg of methyl 2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylate (Intermediate 6A, crude product, containing a triphenylphosphine oxide fraction) in 8 ml of sulfuric acid was added portionwise 528 mg of potassium nitrate. The mixture was stirred in an ice-water cooling bath for 2 h and at room temperature for 17 h. The mixture was added to ice water and extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter, and concentrated. This afforded 1.14 g of the title compound.

UPLC-MS (Method C): Rt = 0.96 min; mass measured 305.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.00-2.21(m, 4H), 3.31(s, 1H), 3.43-3.62(m, 2H), 4.03(dt, 2 H), 4.85-4.99 (m, 1H), 8.07-8.12 (m, 1H), 8.69 (s, 1H), 8.89-8.91 (m, 1H).

Preparation method b), Mitsunobu reaction:

First 2.00g 5-nitro-1H-indazole-6-methyl-formiate (intermediate 7A) is joined among the 15mlTHF.Afterwards, add 3.56g triphenylphosphine, 1.20g tetrahydrochysene-2H-pyran-4-ol, 1.9mlN-ethyl-N-isopropylpropane-2-amine and 1.9ml diisopropyl azodicarboxylate, and the mixture is at room temperature stirred for 20h.Afterwards, add 0.3 equivalent of tetrahydrochysene-2H-pyran-4-ol, 0.5 equivalent of triphenylphosphine and 0.5 equivalent of diisopropyl azodicarboxylate, and the mixture is at room temperature stirred for 4.5h.Add water, the mixture is extracted with ethyl acetate three times, the extract is washed with sodium chloride solution, filtered and concentrated by hydrophobic filter.Resistates is passed through silica gel column chromatography (Isolera, hexane/ethyl acetate).Obtain 1.92g title compound (containing triphenylphosphine oxide as accompanying component).

UPLC-MS (Method C): Rt = 0.96 min; mass measured 305.00.

Intermediate 3L

5-Nitro-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylic acid methyl ester

First 3.00g 5-nitro-1H-indazole-6-methyl-formiate (intermediate 7A) is joined among the 25ml THF.Afterwards, add 5.34g triphenylphosphine, 1.55g (3R)-tetrahydrofuran-3-ol, 3.5ml N-ethyl-N-isopropylpropane-2-amine and 4.0ml diisopropyl azodicarboxylate, and the mixture is at room temperature stirred for 17h.Afterwards, add 0.3 equivalent of (3R)-tetrahydrofuran-3-ol, 0.5 equivalent of triphenylphosphine and 0.5 equivalent of diisopropyl azodicarboxylate, and the mixture is at room temperature stirred for 4h.Add water, the mixture is extracted with ethyl acetate three times, the extract is washed with sodium chloride solution, filtered and concentrated by hydrophobic filter.Resistates is passed through silica gel column chromatography (Isolera, hexane/ethyl acetate).Obtain 1.85g title compound (containing triphenylphosphine oxide as accompanying component).

UPLC-MS (Method C): Rt = 0.90 min; mass measured 291.00.

Intermediate 3M

5-Nitro-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of Intermediate 3L, 3.00 g of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 7A) were reacted with 1.55 g of (3S)-tetrahydrofuran-3-ol to give 3.41 g of the title compound (containing triphenylphosphine oxide as a concomitant component).

UPLC-MS (Method C): Rt = 0.90 min; mass measured 291.00.

Intermediate 3N

5-Nitro-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazole-6-carboxylic acid methyl ester

Step A: Preparation of (3R)-tetrahydrothiophen-3-yl 4-methylbenzenesulfonate

A solution of 1.00 g (3R)-tetrahydrothiophene-3-ol in 20 ml dichloromethane was cooled with an ice-water cooling bath and 1.92 g 4-methylbenzenesulfonyl chloride was added in portions. Afterwards, 2.7 ml triethylamine and 56 mg N, N-dimethylpyridine-4-amine (DMAP) were added and the mixture was stirred at room temperature for 20 h. The mixture was added to a saturated sodium bicarbonate solution and stirred, and the organic phase was removed. The aqueous phase was extracted twice with dichloromethane, the combined organic phase was washed with 1 M hydrochloric acid solution and saturated sodium carbonate solution, filtered through a hydrophobic filter and concentrated. The crude product was purified by silica gel column chromatography (Isolera, hexane/ethyl acetate). 443 mg of colorless oil was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.81-1.92 (m, 1H), 2.08-2.16 (m, 1H), 2.44 (s, 3H), 2.73-2.90 (m, 3H), 3.02 (dd, 1H), 5.22 (tt, 1H), 7.50 (d, 2H), 7.79-7.86 (m, 2H).

Step B:

First, 304mg of 5-nitro-1H-indazole-6-methyl formate (intermediate 7A) and 338mg of (3R)-tetrahydrothiophene-3-yl 4-methylbenzenesulfonate were added to 10ml of 2-methyltetrahydrofuran. 0.54g of potassium carbonate was added, and the mixture was stirred at 70°C for 41.5h. 2ml of DMSO was added, and the mixture was stirred at 70°C for an additional 21h. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated and purified by preparative HPLC. 175mg of 5-nitro-2-[(3S)-tetrahydrothiophene-3-yl]-2H-indazole-6-methyl formate was obtained.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=2.52-2.56 (m, 1H, hidden signal), 2.60-2.68 (m, 1H), 2.92-3.05 (m, 2H), 3.33-3.45 (m, 2H, hidden signal), 3.85 (s, 3H), 5.48 (quintet, 1H), 8.09 (s, 1H), 8.71 (s, 1H), 8.94-8.96 (m, 1H).

Intermediate 3O

5-nitro-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole-6-carboxylic acid methyl ester

Preparation method a):

Analogously to the preparation of intermediate 3N, step B, 2.71 g of methyl 5-nitro-1H-indazole-6-carboxylate (intermediate 7A) were reacted with 5.00 g of tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate in 20 ml of DMF in the presence of 5.07 g of potassium carbonate at 70° C. within 18 h.

Column chromatography on silica gel (Isolera, hexane/ethyl acetate) gave 1.09 g of the title compound.

UPLC-MS (Method C): Rt = 1.12 min; mass measured 321.00.

Preparation method b):

Analogously to the preparation of Intermediate 3L, 2.50 g of methyl 5-nitro-1H-indazole-6-carboxylate (Intermediate 7A) was reacted with 1.74 g of tetrahydro-2H-thiopyran-4-ol. Column chromatography on silica gel (Isolera, hexane/ethyl acetate) gave 1.42 g of the title compound as a crude product.

UPLC-MS (Method C): Rt = 1.12 min; mass measured 321.00.

Intermediate 3P

2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-5-nitro-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of intermediate 3L, 2.00 g of methyl 5-nitro-1H-indazole-6-carboxylate (intermediate 7A) was reacted with 2.37 g of tert-butyl 4-hydroxypiperidine-1-carboxylate, 3.56 g of triphenylphosphine, 2.3 ml of N-ethyl-N-isopropylpropan-2-amine and 2.6 ml of diisopropyl azodicarboxylate in 20 ml of THF at room temperature over 20.5 h. After column chromatography on silica gel, 1.44 g of the title compound was obtained as a crude product (containing a triphenylphosphine oxide fraction as well as other components).

¹ H-NMR (500 MHz, DMSO-d ₆ , selected signals): δ [ppm]=1.43 (s), 2.12-2.19 (m, 2H), 2.97 (broad singlet, 2H), 3.84 (s, 3H), 4.03 (d, 3H), 4.06-4.19 (broad signal, 2H), 4.82-4.91 (m, 1H), 7.52-7.67 (m, 13H), 8.07 (s, 1H), 8.68 (s, 1H), 8.89-8.91 (m, 1H).

Intermediate 4A

6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine

First, under nitrogen, 222 mg of 10% palladium on carbon (50% w/w) was added, followed by a solution of 2.22 g (8.0 mmol) of 6-methoxy-5-nitro-2-(tetrahydro-2H-pyran-4)-2H-indazole (intermediate 3A) in 120 ml of ethanol. The reaction was then stirred under standard pressure for 17 h in a hydrogen atmosphere. The solution was filtered through diatomaceous earth, which was then washed with ethanol and 20% ethanol/dichloromethane. The filtrate was concentrated under reduced pressure and mixed with ethanol, and the formed solid was filtered off and dried. 1.5 g (6.0 mmol) of the title compound was obtained.

LC-MS (Method A): Rt = 0.43 min; m/z = 248 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=2.14-2.24(m, 4H), 3.53-3.63(m, 2H), 3.82-3.90(m, 2H), 3.92(s, 3H), 4.10-4.17(m, 2H), 4.45-4.57(m, 1H), 6.75(s, 1H), 6.95(s, 1H), 7.63(d, 1H)

Intermediate 4B

tert-Butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate

First add 220mg 10% palladium on carbon (50%w/w), evaporate subsequently and use nitrogen purge.Then add 2.1g (5.6mmol) 4-(6-methoxyl group-5-nitro-2H-indazole-2-yl) piperidine-1-t-butyl formate (intermediate 3B) in 80ml ethanol.Mixture is stirred 24h under standard pressure in hydrogen atmosphere.Solution is filtered through diatomite and washed with ethanol, and filtrate is concentrated under reduced pressure.Afterwards, add dichloromethane and cyclohexane, and concentrate the mixture.Obtain 1.81g (5.2mmol) title compound.

LC-MS (Method A): Rt = 2.53 min; m/z = 347 (M+H) +

¹ H NMR (300MHz, CDCl ₃ ): δ = 1.48 (9H, s), 2.04 (2H, ddd), 2.19 (2H, d), 2.92 (2H, t), 3.84 (2H, s), 3.91 (3H , s), 4.21-4.34 (2H, m), 4.36-4.48 (1H, m), 6.75 (1H, s), 6.94 (1H, s), 7.60 (1H, s)

Intermediate 4C

2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-amine

4.39 g (13.5 mmol) of 2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-5-nitro-2H-indazole (Intermediate 3C) and 439 mg of 10% palladium on carbon in 150 ml of ethanol were stirred at room temperature under a hydrogen atmosphere for 21 h. The hydrogen atmosphere was removed, and 439 mg of 10% palladium on carbon were added, and the mixture was stirred under a hydrogen atmosphere for 71 h. The hydrogen atmosphere was removed, and 50 ml of ethanol and 439 mg of 10% palladium on carbon were added, and the mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered through celite, and the celite was washed with ethanol, 10% ethanol/dichloromethane, and 25% ethanol/dichloromethane. After concentration, 2.55 g (8.6 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 0.43 min; m/z = 296 (M+H) +

¹ H-NMR (300MHz, DMSO-d6): δ=2.32-2.39(m, 2H), 2.44-2.58(m, 2H), 3.22-3.29(m, 2H), 3.37-3. 45(m, 2H), 3.82(s, 3H), 4.62(s, 2H), 4.68-4.79(m, 1H), 6.62(s, 1H), 6.86(s, 1H), 7.91(s, 1H)

Intermediate 4D

6-Methoxy-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine (isomer mixture)

A mixture of 710 mg (2.3 mmol) of 6-methoxy-5-nitro-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazole (Intermediate 3E) and 71 mg of 10% palladium on carbon in 50 ml of ethanol was placed under a hydrogen atmosphere for 24 hours. An additional 71 mg of 10% palladium on carbon was then added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction was filtered through celite, the celite was washed with ethanol, and the filtrate was concentrated under reduced pressure. This yielded 426 mg (1.5 mmol) of the title compound.

LC-MS (Method A): Rt = 0.44 min; m/z = 280 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=2.26-2.44(m, 2H), 2.63-2.96(m, 4H), 3.20-3.28(m, 1H), 3.35-3.46( m, 1H), 3.91-3.93 (m, 3H), 4.50-4.62 (m, 1H), 6.74-6.77 (m, 1H), 6.92 (s, 1H), 7.61-7.71 (m, 1H)

Intermediate 4E

rel-(1S,4S,5R)-5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

A mixture of 193 mg (0.497 mmol) of tert-butyl rel-(1S,4S,5R)-5-(6-methoxy-5-nitro-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 3F) and 40 mg of 10% palladium on carbon in 20 ml of ethanol was treated with a hydrogen atmosphere for 5 h. The mixture was filtered through celite and washed with ethanol, and the solvent was removed under reduced pressure. This gave 150 mg (0.418 mmol) of the title compound.

LC-MS (Method A): Rt = 2.64 min; m/z = 359 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=1.49 (s, 9H), 1.72 (t, 1H), 2.23-2.42 (m, 3H), 2.88 (s, 1H), 3.11-3.21 (m, 1H), 3 .35(dd, 1H), 3.85(s, 2H), 3.91(s, 3H), 4.40(d, 1H), 4.58(dd, 1H), 6.73(s, 1H), 6.94(s, 1H), 7.63(s, 1H).

Intermediate 4F

rel-(1S,4S,5S)-5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

A mixture of 336 mg (0.865 mmol) of rel-(1S, 4S, 5S)-5-(6-methoxy-5-nitro-2H-indazole-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (intermediate 3G) and 72 mg of 10% palladium on carbon in 20 ml of ethanol was treated with a hydrogen atmosphere for 19 h. The mixture was filtered through celite and washed with ethanol, and the solvent was removed under reduced pressure. 297 mg (0.829 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 2.50 & 2.53 min; m/z = 359 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=1.45 (d, 9H), 1.74-1.91 (m, 2H), 2.27-2.51 (m, 2H), 2.72-3.01 (m, 1H), 3.08-3.18 (m, 2H), 3. 84-3.85 (m, 2H), 3.91 (s, 3H), 4.29-4.40 (m, 1H), 5.00-5.07 (m, 1H), 6.74 (s, 1H), 6.89-6.94 (m, 1H), 7.60-7.65 (m, 1H).

