HK1226409B - Novel indazolecarboxamides, processes for their preparation, pharmaceutical preparations comprising them and their use for producing medicaments - Google Patents

Description

New indazole carboxamide, its preparation method, pharmaceutical preparation containing the same