Intermediate 4G

6-Chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine

First, 1.39 g of 6-chloro-5-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole (intermediate 3H) was added to 20 ml of ethanol and 3 ml of water. Subsequently, 132 mg of ammonium chloride and 2.76 g of iron were added, and the mixture was stirred at 90° C. for 1.5 h. The mixture was filtered through celite, washed with ethanol, and concentrated. During this process, a solid precipitated, which was filtered off with suction and washed with water and ether. After drying the solid, 183 mg of the title compound was obtained. The celite was washed again with a dichloromethane/THF mixture, then concentrated and the residue was extracted by stirring with ether and dried to give a further 617 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.99-2.12 (m, 4H), 3.43-3.55 (m, 2H), 3.93-4.03 (m, 2H), 4.54-4.67 (m, 1H), 4.93 (s, 2H), 6.87 (s, 1H), 7.60 (s, 1H), 8.09 (s, 1H).

Intermediate 4H

6-Chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine

To a mixture of 2.78 g (8.4 mmol) of 6-chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-nitro-2H-indazole (Intermediate 3I) and 2.35 g (42 mmol) of iron powder in 44 ml of ethanol was added a solution of 1.35 g (25.3 mmol) of ammonium chloride in 22 ml of water, and the mixture was heated at 70° C. for 40 min. After cooling to room temperature, the mixture was filtered (Whatman filter cup, washed with ethanol), and the filtrate was concentrated. The mixture was then partitioned between a saturated aqueous sodium bicarbonate solution and a mixture of 10% methanol in dichloromethane. The aqueous phase was extracted again, and the combined organic phases were filtered. After concentration under reduced pressure, 2.22 g of the title compound were obtained.

¹ H-NMR (300MHz, CDCl3): δ=2.60-2.76 (m, 4H), 3.06-3.18 (m, 2H), 3.51-3.63 (m, 2H), 4.00 (s, 2H), 4.62-4.71 (m, 1H), 6.87 (s, 1H), 7.70 (s, 2H).

Intermediate 4I

rac-4-(5-amino-6-methoxy-2H-indazol-2-yl)pyrrolidin-2-one

To 200 mg (0.724 mmol) of 4-(6-methoxy-5-nitro-2H-indazol-2-yl)pyrrolidin-2-one (Intermediate 3J) in 20 ml of ethanol was added 20 mg of 10% palladium on carbon (50% wet with water), and the mixture was stirred under a hydrogen atmosphere for 18 h. 20 mg of 10% palladium on carbon (50% wet with water) was added, and the mixture was stirred under a hydrogen atmosphere for 21 h. The mixture was filtered through celite, the celite was washed with ethanol, and the filtrate was concentrated. 119 mg of the title compound was obtained as a crude product.

¹ H-NMR (300MHz, CDCl3): d=2.93-2.99 (m, 2H), 3.84-3.98 (m, 7H), 5.23-5.33 (m, 1H), 5.73-5.77 (m, 1H), 6.72 (s, 1H), 6.93 (s, 1H), 7.65 (s, 1H)

Intermediate 4J

5-amino-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylic acid methyl ester

First, 1.13g of 5-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-methyl formate (intermediate 3K) was added to 10ml of ethanol and 2ml of water. Afterwards, 84mg of ammonium chloride and 1.76g of iron were added, and the mixture was stirred at 90°C for 2h. The mixture was filtered through diatomaceous earth and washed with ethanol, and some solvent was removed on a rotary evaporator. Afterwards, the mixture was extracted with ethyl acetate, the extract was washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. 892mg of the title compound was obtained as a crude product.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.01-2.14(m, 4H), 3.44-3.55(m, 2H), 3.84(s, 3H), 3.95-4.03(m, 2H), 4 .61-4.75(m, 1H), 5.81(s, 2H), 6.79-6.82(m, 1H), 8.11(d, 1H), 8.18-8.21(m, 1H).

Intermediate 4K

5-Amino-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of intermediate 4J, 167 mg of methyl 5-nitro-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazole-6-carboxylate (intermediate 3N) was reacted with 303 mg of iron, 15 mg of ammonium chloride in 7.5 ml of ethanol and 2.5 ml of water at 90° C. over 17.5 h. The crude product was purified by preparative HPLC to give 91 mg of the title compound.

UPLC (Method C): Rt = 0.83 min; mass measured 277.00.

Intermediate 4L

5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylic acid methyl ester

To 1.85 g of methyl 5-nitro-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylate (Intermediate 3L, batch containing triphenylphosphine oxide) in 4.9 ml of water and 28 ml of ethanol were added 1.24 g of iron powder and 119 mg of ammonium chloride. The mixture was heated under reflux for 3 h, filtered through celite and washed with ethyl acetate. The filtrate was partially concentrated, ethyl acetate was added, and the mixture was acidified to pH = 3 with 1N aqueous hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate. The aqueous phase was adjusted to pH = 8 with 1M sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were concentrated. This gave 759 mg of the title compound with a small amount of triphenylphosphine oxide.

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 2.35-2.42 (m, 1H), 2.44-2.49 (m), 3.83-3.90 (m, 4H), 3.99-4.10 (m , 3H), 5.26-5.32(m, 1H), 5.83(s, 2H), 6.81(d, 1H), 8.08(d, 1H), 8.21(s, 1H).

Intermediate 4M

5-Amino-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazole-6-carboxylic acid methyl ester

Be similar to the preparation of intermediate 4L, in 3 hours, make 200mg 5-nitro-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazole-6-methyl-formiate (intermediate 3M, batch material contains triphenylphosphine oxide) and 383mg iron and 37mg ammonium chloride in 4ml ethanol and 0.7ml water under reflux.In second reaction batch material, make 3.21g 5-nitro-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazole-6-methyl-formiate (intermediate 3M, batch material contains triphenylphosphine oxide) and 3.99g iron and 383mg ammonium chloride in 42ml ethanol and 7ml water.Two reaction batch materials are merged, and as in the preparation of intermediate 4L, carry out aftertreatment.Obtain 552mg title compound (crude product), it is a brown solid.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.31-2.49 (m), 3.83-3.90 (m, 5H), 3.98-4.12 (m, 3H), 5.26-5.33 (m, 1H), 5.84 (s, 2H), 6.80-6.83 (m, 1H), 8.11 (d, 1H), 8.21 (s, 1H).

Intermediate 4N

5-amino-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of intermediate 4J, 1.09 g of methyl 5-nitro-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole-6-carboxylate (intermediate 3O) was reacted with 1.27 g of iron, 61 mg of ammonium chloride in 10 ml of ethanol and 2 ml of water at 85° C. over 20.5 h. After a similar workup, 992 mg of crude product were obtained.

Intermediate 4O

5-amino-2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of intermediate 4J, 6.09 g of methyl 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-nitro-2H-indazole-6-carboxylate (intermediate 3P) was reacted with 6.06 g of iron, 299 mg of ammonium chloride in 35 ml of ethanol and 7 ml of water at 85° C. over 19.5 h. After a similar workup, 5.52 g of crude product were obtained.

Intermediate 5A

N-(6-Methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

3.84 g (23.5 mmol) of 6-methoxy-1H-indazol-5-amine (CAS No. 749223-61-8) and 4.95 g (25.9 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid were dissolved in 150 ml of tetrahydrofuran, and 3.60 g (23.5 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 9.02 g (47.1 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 9.84 ml (70.6 mmol) of triethylamine were added at 25°C. The solution was stirred at 25°C for 24 hours. After concentrating the solution, the residue was dissolved in ethyl acetate, water was added, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution was concentrated. The residue was purified by silica gel column chromatography (Isolera flash purification system (Biotage), hexane/ethyl acetate), to obtain 3.75 g of the title compound.

UPLC-MS (Method C): R _t = 1.12 min

MS (ESIpos): m/z=337 (M+H) ⁺

¹ H-NMR (400MHz, DMSO-d6): δ=4.01(s, 3H), 7.13(s, 1H), 8.02(s, 1H), 8.21(d d, 1H), 8.40 (t, 1H), 8.47 (d, 1H), 8.74 (s, 1H), 10.42 (s, 1H), 12.91 (s, 1H).

Intermediate 6A

2-(Tetrahydro-2H-pyran-4-yl)-2H-indazole-6-carboxylic acid methyl ester

Preparation method A: Mitsunobu reaction:

A suspension of 7.00 g of methyl 1H-indazole-6-carboxylate in 80 ml of THF was cooled in an ice-water cooling bath. 4.5 ml of tetrahydro-2H-pyran-4-ol, 3.1 g of triphenylphosphine, and 2.3 ml of diisopropyl azodicarboxylate (DIAD, CAS 2446-83-5) were added, and the mixture was stirred at room temperature for 19 hours. An additional 3.1 g of triphenylphosphine and 2.3 ml of diisopropyl azodicarboxylate were added, and the mixture was stirred at room temperature for 71 hours and at 70°C for 5 hours. Water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution and concentrated. The residue was purified by silica gel column chromatography (Isolera, eluent: hexane/ethyl acetate). 11.0 g of a solid was obtained, which was extracted by stirring with diethyl ether. After drying, 8.95 g of crude product (containing the title compound and triphenylphosphine oxide according to UPLC analysis) was obtained. The diethyl ether washes were concentrated. 1.78 g of a solid was obtained (the title compound as a crude product, containing triphenylphosphine oxide).

UPLC-MS (Method C): Rt = 0.94 min; mass measured 260.00

Preparation Method B: Alkylation

First, 5.00 g of 1H-indazole-6-carboxylic acid methyl ester was added to 50 ml of DMF. 7.0 g of 4-bromotetrahydro-2H-pyran, 11.8 g of potassium carbonate, and 7.07 g of potassium iodide were added, and the mixture was stirred at 100° C. for 16.5 h. Water was added, the mixture was extracted five times with ethyl acetate, the extracts were washed with sodium chloride solution, and concentrated. 8.99 g of an oily substance was obtained, which was first added to 30 ml of DMF. 6.0 g of 4-bromotetrahydro-2H-pyran and 10.2 g of potassium carbonate were added, and the mixture was stirred at 120° C. for 20.5 h. Water was added, the mixture was extracted with ethyl acetate, the extracts were washed with sodium chloride solution, and concentrated. 5.73 g of a residue was obtained (containing product according to UPLC, Rt = 0.94 min). This was combined with 8.95 g of the crude product from Preparation A and purified by silica gel column chromatography (Isolera, hexane/ethyl acetate). 1.41 g of a solid was obtained, which was extracted by stirring with diethyl ether. After drying, 991 mg of the title compound were obtained.

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 2.08-2.19 (m, 4H), 3.54 (td, 2H), 3.88 (s, 3H), 3.99-4.06 (m, 2 H), 4.83 (tt, 1H), 7.57 (dd, 1H), 7.81 (dd, 1H), 8.31 (q, 1H), 8.58 (d, 1H).

Intermediate 7A

5-Nitro-1H-indazole-6-carboxylic acid methyl ester

4.60 g (26.1 mmol) of methyl 1H-indazole-6-carboxylate (CAS No. 170487-40-8) was dissolved in 120 ml of 96% sulfuric acid and cooled to -15°C in a three-necked flask equipped with a CPG stirrer, a dropping funnel, and an internal thermometer. Pre-prepared and cooled nitrating acid (10 ml of 96% sulfuric acid in 5 ml of 65% nitric acid) was added dropwise to the solution over 15 minutes. After the addition was complete, the mixture was stirred for a further 1 hour (internal temperature -13°C). The reaction mixture was poured into ice, the precipitate was filtered off with suction, washed with water, and dried under reduced pressure in a drying cabinet at 50°C. 5.49 g of the title compound were obtained.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] = 3.87 (s, 3H), 7.96 (s, 1H), 8.44 (s, 1H), 8.70 (s, 1H), 13.98 (br.s., 1H).

Working Examples

Example 1

N-[6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a mixture of 260 mg (1.05 mmol) of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A), 201 mg (1.05 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [CAS 131747-42-7], and 440 mg (1.2 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 5 ml of anhydrous dimethylformamide was added 0.366 ml (2.1 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 64 hours. Ethyl acetate and water were added to the reaction, the organic phase was removed, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. After purification (Biotage Isolera, 50 g silica gel column, cyclohexane/ethyl acetate), 290 mg (0.69 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 4.51 min; m/z = 421 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=2.02-2.11(m, 4H), 3.47-3.54(m, 2H), 3.95-4.00(m, 5H), 4. 59-4.69 (m, 1H), 7.15 (s, 1H), 8.19 (dd, 1H), 8.35-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H)

Example 2

N-[6-Methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Step A

tert-Butyl 4-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]piperidine-1-carboxylate

To a mixture of 913 mg (2.6 mmol) of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (Intermediate 4B), 500 mg (2.6 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [131747-42-7], and 1.1 g (2.9 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 10 ml of anhydrous dimethylformamide was added 0.918 ml (5.3 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate and water were added, the organic phase was removed and extracted twice with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. After purification by column chromatography (Biotage Isolera, 50 g silica gel column, cyclohexane/ethyl acetate), 1.13 g (2.2 mmol) of tert-butyl 4-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]piperidine-1-carboxylate was obtained.

LC-MS (Method A): Rt = 4.49 min; m/z = 464 (M-(tBu+H))+

¹ H-NMR (300MHz, CDCl ₃ ): δ = 1.49 (s, 9H), 2.05-2.26 (m, 4H), 2.88-2.99 (m, 2H), 4.03 (s, 3H), 4.26-4.35 (m, 2H), 4.46-4. 56(m, 1H), 7.07(s, 1H), 7.83-7.88(m, 2H), 8.12(dd, 1H), 8.49(d, 1H), 8.82(s, 1H), 10.70(s, 1H)

Step B

To 1.13 g (2.18 mmol) of tert-butyl 4-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]piperidine-1-carboxylate was added 10 ml of a 4 M solution of hydrogen chloride in dioxane and 2 ml of methanol, and the mixture was stirred at room temperature for 45 minutes. The solvent was concentrated under reduced pressure. The residue was purified (SCX column, eluent: 2 M ammonia in methanol) to give 820 mg (2.0 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide.

LC-MS (Method B): Rt = 3.23 min; m/z = 420 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=2.00-2.15(m, 2H), 2.23-2.32(m, 2H), 2.79-2.90(m, 2H), 3.31(td, 2H), 4.03(s, 3H), 4.40-4.52(m, 1H), 7.07(s, 1H), 7.83-7.90(m, 2H), 8.12(dd, 1H), 8.49(d, 1H), 8.83(s, 1H), 10.68-10.72(m, 1H)

Example 3

N-{6-methoxy-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of 132 mg (0.315 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 5 ml of dichloromethane was added 0.088 ml (0.63 mmol) of triethylamine and 0.091 ml (0.63 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate [6226-25-1]. The reaction was stirred at room temperature for 2 hours. Anhydrous tetrahydrofuran was then added, and the reaction was heated at 55°C for 19.5 hours. The reaction was cooled to room temperature, then dichloromethane and water were added. The organic phase was removed, the aqueous phase was extracted twice with dichloromethane, and the combined organic phases were concentrated under reduced pressure. Purification (Biotage Isolera, 25 g silica gel column, cyclohexane/ethyl acetate) yielded 107 mg (0.213 mmol) of the title compound.

LC-MS (Method B): Rt = 5.11 min; m/z = 502 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=2.02-2.12(m, 4H), 2.52-2.61(m, 2H), 3.03(d, 2H), 3.19-3.26(m, 2H), 3. 96 (s, 3H), 4.35-4.45 (m, 1H), 7.13 (s, 1H), 8.19 (dd, 1H), 8.35-8.45 (m, 3H), 8.66 (s, 1H), 10.47 (s, 1H)

Example 4

N-[6-Methoxy-2-(1-methylpiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of 150 mg (0.358 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 0.5 ml of tetrahydrofuran and 0.5 ml of methanol was added 0.1 ml of 37% aqueous formaldehyde solution [50-00-0], and the mixture was stirred at room temperature for 20 minutes. 108 mg (0.508 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 1 hour. The mixture was acidified dropwise with 1 M aqueous hydrochloric acid and concentrated under reduced pressure. After prepurification (SCX column, 2 M ammonia in methanol), purification was performed by column chromatography (Biotage Isolera, 25 g silica gel column, dichloromethane/methanol). After freeze-drying, 113 mg (0.261 mmol) of the title compound was obtained.

LC-MS (Method B): Rt = 3.24 min; m/z = 434 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=2.05 (dd, 6H), 2.20 (s, 3H), 2.84-2.90 (m, 2H), 3.95 (s, 3H), 4 .29-4.38(m, 1H), 7.15(s, 1H), 8.19(dd, 1H), 8.33-8.45(m, 3H), 8.66(s, 1H), 10.47(s, 1H)

Example 5

N-[2-(1-hydroxyacetylpiperidin-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a mixture of 75 mg (0.179 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2), 15 mg (0.197 mmol) of glycolic acid [79-14-1], and 75 mg (0.197 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 2 ml of N,N-dimethylformamide was added 0.062 ml (0.358 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 22 hours. Ethyl acetate and water were added to the mixture, the organic phase was removed and extracted twice with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. After purification (Biotage Isolera, 25 g silica column, ethyl acetate/methanol, followed by mass-based automated purification (Method E)), 19.2 mg (0.040 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 4.03 min; m/z = 478 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=1.85-2.05(m, 2H), 2.12(dd, 2H), 2.83(dd, 1H), 3.16(dd, 1H), 3.84(d, 1H), 3.95(s, 3H), 4.13(d , 2H), 4.46(d, 1H), 4.55(s, 1H), 4.63-4.73(m, 1H), 7.13(s, 1H), 8.19(dd, 1H), 8.34-8.45(m, 3H), 8.66(s, 1H), 10.47(s, 1H)

Example 6

N-[6-methoxy-2-(1'-methyl-1,4'-bipiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To 14 mg (0.119 mmol) of 1-methylpiperidin-4-one [1445-73-4] in 2 ml of dichloromethane were added 50 mg (0.119 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) and 7 microliters of acetic acid. The mixture was stirred at room temperature for 45 minutes, then 38 mg (0.179 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 19 hours. An additional 14 mg (0.119 mmol) of 1-methyl-4-piperidinone in 1 ml of dichloromethane and 7 microliters of acetic acid were added, and the mixture was stirred at room temperature for 45 minutes. Then, 38 mg (0.179 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 24 hours. Under reduced pressure, remove solvent, mixture is distributed between saturated sodium bicarbonate solution and dichloromethane/methanol mixture, organic phase is shifted out and under reduced pressure, concentrated.Purification (Biotage Isolera, 25g silica gel column, 2M ammonia methanol/dichloromethane solution, then Biotage Isolera (11g KP-SI NH , hexamethylene/ethyl acetate and ethyl acetate/methanol gradient)) and after lyophilizing, obtain 21mg (0.041mmol) title compound.

LC-MS (Method B): Rt = 2.78 min; m/z = 517 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 1.38-1.50 (m, 2H), 1.67 (d, 2H), 1.81 (dd, 2H), 1.97-2.09 (m, 4H), 2.10 (s, 3H), 2.18-2.35 (m, 3H), 2. 77(dd, 2H), 2.97(d, 2H), 3.95(s, 3H), 4.27-4.37(m, 1H), 7.13(s, 1H), 8.19(dd, 1H), 8.33-8.45(m, 3H), 8.65(s, 1H), 10.47(s, 1H)

Example 7

N-[6-Methoxy-2-(1-sulfamoylpiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To 50 mg (0.119 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 2 ml of dioxane was added 23 mg (0.239 mmol) of sulfamide [7803-58-9]. The mixture was heated to 110° C. for 10 h. The mixture was cooled, dichloromethane, methanol, and water were added, and the organic phase was removed and filtered. The solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography (Biotage Isolera, 25 g silica gel column, dichloromethane/methanol). 45 mg (0.090 mmol) of the title compound was obtained.

LC-MS (Method A): Rt = 3.69 min; m/z = 499 (M+H) +

¹ H-NMR (300MHz, DMSO-d6): 2.13-2.24(m, 4H), 2.72-2.85(m, 2H), 3.58-3.64(m, 2H), 3.99(s, 3H), 4.5 2-4.57(m, 1H), 6.84(s, 2H), 7.18(s, 1H), 8.22(dd, 1H), 8.37-8.49(m, 3H), 8.70(s, 1H), 10.51(s, 1H)

Example 8

N-{2-[1-(Acetylsulfamoyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To 44 mg (0.088 mmol) of N-[6-methoxy-2-(1-sulfamoylpiperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 7) in 2 ml of acetonitrile were added 0.031 ml (0.177 mmol) of N,N-diisopropylethylamine, 11 mg (0.088 mmol) of N,N-dimethylpyridin-4-amine, and 0.1 ml of a solution of 0.1 ml of acetyl chloride in 1.0 ml of acetonitrile. The mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added, the organic phase removed and extracted twice with ethyl acetate. The organic phases were combined, washed with sodium chloride solution, filtered, and concentrated under reduced pressure. After purification (Biotage Isolera, 25 g silica gel column, cyclohexane/ethyl acetate) and overnight lyophilization, 21.8 mg (0.04 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 4.36 min; m/z = 541 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): 1.97 (s, 3H), 2.05-2.21 (m, 4H), 3.06 (t, 2H), 3.74 (d, 2H), 3.96 (s, 3H), 4.5 1-4.61 (m, 1H), 7.15 (s, 1H), 8.19 (dd, 1H), 8.34-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H), 11.48 (s, 1H)

Example: 9

N-(2-{1-[2-(Dimethylamino)ethyl]piperidin-4-yl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

To 50 mg (0.119 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 2 ml of anhydrous dimethylformamide were added 41 mg (0.298 mmol) of potassium carbonate and 24 mg (0.167 mmol) of 2-chloro-N,N-dimethylethanamine hydrochloride (1:1) [4584-46-7]. The mixture was stirred at room temperature for 18 h and at 60° C. for 8 h, then cooled to room temperature. Ethyl acetate and water were added to the mixture, the organic phase was removed, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with sodium chloride solution, dried (sodium sulfate), filtered, and concentrated. After purification of the residue (Biotage Isolera (11 g KP-NH2), cyclohexane/ethyl acetate gradient, methanol/ethyl acetate gradient, then overnight lyophilization), 6.9 mg (0.014 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 2.91 min; m/z = 491 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=2.00-2.10(m, 12H), 2.31-2.44(m, 4H), 2.99(d, 2H), 3.95(s, 3H) , 4.30-4.39(m, 1H), 7.14(s, 1H), 8.19(dd, 1H), 8.34-8.45(m, 3H), 8.66(s, 1H), 10.47(s, 1H)

Example: 10

N-{6-methoxy-2-[1-(oxetan-3-yl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To 100 mg (0.24 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 3 ml of dichloromethane was added a solution of 26 mg (0.36 mmol) of 3-oxetanone [6704-31-0] in 1 ml of dichloromethane and 0.027 ml (0.48 mmol) of acetic acid. The mixture was stirred at room temperature for 0.5 h. 76 mg (0.36 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 67 h. Two phases were generated by adding a dichloromethane/methanol mixture and saturated sodium bicarbonate solution, the organic phase was removed, and the solvent was removed under reduced pressure. After purification (Biotage Isolera, 25 g silica gel column, dichloromethane/methanol), 36.5 mg (0.077 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 3.27 min; m/z = 476 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=1.95-2.12(m, 6H), 2.81(d, 2H), 3.40-3.48(m, 1H), 3.96(s, 3H), 4.41- 4.46(m, 3H), 4.54(dd, 2H), 7.14(s, 1H), 8.19(dd, 1H), 8.35-8.45(m, 3H), 8.66(s, 1H), 10.48(s, 1H)

Example: 11

N-[2-(1,1-Dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a mixture of 2.55 g (8.6 mmol) of 2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-amine (Intermediate 4C), 1.73 g (9.1 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [131747-42-7] and 3.45 g (9.1 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 30 ml of DMF was added 3 ml (17.3 mmol) of N-ethyl-N-isopropylpropan-2-amine and the mixture was stirred at room temperature for 15 h. Ethyl acetate and water were added, the organic phase was removed and extracted three times with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was mixed with dichloromethane and the resulting solid was extracted by stirring with 100 ml of ethyl acetate. The solvent was concentrated under reduced pressure and the residue was dried at 60° C. for 24 h and at 90° C. for 24 h. 2.57 g (5.5 mmol) of the title compound were obtained.

LC-MS (Method B): Rt = 4.29 min; m/z = 469 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 2.40 (dd, 2H), 2.49-2.61 (m, 2H), 3.21-3.25 (m, 2H), 3.44 (t, 2H), 3.96 (s, 3H), 4.80-4.89 (m, 1H), 7.17 (s, 1H), 8.19 (dd, 1H), 8.37-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H)

Example 12

rac-N-[6-methoxy-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a mixture of 426 mg (1.52 mmol) of rac-6-methoxy-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine (Intermediate 4D), 306 mg (1.6 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [131747-42-7], and 609 mg (1.6 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 10 ml of dimethylformamide was added 0.531 ml (3.0 mmol) of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 23 hours. Ethyl acetate and water were added to the reaction, the organic phase was removed and extracted three times with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. After purification (Biotage Isolera, 50 g silica gel column, dichloromethane/methanol), 560 mg (1.2 mmol) of the title compound were obtained.

LC-MS (Method A): Rt = 3.42 & 3.47 min; m/z = 453 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=2.31-2.47(m, 2H), 2.66-3.02(m, 4H), 3.24-3.29(m, 1H), 3.39-3.49(m, 1H), 4.04(d , 3H), 4.62-4.70(m, 1H), 7.05(d, 1H), 7.85-7.89(m, 2H), 8.12(dd, 1H), 8.49(d, 1H), 8.84(d, 1H), 10.71(s, 1H)

Example: 13

N-{2-[1-(2-Hydroxyethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Step A:

N-{2-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of 85 mg (0.2 mmol) of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) in 5 ml of dichloromethane were added 0.155 ml (0.81 mmol) of {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde [102191-92-4] and 0.046 ml (0.81 mmol) of acetic acid. The mixture was stirred for 5 minutes, then 86 mg (0.41 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred for 1 hour. Saturated sodium bicarbonate solution was added, the mixture was stirred for 5 minutes, filtered, and the solvent was removed under reduced pressure. After purification on silica gel (Biotage Isolera, 25 g silica column, cyclohexane/ethyl acetate gradient then ethyl acetate/methanol gradient), 57 mg (0.099 mmol) of N-{2-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide were obtained.

LC-MS (Method A): Rt = 3.41 min; m/z = 578 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=0.08(s, 6H), 0.91(s, 9H), 2.24-2.26(m, 6H), 2.57-2.66(m, 2H), 3.06-3.18(m, 2H), 3.75-3.83(m, 2H), 4.03(s, 3H) , 4.30-4.40 (m, 1H), 7.06 (s, 1H), 7.83-7.90 (m, 2H), 8.11 (dd, 1H), 8.47-8.51 (m, 1H), 8.82 (s, 1H), 10.69-10.71 (m, 1H)

Step B:

To 57 mg (0.099 mmol) of N-{2-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Step A) was added 3 ml of a 4M solution of hydrogen chloride in dioxane, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by SCX column (solvent: 2M ammonia in methanol). After removal of the solvent under reduced pressure and overnight lyophilization, 41 mg (0.088 mmol) of N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide was obtained.

LC-MS (Method B): Rt = 3.22 min; m/z = 464 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 2.01-2.19 (m, 6H), 2.42 (t, 2H), 2.98 (d, 2H), 3.50 (ddd, 2H), 3.96 (s , 3H), 4.34-4.39(m, 2H), 7.14(s, 1H), 8.19(dd, 1H), 8.33-8.45(m, 3H), 8.66(s, 1H), 10.47(s, 1H)

Example 14

rel-N-{2-[(1S,4S,5R)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Step A:

rel-(1S,4S,5R)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

To a mixture of 150 mg (0.418 mmol) of tert-butyl rel-(1S,4S,5R)-5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 4E), 84 mg (0.439 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [131747-42-7] and 167 mg (0.439 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 3 ml of DMF was added 0.146 ml (0.84 mmol) of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 16 h. Water and ethyl acetate were added, the organic phase was removed and extracted twice with ethyl acetate, the combined organic phases were washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After purification (Biotage Isolera (25 g silica gel column), cyclohexane/ethyl acetate), 151 mg (0.284 mmol) of rel-(1S,4S,5R)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester were obtained.

LC-MS (Method A): Rt=4.62min; m/z=532(M+H)+

¹ H-NMR (300MHz, CDCl ₃ ): δ=1.50 (s, 9H), 1-81-1.72 (m, 1H), 2.28-2.43 (m, 3H), 2.93 (d, 1H), 3.14-3.40 (m, 2H), 4.03 (s, 3H), 4.41 (d, 1H), 4.64-4.69(m, 1H), 7.06(s, 1H), 7.83-7.91(m, 2H), 8.11(dd, 1H), 8.49(d, 1H), 8.81(s, 1H), 10.70(s, 1H).

Step B:

To 151 mg (0.284 mmol) of tert-butyl rel-(1S,4S,5R)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate were added 3 ml of a 4 M solution of hydrogen chloride in dioxane and 1 ml of methanol, and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the product was purified by SCX column (eluent: 2 M solution of ammonia in methanol) and the solvent was removed under reduced pressure to give 116 mg (0.269 mmol) of the title compound.

LC-MS (Method A): Rt = 2.73 & 2.82 min; m/z = 432 (M+H) +

¹ H-NMR (300MHz, CDCl ₃ ): δ=1.59 (s, 1H), 2.14-2.31 (m, 2H), 2.39-2.48 (m, 1H), 2.78-2.89 (m, 2H), 3.05 (dd, 1H), 3.68-3.72 (m, 1H), 4. 02(s, 3H), 4.64(dd, 1H), 7.07(s, 1H), 7.83-7.92(m, 2H), 8.11(dd, 1H), 8.49(d, 1H), 8.81(s, 1H), 10.70(s, 1H).

Example 15

rel-N-{2-[(1S,4S,5S)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Step A:

rel-(1S,4S,5S)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

To a mixture of 297 mg (0.829 mmol) of rel-(1S,4S,5S)-tert-butyl 5-(5-amino-6-methoxy-2H-indazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 4F), 166 mg (0.87 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid [131747-42-7] and 331 mg (0.87 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) [148893-10-1] in 3 ml of DMF was added 0.289 ml (1.66 mmol) of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 17 h. Ethyl acetate and water were added, the organic phase was removed, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. After purification (Biotage Isolera (25 g silica gel column), cyclohexane/ethyl acetate), 383 mg (0.721 mmol) of tert-butyl rel-(1S,4S,5S)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate were obtained.

LC-MS (Method A): Rt = 4.47 min; m/z = 532 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ = 1.50 (d, 9H), 1.80 (d, 1H), 1.88-1.95 (m, 1H), 2.32-2.42 (m, 2H), 2.53 (d, 0.5H), 2.98 (d, 0.5H), 3.13-3.21 (m, 2H) , 4.04(s, 3H), 4.38(d, 1H), 5.07-5.07(m, 1H), 7.04(s, 1H), 7.83-7.9 1(m, 2H), 8.12(dd, 1H), 8.50(d, 1H), 8.81(s, 1H), 10.68-10.73(m, 1H)

Step B:

To 383 mg (0.72 mmol) of tert-butyl rel-(1S,4S,5S)-5-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate was added 3 ml of a 4 M solution of hydrogen chloride in dioxane and 1 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified using an SCX column with 2 M ammonia in methanol. The solvent was removed under reduced pressure to give 245 mg (0.568 mmol) of the title compound.

LC-MS (Method A): Rt = 2.74 & 2.84 min; m/z = 432 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=1.79-1.89 (m, 2H), 2.27-2.39 (m, 2H), 2.65 (d, 1H), 2.78 (d, 1H), 2.97 (s, 1H), 3.69 (d, 1H), 4.03 (s, 3H), 4.96-5.02 (m, 1H), 7.07 (s, 1H), 7.85 (dd, 1H), 8.00 (s, 1H), 8.11 (dd, 1H), 8.49 (d, 1H), 8.82 (s, 1H), 10.70 (s, 1H).

Example 16

N-[2-(1,1-Dioxotetrahydro-2H-thiopyran-4-yl)-6-hydroxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Under argon, a mixture of 0.216 g (0.461 mmol) of N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 11) and 0.187 g (0.507 mmol) of tetra-n-butylammonium iodide in 10 ml of dichloromethane was cooled to -70°C. 3.7 ml (3.7 mmol) of a 1M solution of boron trichloride in dichloromethane were gradually added, and the mixture was stirred at -70°C for 10 minutes and then at room temperature for 1 hour. The mixture was cooled to -70°C, and 0.92 ml (0.92 mmol) of a 1M solution of boron trichloride in dichloromethane was added, and the mixture was stirred at room temperature for 7 hours. The mixture was poured into water and extracted with dichloromethane/methanol (5 x 25 ml 9:1, then 4 x 25 ml 4:1). The aqueous phase was basified with sodium bicarbonate solution and extracted with dichloromethane/methanol (10×25 ml 4:1). The combined organic phases were dried, concentrated and purified by flash chromatography (Biotage Isolera (50 g silica gel), methanol in dichloromethane). 0.110 g of the title compound was obtained as a solid.

LC-MS (Method B): Rt = 3.41 min; m/z = 455 (M+H) +

1H-NMR (300 MHz, DMSO-d6): δ [ppm] = 2.35-2.65 (m, 4H, under DMSO), 3.2-3.36 (m, 2H, under HOD), 3.38-3.52 (m, 2H), 4.76-4.89 (m, 1H), 6.95 (s, 1H), 8.21 (dd, 1H), 8.34 (s, 1H), 8.37-8.49 (m, 2H), 8.68 (s, 1H), 10.55 (s, 1H), 10.71 (s, 1H).

Example 17

N-[6-(cyclopropylmethoxy)-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a mixture of 0.107 g (0.235 mmol) of N-[2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-hydroxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 16), 0.080 g (0.307 mmol) of triphenylphosphine and 0.022 g (0.307 mmol) of cyclopropylmethanol in 4 ml of tetrahydrofuran was added 0.060 ml (0.307 mmol) of diisopropyl azodicarboxylate. The mixture was stirred at room temperature under argon for 3 hours. Triphenylphosphine (approximately 40 mg) and diisopropyl azodicarboxylate (approximately 0.03 ml) were dissolved in 0.5 ml of tetrahydrofuran and the solution was added to the reaction mixture. The mixture was diluted with water and extracted three times with dichloromethane, and the combined organic phases were concentrated. The residue was purified by flash chromatography (Biotage Isolera (50 g silica gel), ethyl acetate/cyclohexane) and additionally by preparative HPLC (Method F). This gave 0.015 g of the title compound in the form of a solid.

LC-MS (Method B): Rt = 4.87 min; m/z = 509 (M+H) +

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.40-0.47 (m, 2H), 0.62-0.69 (m, 2H), 1.29-1.40 (m, 1H), 2.37-2.46 (m, 2H, under DMSO), 2.51-2.63 (m, 2H), 3.23-3.33 (m, 2H, under HOD), 3.4-3.5 (m, 2H), 4.03 (d, 2H), 4.82-4.91 (m, 1H), 7.12 (s, 1H), 8.22 (dd, 1H), 8.38-8.49 (m, 3H), 8.75 (s, 1H), 10.71 (s, 1H).

Example 18

rel-N-{6-methoxy-2-[(1S,4S,5R)-2-methyl-2-azabicyclo[2.2.1]hept-5-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To 114 mg (0.265 mmol) of rel-N-{2-[(1S,4S,5R)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 14) in 0.5 ml of tetrahydrofuran and 0.5 ml of methanol was added 0.065 ml of 37% (by weight) aqueous formaldehyde solution, and the mixture was stirred at room temperature for 0.5 h. 80 mg (0.376 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 1 h. 1 M hydrochloric acid was added to the mixture, and the product was purified using an SCX column with 2 M ammonia in methanol. The solvent was removed and dried to yield 104 mg (0.233 mmol) of the title compound.

LC-MS (Method B): Rt = 3.38 min; m/z = 446 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 1.59 (d, 1H), 1.92 (d, 1H), 2.10-2.17 (m, 1H), 2.25-2.28 (m, 4H), 2.30-2.40 (m, 1H), 2.59-2.60 (m, 1H) , 2.67 (dd, 1H), 3.18 (s, 1H), 3.95 (s, 3H), 4.59 (dd, 1H), 7.15 (s, 1H), 8.19 (dd, 1H), 8.35-8.45 (m, 3H), 8.65 (s, 1H), 10.47 (s, 1H).

Example 19

rel-N-{6-methoxy-2-[(1S,4S,5S)-2-methyl-2-azabicyclo[2.2.1]hept-5-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

To 245 mg (0.568 mmol) of rel-N-{2-[(1S,4S,5S)-2-azabicyclo[2.2.1]hept-5-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 15) in 2.0 ml of tetrahydrofuran and 2.0 ml of methanol was added 0.139 ml of 37% (weight percent) aqueous formaldehyde [50-00-0], and the mixture was stirred at room temperature for 0.5 h. 171 mg (0.807 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred for 1 h. 1 M hydrochloric acid was added to the mixture, and the product was purified using an SCX column with 2 M ammonia in methanol. The solvent was removed and dried to yield 237 mg (0.532 mmol) of the title compound.

LC-MS (Method B): Rt = 3.35 min; m/z = 446 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 1.60 (d, 1H), 1.78 (dd, 1H), 1.93-2.08 (m, 2H), 2.22 (s, 3H), 2.34-2.40 (m, 1H), 2.50-2.53 (m, 1H), 2.8 6 (dd, 1H), 3.13 (s, 1H), 3.96 (s, 3H), 4.86-4.93 (m, 1H), 7.15 (s, 1H), 8.19 (dd, 1H), 8.37-8.46 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H).

Example 20 and Example 21

N-[2-(1-Imino-1-oxohexahydro-1λ ⁴ -thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Isomer 1, Example 20)

N-[2-(1-Imino-1-oxohexahydro-1λ ⁴ -thiopyran-4-yl)-6-methoxy-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Isomer 2, Example 21)

Step A:

N-(6-methoxy-2-{1-oxo-1-[(trifluoroacetyl)imino]hexahydro-1λ ⁴ -thiopyran-4-yl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

To 335 mg (0.74 mmol) of rac-N-[6-methoxy-2-(1-oxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 12) in 12 ml of dichloromethane were added 167 mg (1.48 mmol) of 2,2,2-trifluoroacetamide [354-38-1], 358 mg (1.1 mmol) of diacetoxy(phenyl)-λ ³ -iodoalkane [3240-34-4], 119 mg (3.0 mmol) of magnesium oxide [1309-48-4] and 32.7 mg (0.074 mmol) of rhodium(II) acetate dimer [15956-28-2], and the mixture was stirred at room temperature under argon for 18 h. 167 mg (1.48 mmol) of 2,2,2-trifluoroacetamide [354-38-1], 358 mg (1.1 mmol) of diacetoxy(phenyl)-λ ³ -iodoalkane [3240-34-4], 119 mg (3.0 mmol) of magnesium oxide [1309-48-4], and 32.7 mg (0.074 mmol) of rhodium(II) acetate dimer [15956-28-2] were added, and the mixture was stirred for a further 24 h. 50 ml of dichloromethane were added, and the mixture was stirred for 1 h, then filtered (Whatman PTFE filter cup) and washed with 50 ml of dichloromethane. The solvent was removed under reduced pressure, and the residue was purified (Biotage Isolera (50 g silica gel column), cyclohexane/ethyl acetate). This gave 265 mg (0.47 mmol) of N-(6-methoxy-2-{1-oxo-1-[(trifluoroacetyl)imino]hexahydro-1λ ⁴ -thiopyran-4-yl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide.

LC-MS (Method A): Rt = 4.28 min; m/z = 564 (M+H) +

¹ H-NMR (300MHz, CDCl3): δ=2.69-3.04 (m, 6H), 3.38 (t, 1H), 3.83 (s, 1H), 3.98 (d, 3H), 4.20-4.2 5(m, 1H), 7.29(s, 1H), 7.88(d, 1H), 8.11-8.17(m, 2H), 8.53(d, 1H), 8.97(s, 1H), 10.77(d, 1H)

Step B:

To 265 mg (0.471 mmol) of N-(6-methoxy-2-{1-oxo-1-[(trifluoroacetyl)imino]hexahydro-1λ ⁴ -thiopyran-4-yl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide in 20 ml of methanol was added 325 mg (2.4 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. An additional 325 mg (2.4 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 67 hours. The methanol was removed, water was added, and the resulting solid was filtered and purified (Biotage Isolera (25 g silica gel column), methanol/dichloromethane). Two isomers of the title compound were obtained (Isomer 1 (Example 20): 46.2 mg (0.099 mmol) and Isomer 2 (Example 21): 10 mg (0.021 mmol)).

Example 20

LC-MS (Method B): Rt = 3.79 min; m/z = 468 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ=2.26-2.34(m, 2H), 2.50-2.60(m, 2H), 3.10-3.18(m, 2H), 3.33-3.38(m, 2H), 3.65(s, 1 H), 3.96 (s, 3H), 4.77-4.86 (m, 1H), 7.16 (s, 1H), 8.19 (dd, 1H), 8.45-8.33-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H).

Example 21

LC-MS (Method B): Rt = 3.86 min; m/z = 468 (M+H) +

¹ H-NMR (400MHz, DMSO-d6): δ = 2.34 (dd, 2H), 2.50-2.58 (m, 2H), 3.12-3.27 (m, 4H), 3.80 (s, 1H), 3.96 ( s, 3H), 4.75-4.84 (m, 1H), 7.17 (s, 1H), 8.19 (dd, 1H), 8.36-8.45 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H).

Example 22

N-[6-Methoxy-2-(5-oxopyrrolidin-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

A mixture of 119 mg (0.483 mmol) of 4-(5-amino-6-methoxy-2H-indazol-2-yl)pyrrolidin-2-one (Intermediate 4I), 92 mg (0.483 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, and 193 mg (0.507 mmol) of HATU in 5 ml of DMF and 0.168 ml (0.966 mmol) of N,N-diisopropylethylamine was stirred at room temperature for 18 hours. Water and ethyl acetate were added, and the solvent was partially removed under reduced pressure. Water was added, and the mixture was extracted with a methanol/dichloromethane mixture. The mixture was filtered and concentrated. The crude product was then recrystallized from hot ethanol. This yielded 64 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d6): d=2.65 (dd, 1H), 2.83 (dd, 1H), 3.48 (dd, 1H), 3.82 (dd, 1H), 3.96 (s, 3H), 5.3 4-5.42 (m, 1H), 7.18 (s, 1H), 7.83 (s, 1H), 8.19 (dd, 1H), 8.37-8.46 (m, 3H), 8.67 (s, 1H), 10.48 (s, 1H).

Example 23

6-(Difluoromethyl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

To a mixture of 80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A), 73 mg of 6-(difluoromethyl)pyridine-2-carboxylic acid [1256824-41-5], 124 mg of N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (EDC, CAS 1892-57-5), and 50 mg of 1H-benzotriazol-1-ol hydrate (1:1) (HOBt, CAS 123333-53-9) in 2.5 ml of dimethylformamide was added 135 microliters of triethylamine, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate and water were added to the reaction, the organic phase was removed, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were concentrated, and the residue was purified by preparative HPLC. This yielded 56 mg of the title compound.

UPLC-MS (Method C): Rt = 1.11 min; mass measured 402.15.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.02-2.16(m, 4H), 3.46-3.57(m, 2H), 3.95-4.04(m, 5H), 4.60-4.70(m, 1H), 7. 14 (t, 1H), 7.16 (s, 1H), 7.97-8.00 (m, 1H), 8.27-8.37 (m, 3H), 8.69 (s, 1H), 10.55 (s, 1H).

Example 24

N-[6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(morpholin-4-yl)pyridine-2-carboxamide

30 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) were reacted with 33 mg of 6-(morpholin-4-yl)pyridine-2-carboxylic acid in analogy to Example 23. Purification by preparative HPLC gave 9 mg of the title compound.

UPLC-MS (Method C): Rt = 1.08 min; mass measured 437.21.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.03-2.16(m, 4H), 3.48-3.57(m, 2H), 3.57-3.65(m, 4H), 3.76-3.85(m, 4H), 3.97(s, 3H), 3.98-4.05( m, 2H), 4.61-4.70 (m, 1H), 7.13-7.19 (m, 2H), 7.46 (d, 1H), 7.82 (dd, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 10.80 (s, 1H).

Example 25

N-[6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-2-methyl-1,3-thiazole-4-carboxamide

30 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) and 23 mg of 2-methyl-1,3-thiazole-4-carboxylic acid were reacted in analogy to Example 23. Purification by preparative HPLC gave 19 mg of the title compound.

UPLC-MS (Method C): Rt = 1.03 min; mass measured 372.13.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.03-2.16 (m, 4H), 2.77 (s, 3H), 3.47-3.59 (m, 2H), 3.94-4.05 (m, 5H), 4 .61-4.71 (m, 1H), 7.16 (s, 1H), 8.30 (s, 1H), 8.36 (s, 1H), 8.63 (s, 1H), 9.83 (s, 1H).

Example 26

6-amino-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

30 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) and 22 mg of 6-aminopyridine-2-carboxylic acid were reacted in analogy to Example 23. Purification by preparative HPLC gave 23 mg of the title compound.

UPLC-MS (Method C): Rt = 0.87 min; mass measured 367.16.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.01-2.14 (m, 4H), 3.45-3.56 (m, 2H), 3.94-4.04 (m, 5H), 4.59-4.68 (m, 1H), 6.35 (broad singlet, 2H), 6.66-6.71 (m, 1H), 7.11 (s, 1H), 7.27-7.31 (m, 1H), 7.59 (dd, 1H), 8.32 (s, 1H), 8.66 (s, 1H), 10.57 (s, 1H).

Example 27

2-Isopropyl-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyrimidine-4-carboxamide

Analogously to Example 23, 30 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-5-amine (Intermediate 4A) and 26 mg of 2-isopropylpyrimidine-4-carboxylic acid were reacted. For post-treatment, the mixture was added to water, the precipitate was filtered off with suction, washed with water and ether, and dried. This gave 33 mg of the title compound.

UPLC-MS (Method C): Rt = 1.19 min; mass measured 395.00.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.38 (d, 6H), 2.00-2.17 (m, 4H), 3.21-3.31 (m, signal hidden by DMSO signal), 3.45-3.59 (m, 2H), 3.94-4.06 (m, 5H), 4.60-4.71 (m, 1H), 7.18 (s, 1H), 7.96 (d, 1H), 8.38 (s, 1H), 8.68 (s, 1H), 9.08 (d, 1H), 10.81 (s, 1H).

Example 28

6-(2-Hydroxypropan-2-yl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]pyridine-2-carboxamide

80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) and 85 mg of potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (Intermediate V3-1) were reacted in THF in analogy to Example 23. Purification by preparative HPLC gave 62 mg of the title compound.

UPLC-MS (Method C): Rt = 0.99 min; mass measured 410.20.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.56 (s, 6H), 2.02-2.15 (m, 4H), 3.47-3.56 (m, 2H), 3.95-4.03 (m, 5H), 4.58-4.70 (m, 1H), 5.43 (s, 1H), 7.15 (s, 1H), 7.92 (dd, 1H), 7.98-8.08 (m, 2H), 8.35 (s, 1H), 8.66 (s, 1H), 10.91 (s, 1H).

Example 29

N-[6-Methoxy-2-(tetrahydrofuran-3-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

A mixture of 250 mg of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5A), 174 mg of 3-iodotetrahydrofuran (1.5 equivalents), and 244 mg of potassium carbonate (3.0 equivalents) in 4 ml of DMF was stirred at 100° C. for 16 h. An additional 0.7 equivalents of 3-iodotetrahydrofuran and 1.5 equivalents of potassium carbonate were added, and the mixture was stirred at 100° C. for 24 h. Water was added, the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The crude product was purified by HPLC. 49.3 mg of the title compound was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.35-2.48 (m, 2H, hidden by solvent signal), 3.89 (td, 1H), 3.97-4.12 (m, 6H), 5.25-5.32 (m, 1H), 7.18 (s, 1H), 8.21 (dd, 1H), 8.35-8.43 (m, 2H), 8.45-8.48 (m, 1H), 8.69 (s, 1H), 10.51 (s, 1H).

Example 30

N-[6-Chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

100 mg of 6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4G) and 99 mg of 6-(trifluoromethyl)pyridine-2-carboxylic acid were converted in THF analogously to Example 23. Purification by preparative HPLC gave 21 mg of the title compound.

UPLC-MS (Method C): Rt = 1.29 min; mass measured 424.09.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 2.03-2.19 (m, 4H), 3.43-3.59 (m, 2H), 3.96-4.06 (m, 2H), 4.76 (dt, 1H), 7. 95 (s, 1H), 8.23 (dd, 1H), 8.37-8.48 (m, 2H), 8.57 (s, 1H), 8.63 (s, 1H), 10.52 (s, 1H).

Example 31

N-[6-Chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(difluoromethyl)pyridine-2-carboxamide

100 mg of 6-chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-5-amine (Intermediate 4G) and 89 mg of 6-(difluoromethyl)pyridine-2-carboxylic acid were converted in THF in a similar manner to Example 23. For workup, the mixture was mixed with water, the precipitate was filtered off with suction, washed with water and ether, and dried. This gave 138 mg of the title compound.

UPLC-MS (Method C): Rt = 1.22 min; mass measured 406.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.04-2.17(m, 4H), 3.46-3.61(m, 2H), 3.96-4.05(m, 2H), 4.70-4.81(m, 1H), 7.13(t, 1H) , 7.94 (s, 1H), 7.97-8.04 (m, 1H), 8.28-8.37 (m, 2H), 8.52-8.58 (m, 1H), 8.64 (s, 1H), 10.58 (s, 1H).

Example 32

N-[6-Chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(2-hydroxypropan-2-yl)pyridine-2-carboxamide

A mixture of 100 mg of 6-chloro-2-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-amine (Intermediate 4H), 110 mg of potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (Intermediate V3-1), 140 mg of HATU, and 63 microliters of N-ethyl-N-isopropylpropan-2-amine in 2 ml of DMF was stirred at room temperature for 20 hours. The mixture was mixed with water, and the precipitated solid was filtered off, washed three times with water, three times with diethyl ether, and dried. This yielded 144 mg of the title compound.

UPLC-MS (Method C): Rt = 0.99 min; mass measured 462.00.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.55 (s, 6H), 2.40-2.65 (m, partially hidden by the solvent signal), 2.51-2.67 (m, 3H), 3.22-3.28 (m, partially hidden by the solvent signal), 3.41-3.52 (m, 2H), 4.95 (tt, 1H), 5.46 (s, 1H), 7.92-8.10 (m, 4H), 8.57 (d, 1H), 8.74 (s, 1H), 10.88 (s, 1H).

Example 33

2-(tetrahydro-2H-pyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

To a solution of 450mg of 5-amino-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-6-methyl formate (intermediate 4J) in 10ml of DMF, 406mg of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 684mg of HATU and 307 microlitres of N-ethyl-N-isopropylpropan-2-amine were added, and the mixture was stirred at room temperature for 24h. The mixture was mixed with water, the precipitate was filtered off with suction, washed three times with water and three times with ether. After drying, 677mg of the title compound was obtained.

UPLC-MS (Method C): Rt = 1.27 min; mass measured 448.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.07-2.24(m, 4H), 3.49-3.63(m, 2H), 3.97(s, 3H), 3.99-4.11(m, 2H), 4.78-4. 92(m, 1H), 8.18-8.28(m, 1H), 8.37-8.55(m, 3H), 8.64(s, 1H), 9.08(s, 1H), 12.55(s, 1H).

Example 34

N-[6-(2-Hydroxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

First, 300mg of 2-(tetrahydro-2H-pyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-methyl formate (Example 33) was added to 5ml of THF. The mixture was cooled with an ice-water cooling bath and 1.1ml of a 3M methylmagnesium bromide solution (in ether) was carefully added. The mixture was stirred for 1h while being cooled by a cooling bath, and then at room temperature for 4.5h. Saturated aqueous ammonium chloride solution was added, the mixture was extracted three times with ethyl acetate, the organic phases combined were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. Residue was mixed with ether and stirred for 10min. The solid was filtered off with suction, washed three times with ether and dried. 241mg of the title compound was obtained.

UPLC-MS (Method C): Rt = 1.11 min; mass measured 448.0.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.61 (s, 6H), 2.02-2.18 (m, 4H), 3.52 (td, 2H), 3.95-4.05 (m, 2H), 4.71 (tt, 1H) ), 5.93 (s, 1H), 7.58 (s, 1H), 8.15 (d, 1H), 8.33-8.47 (m, 3H), 8.72 (s, 1H), 12.36 (s, 1H).

Example 35

2-[(3S)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

To 759mg 5-amino-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazole-6-methyl-formiate (intermediate 4L) in the solution in 10ml THF, add 666mg 6-(trifluoromethyl) pyridine-2-formic acid, 1.12g O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl uronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 0.61ml N-ethyl-N-sec.-propyl third-2-amine, and mixture is at room temperature stirred to 18h.Add entry, mixture is extracted with ethyl acetate three times, extract is washed with sodium chloride solution, filtered and concentrated by hydrophobic filter.Crude product is passed through silica gel chromatography (Isolera, hexane/ethyl acetate), obtains the 824mg title compound.

UPLC-MS (Method C): Rt = 1.24 min; mass measured 434.00.

¹ H-NMR (400 MHz, DMSO-d ₆ , selected signal from the crude product): δ [ppm]=2.38-2.59 (m, obscured by the solvent signal), 3.85-3.98 (m, 4H), 4.03-4.14 (m, 3H), 5.38-5.46 (m, 1H), 8.17-8.22 (m, 1H), 8.35-8.41 (m, 1H), 8.44-8.48 (m, 2H), 8.58 (s, 1H), 9.05 (s, 1H), 12.51 (s, 1H).

Example 36

N-{6-(2-hydroxypropan-2-yl)-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to Example 34, 819 mg of methyl 2-[(3S)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 35) were reacted with 2.42 ml of a 3M solution of methylmagnesium bromide in diethyl ether in 13 ml of THF. This gave 774 mg of crude product, which was purified by silica gel column chromatography (Biotage Isolera, hexane/ethyl acetate). After further purification by preparative HPLC, 431 mg of the title compound were obtained (chiral HPLC analysis: ee 98.5%).

Chiral analysis:

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.63 (s, 6H), 2.37-2.49 (m, hidden by solvent signal), 2.53-2.58 (m, 1H), 3.90 (td, 1H), 3.99-4.15 (m, 3H), 5.30-5.38 (m, 1H), 5.97 (s, 1H), 7.60 (s, 1H), 8.17 (dd, 1H), 8.34-8.48 (m, 3H), 8.73 (s, 1H), 12.38 (s, 1H).

Example 37

2-[(3R)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

By analogy to the preparation of Example 35, 552 mg of 5-amino-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazole-6-methyl carboxylate (intermediate 4M) was reacted and purified in 10 ml of THF with 460 mg of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 773 mg of O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 0.42 ml of N-ethyl-N-isopropylpropan-2-amine. 794 mg of the title compound was obtained as a solid.

UPLC-MS (Method C): Rt = 1.23 min; mass measured 434.00.

Example 38

N-{6-(2-hydroxypropan-2-yl)-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to the preparation of Example 36, 794 mg of methyl 2-[(3R)-tetrahydrofuran-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 37) was reacted with 2.35 ml of a 3M solution of methylmagnesium bromide in diethyl ether in 11 ml of THF. This gave 777 mg of crude product, which was purified by silica gel column chromatography (Biotage Isolera, hexane/ethyl acetate). Further purification by preparative HPLC gave 394 mg of the title compound (chiral HPLC analysis: ee 99.1%).

Chiral analysis:

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.62 (s, 6H), 2.37-2.49 (m, hidden by solvent signal), 3.90 (td, 1H), 3.99-4.15 (m, 3H), 5.30-5.39 (m, 1H), 5.97 (s, 1H), 7.60 (s, 1H), 8.17 (dd, 1H), 8.34-8.49 (m, 3H), 8.73 (s, 1H), 12.38 (s, 1H).

Example 39

2-[(3S)-tetrahydrothiophen-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

Similar to the preparation of Example 35, 91 mg of 5-amino-2-[(3S)-tetrahydrothiophene-3-yl]-2H-indazole-6-methyl carboxylate (intermediate 4K) was reacted in 3 ml of THF with 72 mg of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 120 mg of O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 65 microliters of N-ethyl-N-isopropylpropan-2-amine at room temperature over 23 h. After aqueous workup, the crude product was mixed with dimethyl sulfoxide, the remaining solid was filtered off, washed three times with ether and dried. 50 mg of the title compound was obtained.

UPLC-MS (Method C): Rt = 1.38 min; mass measured 450.00.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.60-2.73 (m, 1H), 2.96-3.07 (m, 2H), 3.35-3.46 (m, 2H), 3.97 (s, 3H), 5.41 (quintet, 1H), 8.19-8.24 (m, 1H), 8.37-8.44 (m, 1H), 8.45-8.51 (m, 2H), 8.68 (s, 1H), 9.08 (s, 1H), 12.54 (s, 1H).

Example 40

N-{6-(2-hydroxypropan-2-yl)-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

A solution of 50mg 2-[(3S)-tetrahydrothiophene-3-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-methyl-formiate (embodiment 39) in 2ml THF was cooled with an ice-water cooling bath and methylmagnesium bromide solution (3M in ether) was added. The mixture was stirred for 30min while cooling with an ice bath, then at room temperature stirred for 69h. The mixture was mixed with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate, the extract was filtered through a hydrophobic filter and concentrated. 51mg title compound was obtained as a crude product.

UPLC-MS (Method C): Rt = 1.23 min; mass measured 450.00.

Example 41

N-{2-[(3S)-1,1-dioxotetrahydrothiophen-3-yl]-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

A mixture of 51 mg of N-{6-(2-hydroxypropan-2-yl)-2-[(3S)-tetrahydrothiophen-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 40) in 3 ml of dichloromethane was cooled in an ice-water cooling bath. 56 mg of 3-chloroperoxybenzoic acid (CAS 937-14-4, approximately 77%) was added portionwise, and the mixture was stirred at room temperature for 19 h. An additional 50 mg of 3-chloroperoxybenzoic acid was added, and the mixture was stirred at room temperature for 26 h. The mixture was concentrated, and the residue was purified by preparative HPLC. This gave 7 mg of the title compound, which was overlaid three times with pentane and a small amount of dichloromethane, decanting the solvent each time. Drying gave 7 mg of the title compound.

UPLC-MS (Method C): Rt = 1.08 min; mass measured 482.00.

¹ H-NMR (400 MHz, CHLOROFORM-d): δ [ppm] = 1.33-2.34 (broad signal, containing a singlet at 1.84 ppm), 2.88 (q, 2H), 3.23-3.34 (m, 1H), 3.62-3.76 (m, 2H), 3.81-3.89 (m, 1H), 5.39 (quintet, 1H), 7.75 (s, 1H), 7.88 (d, 1H), 8.02 (s, 1H), 8.11-8.17 (m, 1H), 8.53 (d, 1H), 8.90 (s, 1H), 12.35 (s, 1H).

Example 42

2-(tetrahydro-2H-thiopyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

Analogously to the preparation of Example 35, a solution of 992 mg of 5-amino-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazole-6-methyl carboxylate (Intermediate 4N) in 10 ml of THF was reacted with 694 mg of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 1.08 g of O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 0.59 ml of N-ethyl-N-isopropylpropan-2-amine. The crude product was extracted by stirring with ether to give 1.29 g of the title compound.

UPLC-MS (Method C): Rt = 1.39 min; mass measured 464.00.

Example 43

N-[6-(2-Hydroxypropan-2-yl)-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to the preparation of Example 34, 1.29 g of methyl 2-(tetrahydro-2H-thiopyran-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 42) were reacted in 10 ml of THF with 3.1 ml of a 3M solution of methylmagnesium bromide in diethyl ether. The crude product obtained after a similar aqueous workup was extracted by stirring with diethyl ether. This gave 893 mg of the title compound.

UPLC-MS (Method C): Rt = 1.25 min; mass measured 464.00.

Example 44

N-[2-(1,1-Dioxotetrahydro-2H-thiopyran-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

A solution of 893 mg of N-[6-(2-hydroxypropan-2-yl)-2-(tetrahydro-2H-thiopyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 43) in 15 ml of dichloromethane was cooled with an ice-water cooling bath, and 1.16 g of 3-chloroperoxybenzoic acid (CAS 937-14-4, approximately 77%) was added portionwise. The mixture was then stirred in an ice-water cooling bath for 1 hour and at room temperature for 19 hours. Water was added, the organic phase was removed and extracted three times with dichloromethane. The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The crude product was purified by preparative HPLC to give 342 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.63 (s, 6H), 2.38-2.66 (m, partially hidden by the solvent signal), 3.25-3.54 (m, partially hidden by the solvent signal), 4.93 (tt, 1H), 5.99 (s, 1H), 7.62 (s, 1H), 8.17 (dd, 1H), 8.37 (t, 1H), 8.42-8.50 (m, 2H), 8.74 (s, 1H), 12.40 (s, 1H).

Example 45

2-(Piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

Step A

2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

Be similar to the preparation of embodiment 35, make 5.52g 5-amino-2-[1-(tert-butoxycarbonyl) piperidin-4-yl]-2H-indazole-6-methyl-formiate (intermediate 4O) solution in 30ml THF and 2.66g 6-(trifluoromethyl) pyridine-2-formic acid, 3.58g O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyluronium tetrafluoroborate (TBTU, CAS 125700-67-6) and 1.9ml N-ethyl-N-isopropylpropane-2-amine reaction.After similar aftertreatment, crude product is passed through silica gel column chromatography purification (Isolera, hexane/ethyl acetate).Obtain 3.85g yellow foam, it is mixed with ether.Remaining solid suction filtration is gone out, with ether washing three times and dry.Obtain 1.70g title compound.

UPLC-MS (Method C): Rt = 1.46 min; mass measured 547.00.

Step B

First, 1.70 g of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-methyl carboxylate was added to 20 ml of dichloromethane. 2.4 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 20 h. Subsequently, the mixture was concentrated, the residue was diluted with ethyl acetate, and saturated sodium bicarbonate solution was carefully added. During this process, a solid precipitated out. The dichloromethane and ethyl acetate were removed on a rotary evaporator, the solid was filtered off, washed twice with water, three times with ether, and dried. This gave 1.39 g of 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-methyl carboxylate as a solid.

UPLC-MS (Method C): Rt = 0.93 min; mass measured 447.00.

Example 46

N-[6-(2-Hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

First 595mg 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-methyl formate (embodiment 45) is joined in 10ml THF.The mixture is cooled with an ice-water cooling bath and carefully added with 2.2ml 3M methylmagnesium bromide solution (in ether).The mixture is stirred for 2h while being cooled by a cooling bath, then at room temperature stirred for 24h.Add 2.5 equivalents of methylmagnesium bromide solution again, and the mixture is at room temperature stirred for 93h.Add saturated aqueous ammonium chloride solution, the mixture is extracted three times with ethyl acetate, the organic phase merged is washed with sodium chloride solution, filtered and concentrated by a hydrophobic filter.By preparation HPLC purification of residue, 81mg title compound is obtained.

UPLC-MS (Method C): Rt = 1.02 min; mass measured 447.19.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.62 (s, 6H), 1.88-2.11 (m, 4H), 2.39 (br.s., 1H), 2.65 (t, 2H), 3.09 (d, 2H), 4.45-4. 56 (m, 1H), 5.97 (s, 1H), 7.59 (s, 1H), 8.17 (d, 1H), 8.34-8.49 (m, 3H), 8.72 (s, 1H), 12.38 (s, 1H).

Example 47

N-[6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide

To a solution of 80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) in 2 ml of THF were added 77 mg of 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid, 148 mg of HATU, and 68 microliters of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 21.5 hours. The mixture was mixed with water, the precipitated solid was filtered off with suction, washed three times with water, three times with diethyl ether, and dried. This yielded 121 mg of the title compound.

UPLC-MS (Method C): Rt = 1.22 min; mass measured 426.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.03-2.16 (m, 4H), 3.48-3.57 (m, 2H), 3.94-4.04 (m, 5H), 4.63-4. 72(m, 1H), 7.19(s, 1H), 8.41(s, 1H), 8.43(s, 1H), 8.90(d, 1H), 9.78(s, 1H).

Example 48

N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-3-(pyridin-4-yl)-1,2,4-oxadiazole-5-carboxamide

To a solution of 80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) in 2 ml of THF were added 77 mg of 3-(pyridin-4-yl)-1,2,4-oxadiazole-2-carboxylic acid, 148 mg of HATU, and 68 μl of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 21.5 h. The mixture was mixed with water, and the precipitated solid was filtered off with suction, washed three times with water, three times with diethyl ether, and dried. This yielded 99 mg of the title compound.

UPLC-MS (Method C): Rt = 0.98 min; mass measured 420.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.04-2.16 (m, 4H), 2.53 (br.s., 1H), 3.48-3.58 (m, 2H), 3.95-4.05 (m, 5H), 4.64-4.75 ( m, 1H), 7.21 (s, 1H), 8.03-8.07 (m, 2H), 8.39 (s, 1H), 8.44 (s, 1H), 8.86-8.91 (m, 2H), 10.11 (s, 1H).

Example 49

N-[6-Methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-3-methyl-1,2,4-oxadiazole-5-carboxamide

To a solution of 80 mg of 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-amine (Intermediate 4A) in 2 ml of THF were added 50 mg (1.2 equivalents) of 3-methyl-1,2,4-oxadiazole-5-carboxylic acid, 148 mg (1.2 equivalents) of HATU, and 68 microliters of N-ethyl-N-isopropylpropan-2-amine, and the mixture was stirred at room temperature for 21.5 hours. An additional 0.6 equivalents of HATU and 0.6 equivalents of 3-methyl-1,2,4-oxadiazole-5-carboxylic acid were then added, and the mixture was stirred at room temperature for 24 hours. The mixture was mixed with water, and the precipitated solid was filtered off with suction, washed three times with water, three times with diethyl ether, and dried. The solid was purified by preparative HPLC to yield 25 mg of the title compound as a solid.

UPLC-MS (Method C): Rt = 0.96 min; mass measured 357.14.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.03-2.16 (m, 4H), 2.49 (s, obscured by solvent signal), 3.47-3.58 (m, 2H), 3.91-4.05 (m, 5H), 4.63-4.73 (m, 1H), 7.18 (s, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 9.89 (br. s., 1H).

Example 50

N-[6-Chloro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide

To a solution of 80 mg 6-chloro-2-(tetrahydrochysene-2H-pyran-4-yl)-2H-indazole-5-amine (intermediate 4G) in 2 ml THF, 75 mg 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid, 145 mg HATU and 66 microlitres of N-ethyl-N-isopropylpropane-2-amine were added, and the mixture was stirred at room temperature for 20 h. The mixture was mixed with water and extracted three times with ethyl acetate, the combined organic phases were concentrated and purified by preparative HPLC. 84 mg of the title compound was obtained as a solid.

UPLC-MS (Method C): Rt = 1.27 min; mass measured 430.05

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.05-2.18 (m, 5H), 3.46-3.59 (m, 2H), 3.98-4.06 (m, 2H), 4.74-4. 83 (m, 1H), 7.92 (s, 1H), 8.06 (s, 1H), 8.58 (d, 1H), 8.90 (d, 1H), 10.54 (s, 1H).

Example 51

1-(Difluoromethyl)-N-[6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-1H-pyrazole-3-carboxamide

To a solution of 100mg 6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-2H-indazole-5-amine (intermediate 4A) in 2.5ml THF was added 50mg 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid, 185mg HATU and 85 microlitres of N-ethyl-N-isopropylpropane-2-amine, and the mixture was stirred at room temperature for 21.5h. Water was added, the mixture was extracted three times with ethyl acetate, and the extract was concentrated. Residue was purified by preparative HPLC (method including adding ammonia). 109mg of the title compound was obtained as a solid.

UPLC-MS (Method D): Rt = 0.99 min; mass measured 391.15.

¹ H-NMR (500MHz, DMSO-d ₆ ): δ [ppm] = 2.02-2.13 (m, 4H), 3.51 (td, 2H), 3.92-4.02 (m, 5H), 4.64 (tt, 1H), 7.02 (d, 1 H), 7.15 (s, 1H), 7.96 (t, 1H), 8.34-8.36 (m, 1H), 8.44 (d, 1H), 8.50 (s, 1H), 9.39 (s, 1H).

Example 52

N-{2-[1-(3-Hydroxy-3-methylbutyl)piperidin-4-yl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to the preparation of Example 9, 200 mg of N-[6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Example 2) was reacted with 88 mg of 4-bromo-2-methylbutan-2-ol, potassium carbonate, and potassium iodide. Purification by preparative HPLC gave 38 mg of the title compound.

UPLC-MS (Method D): Rt = 0.92 min; mass measured 505.23

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=1.12(s, 6H), 1.53-1.60(m, 2H), 2.00-2.17(m, 6H), 2.43-2.49(m), 3.03(d, 2H), 3.99(s) , 3H), 4.40 (dt, 1H), 7.18 (s, 1H), 8.19-8.25 (m, 1H), 8.36-8.49 (m, 3H), 8.69 (s, 1H), 10.51 (s, 1H).

Example 53

2-(Piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

100 mg of methyl 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 45) were stirred with ammonia solution (7M in methanol) in a sealed container at room temperature for 20.5 h and at 50° C. for 22 h. After dilution with water, a solid precipitated. The reaction mixture was slightly concentrated on a rotary evaporator, the solid was filtered off and washed three times with water. Since the washing phase contained some product, the solid and the washing phase were concentrated together and purified by preparative HPLC (the method included the addition of ammonia). After extraction of the HPLC-purified product from diethyl ether by stirring and drying, 14 mg of the title compound were obtained (slightly contaminated with minor components according to UPLC analysis (89% title compound, 11% minor components: UV detector - TIC smooth trace)).

UPLC-MS (Method D): Rt = 0.91 min; mass measured 432.15.

1H-NMR (400MHz, DMSO-d6): δ[ppm]=1.90-2.11(m, 4H), 2.60-2.72(m), 3.04-3.15(m, 2H), 3.36-3.44(m, 1H), 4.57(tt, 1H), 7.89(s, 1H), 8.17(dd, 1H), 8.23(s, 1H), 8.31-8.41(m, 2H), 8.45(d, 1H), 8.52(s, 1H), 9.01(s, 1H), 13.07(s, 1H).

Example 54

2-(Piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid

First, 100 mg of methyl 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 45) were added to 1 ml of THF and 0.4 ml of methanol. A solution of 94 mg of lithium hydroxide monohydrate in 0.8 ml of water was added, and the mixture was stirred at room temperature for 19 h. The mixture was diluted with water and adjusted to pH=7 with 10% aqueous citric acid solution. The precipitated solid was filtered off, washed three times with water, dried under reduced pressure, extracted by stirring with ether, filtered off, washed with ether and dried again under reduced pressure. This gave 65 mg of the title compound.

¹ H-NMR (analysis of the title compound before extraction by stirring with diethyl ether, 400 MHz, DMSO-d ₆ ): δ [ppm]=2.21 (d, 2H), 2.45-2.59 (signal obscured by the DMSO signal), 3.03-3.13 (m, 2H), 3.43-3.51 (signal obscured by the water signal), 4.74-4.90 (m, 1H), 8.12 (dd, 1H), 8.33 (t, 1H), 8.37-8.43 (m, 2H), 8.62 (s, 1H), 9.01 (s, 1H), 15.09 (br. s., 1H).

UPLC-MS (Method C): Rt = 0.84 min; mass measured 433.00.

Example 55

2-(1-methylpiperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester

To 250 mg (0.56 mmol) of methyl 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 45) in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol was added 0.20 ml of formaldehyde solution (37% in water) and the mixture was stirred at room temperature for 45 minutes. 200 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was acidified to pH 4 by adding 10% aqueous citric acid solution, the low boiling point solvent was evaporated, and the mixture was diluted with water. The precipitated solid was filtered off and dissolved in an ethyl acetate/water mixture. The mixture was mixed with saturated aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. 191 mg of the title compound was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.06-2.21(m, 6H), 2.24(s, 3H), 2.92(d, 2H), 3.96(s, 3H), 4.49-4.58(m, 1H), 8. 22 (dd, 1H), 8.40 (t, 1H), 8.45-8.50 (m, 2H), 8.61-8.64 (m, 1H), 9.07 (s, 1H), 12.56 (s, 1H).

Example 56

2-[1-(3-hydroxy-3-methylbutyl)piperidin-4-yl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

A mixture of 250 mg of methyl 2-(piperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 45), 112 mg of 4-bromo-2-methylbutan-2-ol, 463 mg of potassium carbonate, and 139 mg of potassium iodide in 3 ml of DMSO was stirred at 80° C. for 19.5 h. 2.8 ml of 2M sodium hydroxide solution was added, and the mixture was stirred at 50° C. for 3 h. The mixture was acidified to pH = 4 with 10% aqueous citric acid solution, and the precipitated solid was filtered off, washed three times with water, and dried under reduced pressure. The solid was then extracted by stirring with diethyl ether. After drying, 135 mg of a solid was obtained. A mixture of 132 mg of this solid, 130 mg of HATU, and 119 microliters of N-ethyl-N-isopropylpropan-2-amine in 3 ml of THF was stirred at room temperature for 45 min. 100 μl of ammonia solution (33%) were added, the mixture was stirred at room temperature for 17 h, diluted with water and extracted four times with ethyl acetate, the combined organic phases were concentrated and purified by HPLC (eluent contains formic acid). After freeze-drying, 42 mg of the title compound were obtained.

UPLC-MS (Method C): Rt = 0.73 min; mass measured 518.23.

¹ H-NMR (400 MHz, DMSO-d ₆ , a sample of the title compound may contain some formic acid): δ [ppm]=1.11 (s, 6H), 1.54-1.60 (m, 2H), 2.06-2.20 (m, 6H), 3.05 (br d, 3H), 3.35 (br s, 2H), 4.49-4.58 (m, 1H), 7.88 (s, 1H), 8.14-8.23 (m, 2.6H), 8.32-8.39 (m, 2H), 8.42-8.46 (m, 1H), 8.54 (s, 1H), 9.00 (s, 1H), 13.07 (s, 1H).

Example 57

2-(1-methylpiperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxamide

At 50° C., a mixture of 184 mg of methyl 2-(1-methylpiperidin-4-yl)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylate (Example 55) in 5.0 ml of ammonia solution (7M in methanol) was stirred in a pressure vessel for 47.5 h. The mixture was diluted with water and extracted three times with ethyl acetate, and the combined organic phases were concentrated. The residue was mixed with dimethyl sulfoxide, the remaining solid was filtered off and washed with ether. In the washing phase, a solid precipitated again and was filtered off. The washing phase was concentrated and purified by HPLC (eluent contained formic acid). After freeze-drying, 10 mg of the title compound were obtained.

UPLC-MS (Method C): Rt = 0.71 min; mass measured 446.17.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.08-2.21(m, 6H), 2.24(s, 3H), 2.87-2.97(m, 2H), 4.45-4.55(m, 1H), 7.88(s, 1H), 8.15-8. 19 (m, 1H), 8.23 (s, 1H), 8.31-8.40 (m, 2H), 8.42-8.46 (m, 1H), 8.54 (s, 1H), 9.00 (s, 1H), 13.07 (s, 1H).

Example 58

N-{6-methoxy-2-[1-(2-methoxyethyl)piperidin-4-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

At 0°C, 120 mg of N-{2-[1-(2-hydroxyethyl)piperidin-4-yl]-6-methoxy-2H-indazole-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 13) in 5 ml of THF was mixed with 23 mg of sodium hydride (60% in mineral oil) and the mixture was stirred for 0.5 h. 0.1 ml of a solution of 0.17 ml of iodomethane in 1.0 ml of THF was added, and the mixture was heated to room temperature within 3 h. 2 ml of DMF was added, and the mixture was stirred for 3 h. Water and ethyl acetate were added, the organic phase was removed, the aqueous phase was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. Purification (Biotage Isolera, silica gel, then preparative HPLC) gave 13 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 2.03-2.09 (m, 4H), 2.11-2.21 (m, 2H), 2.51 (dd, 2H), 2.98 (d, 2H), 3.22 (s, 3H), 3.44 (t, 2H), 3.9 5(s, 3H), 4.29-4.39(m, 1H), 7.14(s, 1H), 8.18-8.20(m, 1H), 8.34-8.45(m, 3H), 8.66(s, 1H), 10.47(s, 1H).

Physiological efficacy evaluation

IRAK4 kinase assay

The IRAK4 inhibitory activity of the substances according to the invention was measured in the IRAK4 TR-FRET assay (TR-FRET=Time Resolved Fluorescence Resonance Energy Transfer) described below.

As the enzyme, a recombinant fusion protein derived from N-terminal GST (glutathione-S-transferase) and human IRAK4 was expressed in baculovirus-infected insect cells (Hi5, BTI-TN-5B1-4, a cell line purchased from Invitrogen, catalog number B855-02) and purified via affinity chromatography. The substrate for the kinase reaction was the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG (C-terminus in amide form), which can be purchased, for example, from Biosyntan GmbH (Berlin-Buch).

For the assay, 11 different concentrations ranging from 20 μM to 0.073 nM were prepared from a 2 mM solution of the test substance in DMSO. 50 nl of each solution was pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 μl of a solution of IRAK4 in assay buffer [50 mM HEPES pH 7.5, 5 mM MgCl ₂ , 1.0 mM dithiothreitol, 30 μM activated sodium orthovanadate, 0.1% (w/v) bovine gamma-globulin (BGG), 0.04% (v/v) Nonidet-P40 (Sigma)] were added, and the mixture was incubated for 15 min to allow the substances to pre-bind to the enzyme prior to the kinase reaction. The kinase reaction is then initiated by adding 3 μl of a solution of adenosine triphosphate (ATP, 1.67 mM = final concentration in a 5 μl assay volume: 1 mM) and the peptide substrate (0.83 μM = final concentration in a 5 μl assay volume: 0.5 μM) in assay buffer, and the resulting mixture is incubated at 22°C for a reaction time of 45 minutes. The concentration of IRAK4 is adjusted and set according to the corresponding enzyme activity so that the assay is performed within the linear range. Typically, the concentration is on the order of 0.2 nM. The reaction was stopped by adding 5 μl of a solution of TR-FRET detection reagent [0.1 μM streptavidin-XL665 (Cisbio Bioassays; France, catalog number 610SAXLG)], 1.5 nM anti-phosphoserine 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, terbium cryptate-labeled anti-mouse IgG antibody from Cisbio Bioassays can be used) in aqueous EDTA (100 mM EDTA, 0.4% [w/v] bovine serum albumin [BSA] in 25 mM HEPES, pH 7.5).

The resulting mixture was incubated at 22 ° C for 1 h to form a complex of biotinylated phosphorylated substrate and detection reagent. The amount of phosphorylated substrate was then evaluated by measuring the resonance energy transfer from an anti-mouse IgG antibody labeled with a europium chelate to streptavidin-XL665. To this end, a TR-FRET measuring instrument, such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer), was used to measure the fluorescence emission at 620 nm and 665 nm after 350 nm excitation. The emission ratio of 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate. The data were normalized (enzyme reaction without test substance = 0% inhibition; with all other assay components but without synthase = 100% inhibition). Typically, the test substance was tested at 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 nM, and 0.073 nM) in the same microtiter plate. The dilution series was prepared by serial dilution prior to the assay (2 mM to 7.3 nM in 100% DMSO). _IC50 values were calculated using a 4-parameter fit.

Table 1: _IC50 values of example compounds in IRAK4 kinase assay

TNF-α secretion in THP-1 cells

This test allows the ability of substances to inhibit the secretion of TNF-α (tumor necrosis factor α) in THP-1 cells (a human monocytic acute leukemia cell line). TNF-α is a cytokine involved in inflammatory processes. In this test, TNF-α secretion is triggered by incubation with bacterial lipopolysaccharide (LPS).

THP-1 cells were maintained in a continuous suspension cell culture medium [RPMI 1460 medium containing L-Glutamax (Gibco, catalog number 61870-044), supplemented with 10% fetal calf serum (FCS) (Invitrogen, catalog number 10082-147), 1% penicillin/streptomycin (Gibco BRL, catalog number 15140-114)] and the cell concentration should not exceed 1×10 ⁶ cells/ml. The assay was performed in a cell culture medium (RPMI 1460 medium containing L-Glutamax, supplemented with 10% FCS).

In each case, 2-2.5 μl of cell suspension (corresponding to 4000 cells) were dispensed per well into a 384-well assay plate (Greiner, catalog number 784076), wherein in each case 40-50 nl of substance were dissolved in 100% DMSO. This was done using 10 different concentrations ranging from 20 μM to 0.073 nM for each substance. The cells were incubated at room temperature for 15 min. 2-2.5 μl of 0.1 μg/ml LPS (Sigma, Escherichia coli 055:B5, catalog number L5418) dissolved in cell culture medium (final concentration 0.05 μg/ml) were then dispensed into each well. As a neutral control, cells were treated with 0.05 μg/ml LPS and 1% DMSO; as an inhibitor control, cells were treated with 1% DMSO alone.

The plate was centrifuged at 80 g for 30 seconds and incubated for 17 hours at 37°C, 5% _CO₂ , and 95% atmospheric humidity. The amount of TNF-α was determined using the TNF-α HTRF detection kit (Cisbio, catalog number 62TNFPEB/C). To this end, 2 μl of the detection solution, consisting of anti-TNF-α-XL665 conjugate and anti-TNF-α-cryptate conjugate, dissolved in reconstitution buffer according to the manufacturer's instructions, was added for HTRF (homogeneous time-resolved fluorescence) measurement. After addition, the mixture was incubated at room temperature for 3 hours or at 4°C overnight. The signal was then read at 620/665 nm using an HTRF-enabled measuring instrument such as the BMG PheraStar.

The activity of the substances is expressed as the ratio between the neutral control and the inhibitor control in percent. The _IC50 values are calculated using a 4-parameter fit.

Table 2: _IC50 values of the example compounds on TNF-α secretion in THP-1 cells

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

The effects of the compounds of the general formula (I) of the present invention on induced cytokine production in human PBMCs were investigated. In this context, cytokine production was induced by LPS, a TLR4 ligand, which leads to activation of the IRAK4-mediated signaling pathway.

Human PBMCs were obtained from human anticoagulated whole blood. To this end, 15 ml of Ficoll-Paque (Biochrom, catalog number L6115) was first added to a Leucosep tube and 20 ml of human blood was added. After the blood was centrifuged at 800 g for 15 min at room temperature, the plasma containing platelets was removed and discarded. PBMCs were transferred to a centrifuge tube and supplemented with PBS (phosphate-buffered saline) (Gibco, catalog number 14190). The cell suspension was centrifuged at 250 g for 10 min at room temperature and the supernatant was discarded. PBMCs were resuspended in complete culture medium (RPMI 1640, without L-glutamine (PAA, catalog number E15-039), 10% FCS; 50 U/ml penicillin, 50 μg/ml streptomycin (PAA, catalog number P11-010) and 1% L-glutamine (Sigma, catalog number G7513)).

The assay was also performed in complete medium. PBMCs were seeded into 96-well plates at a cell density of 2.5×10 ⁵ cells/well. The compounds of the present invention were serially diluted in a constant volume of 100% DMSO and used in the assay at 8 different concentrations ranging from 10 μM to 3 nM, resulting in a final DMSO concentration of 0.4% DMSO. Prior to the actual stimulation, the cells were pre-incubated with them for 30 min. To induce cytokine secretion, the cells were stimulated with 0.1 μg/ml LPS (Sigma, Escherichia coli 0128:B12, catalog number L2887) for 24 hours. Cell viability was determined using the CellTiter-Glo luminescence assay (Promega, catalog number G7571 (G755/G756A)) according to the manufacturer's instructions. The amount of TNF-α secreted in the cell culture supernatant was determined using the Human ProInflammatory 9-Plex Tissue Culture Kit (MSD, catalog number K15007B) according to the manufacturer's instructions. For example, Example Compounds 44 and 46 and Example Compound 52 had activities of ≤ 1 μM.

Cell proliferation assay

The antiproliferative activity of the compounds of the general formula (I) of the present invention in human ABC-DLBCL cells was investigated in vitro (see Table 3). To this end, 4,000 TMD-8 cells (all from ATCC) in growth medium (RPMI (Biochrom: FG 1215), 20% FCS (Biochrom: S 0615)) were transferred to a 384-well plate (Perkin Elmer, white) at 30 μl/well and incubated overnight at 37°C. After 24 hours, the cells on one plate (the 0h plate) were treated with 30 μl/well of CTG solution (Promega CellTiter Glo (Cat. Nos. G755B and G756B)) and incubated at room temperature for 10 minutes. Luminescence was measured using a VICTOR V (Perkin Elmer) to determine cell viability at the start of treatment. The cells on the test plate were treated with the compounds of the general formula (I) of the present invention and incubated at 37°C for 72 hours. Compound is added to cell with 7 stages, 3 times dilution series using HP D300 digital dispenser.As a control, vehicle (DMSO) is used to treat cell.After 72h, cell is treated with 30 μ l/ well CTG solution (Promega Cell Titer Glo (catalog number G755B and G756B)) and incubated at room temperature for 10min, luminescence is measured by VICTOR V (Perkin Elmer), to determine the cell viability when treatment ends.For each test substance, the effect on cell growth and the _IC50 obtained therefrom are determined using the value from 0h flat board (=maximum inhibition) and DMSO control (=minimum inhibition) _.IC50 value is calculated using 4-parameter fitting.

Table 3: _IC50 values of the example compounds for proliferation inhibition in TMD-8 cells

Example 2 8.61E-06 1 2.82E-05 4 4.08E-06 5 1.55E-05 twenty three 8.52E-06 13 5.85E-06 twenty four 2.81E-05 28 3.51E-06 10 2.33E-05 12 1.15E-05 twenty one 1.48E-05 20 1.61E-05 18 3.45E-06 44 1.88E-05 46 1.41E-05

NF-kB reporter gene assay

The effects of compounds of the present invention represented by general formula (I) on the NF-κB signaling pathway were investigated in vitro in human DLBCL cells (see Table 4). 10,000 TMD-8-NF-κB-luc reporter cells in growth medium (RPMI (Biochrom: FG 1215), 20% FCS (Biochrom: S 0615)) were transferred to a 384-well plate (Perkin Elmer, white) at 30 μl/well and incubated overnight at 37°C. After 24 hours, the cells were treated with the test substances and incubated at 37°C for 6 hours. The test substances were added to the cells in a seven-step, three-fold dilution series using an HP D300 digital dispenser. As a control, the cells were treated with vehicle (DMSO). After 6 hours, the cells were treated with 30 μl/well of One-Glo solution (Promega, E6110) and incubated at room temperature for 10 minutes. Luminescence was measured using a VICTOR V (Perkin Elmer) to determine NF-κB reporter activity at the end of treatment. For each test substance, the effect on NF-κB reporter activity in percentage and the resulting IC50 were determined using the values of the NF-κB pathway inhibitor (I-κB kinase inhibitor) (-)-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one (CAS No. 600734-02-9; see WO 2003076447) (maximum inhibition) and the DMSO control (minimum inhibition ₎ . The _IC50 values were calculated using a 4-parameter fit.

Table 4: _IC50 values of Example compounds for inhibition of NF-kB activity in TMD-8-NF-kB-luc cells

Example 2 9.45E-06 1 1.56E-05 4 7.41E-06 5 5.10E-06 twenty three 3.84E-06 13 5.10E-06 twenty four 2.26E-05 28 2.68E-06 10 2.89E-05 12 6.81E-06 twenty one 5.19E-06 20 2.18E-05 18 5.52E-06 44 1.46E-05 46 1.34E-05

In vivo model of IL-1β-mediated inflammation

In order to evaluate the potential efficacy of the compounds of general formula (I) of the present invention in IL-1β-mediated diseases, female Balb/c mice (approximately 8 weeks old, Charles River Laboratories, Germany) were administered IL-1β intraperitoneally, and the effects of the compounds of the present invention on IL-1β-mediated cytokine secretion were investigated. There were 5 animals in each group. The control group was treated with an excipient for dissolving the substance and IL-1β. The group treated with the substance and the positive control group were each administered 90 μg IL-1β/kg body weight (R&D, catalog number 401-ML/CF) intraperitoneally. Before administering IL-1β, the substance or its vehicle was administered to the positive control group. Two hours after administering IL-1β, TNF-α in plasma was determined after final blood collection using the Mouse Pro Inflammatory 7-Plex Tissue Culture Kit (MSD, catalog number K15012B) according to the manufacturer's instructions.

In vivo adjuvant-induced arthritis model

In order to determine the anti-inflammatory activity of the compounds of the general formula (I) according to the present invention, their in vivo efficacy was investigated in an arthritis model. For this purpose, on day 0, male Lewis rats (approximately 100-125 g, Charles River Laboratories, Germany) were administered subcutaneously at the base of the tail with 100 μl of a complete Freund's adjuvant (CFA) solution (Mycobacterium tuberculosis H37Ra [Difo Lab, catalog number 231141] dissolved in incomplete Freund's adjuvant [Difco Lab, catalog number 263910]). There were n = 8 rats per group. Both healthy and disease control groups were included in the study. Each control group was orally treated with only the vehicle of the test substance. In a preventive manner, i.e., starting from day 0, treatment was carried out with different doses of the test substance by oral administration. On day 0, the initial condition of the animals was also determined according to the disease activity score (rating of the severity of arthritis based on a points system). In this scoring system, both pairs of hind paws are scored from 0 to 4 points (0 = none; 1 = mild; 2 = moderate; 3 = marked; 4 = severe) based on the degree of joint inflammation, including the presence of erythema, including joint swelling, and summed. To determine the anti-inflammatory efficacy of the compounds, the disease status of the animals was scored using the disease activity score starting on day 8 (when the animals first showed signs of arthritis) and then three times a week until the end (day 20). Statistical analysis was performed using one-way analysis of variance (ANOVA) and comparisons with the control group were performed by multiple comparison analysis (Dunnett's test).

Subcutaneous administration of CFA in rats resulted in acute arthritis with marked joint inflammation.

Claims (21)

1. Compounds of general formula (I) in ^R1 is a _C1 - _C6 -alkyl group, wherein the _C1 - _C6 -alkyl group may optionally be monosubstituted by the following groups: hydroxyl group Or it may be a _C1 - _C6 -alkoxy group; ^R2 is a pyridin-2-yl group substituted at the 6 position with a _C1 - _C6 -alkyl group, wherein the _C1 - _C6 -alkyl group is optionally substituted with up to 5 fluorine atoms; ^R3 is selected from the following groups: Where * represents the connection site between the group and the rest of the molecule; R ^6f is hydrogen. R ^6g is hydrogen, or ^R6f and ^R6g together form an oxo group, and R ^6h is hydrogen, and R ⁶ⁱ is hydrogen, or ^R6h and ^R6i together form an oxo group. R ^6j is hydrogen. R ^6k is hydrogen. R ^6l is hydrogen. R ^6m is hydrogen. n is 0 or 1 in equation R ^3a . z is a group selected from NR ⁷ , O, S, S(=O), S(=O) ₂ , S(=O)(=NH); ^R7 is hydrogen. 2. The compound according to claim 1, wherein ^R1 is 2-hydroxypropyl-2-yl. 3. The compound according to claim 1, wherein... ^R2 is a pyridin-2-yl group substituted at the 6 position with the following group: trifluoromethyl. 4. The compound according to claim 1, wherein ^R2 is 6-(trifluoromethyl)pyridin-2-yl. 5. The compound according to claim 1, wherein... ^R1 is 2-hydroxypropyl-2-yl. ^R2 is 6-(trifluoromethyl)pyridin-2-yl. R ³ is tetrahydro-2H-pyran-4-yl, 1,1-dioxotetrahydro-2H-thiaran-4-yl, tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, (3R)-tetrahydrofuran-3-yl, or (3S)-1,1-dioxotetrahydrothiophene-3-yl, or ^R3 is piperidin-4-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 1-methylpiperidin-4-yl, 1-hydroxyacetylpiperidin-4-yl, 1'-methyl-1,4'-bipiperidin-4-yl, 1-(acetylaminosulfonyl)piperidin-4-yl, [2-(dimethylamino)ethyl]piperidin-4-yl, 1-(oxecyclobutane-3-yl)piperidin-4-yl, 1-(2-hydroxyethyl)piperidin-4-yl, or 1-(3-hydroxy-3-methylbutyl)piperidin-4-yl. 6. The compound according to claim 1, as follows: (34)N-[6-(2-hydroxypropyl-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (36)N-{6-(2-hydroxypropyl-2-yl)-2-[(3S)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (38)N-{6-(2-hydroxypropyl-2-yl)-2-[(3R)-tetrahydrofuran-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (40)N-{6-(2-hydroxypropyl-2-yl)-2-[(3S)-tetrahydrothiophene-3-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (41)N-{2-[(3S)-1,1-dioxotetrahydrothiophene-3-yl]-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (43)N-[6-(2-hydroxypropyl-2-yl)-2-(tetrahydro-2H-thiaran-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (44)N-[2-(1,1-dioxotetrahydro-2H-thiaran-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (46)N-[6-(2-hydroxypropyl-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide. 7. A compound of general formula (I) as defined in any one of claims 1 to 6, used for the treatment and/or prevention of disease. 8. A compound of general formula (I) as defined in any one of claims 1 to 6, used in methods of treating and/or preventing diseases of: neoplasms, skin diseases, gynecological diseases, cardiovascular diseases, lung diseases, eye diseases, neurological disorders, metabolic diseases, liver diseases, inflammatory diseases, autoimmune diseases, and pain. 9. A compound of general formula (I) as defined in any one of claims 1 to 6, used in methods of treating and/or preventing the following diseases: lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome, spondyloarthritis and rheumatoid arthritis, endometriosis and pain and other symptoms associated with endometriosis. 10. A compound of general formula (I) as defined in any one of claims 1 to 6, used in a method of treating and/or preventing dysmenorrhea, dyspareunia, dysuria, and dysdefecation. 11. A compound of general formula (I) as defined in any one of claims 1 to 6, wherein the pain is used in a method of treating and/or preventing pain, the pain comprising acute, chronic, inflammatory, and neuropathic pain. 12. A compound of general formula (I) as defined in any one of claims 1 to 6, wherein the pain is used in a method of treating and/or preventing pain, the pain including hyperalgesia, atypical pain, arthritis pain, premenstrual pain, pain associated with endometriosis, postoperative pain, interstitial cystitis pain, CRPS, trigeminal neuralgia, prostatitis pain, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, chemotherapy-related pain, HIV treatment-induced neuropathy, burn pain, and chronic pain. 13. A compound of general formula (I) as defined in any one of claims 1 to 6, wherein the pain is used in a method of treating and/or preventing pain, the pain including osteoarthritis, rheumatoid arthritis and spondylitis pain. 14. Use of a compound of general formula (I) as defined in any one of claims 1 to 6 for the preparation of a medicament. 15. The use according to claim 14, wherein the drug is used to treat and/or prevent tumors, skin diseases, gynecological diseases, cardiovascular diseases, lung diseases, eye diseases, neurological disorders, metabolic diseases, liver diseases, inflammatory diseases, autoimmune diseases, and pain. 16. The use according to claim 14 or 15, for the treatment and/or prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD, gout, NASH, liver fibrosis, insulin resistance, metabolic syndrome, spondyloarthritis and rheumatoid arthritis, endometriosis, and pain and other symptoms associated with endometriosis. 17. The use according to claim 14 or 15, for the treatment and/or prevention of dysmenorrhea, dyspareunia, dysuria, and dysdefecation. 18. The use according to claim 14 or 15, for treating and/or preventing pain, including acute, chronic, inflammatory, and neuropathic pain. 19. The use according to claim 14 or 15, for treating and/or preventing pain, said pain including hyperalgesia, atypical pain, arthritis pain, premenstrual pain, pain associated with endometriosis, postoperative pain, interstitial cystitis pain, CRPS, trigeminal neuralgia, prostatitis pain, pain caused by spinal cord injury, pain caused by inflammation, lower back pain, cancer pain, chemotherapy-related pain, HIV treatment-induced neuropathy, burn pain, and chronic pain. 20. The use according to claim 14 or 15, for treating and/or preventing pain, including osteoarthritis, rheumatoid arthritis, and spondyloarthritis pain. 21. A pharmaceutical product comprising a compound of formula (I) as defined in any one of claims 1 to 6 and an inert, non-toxic, pharmaceutically suitable excipient.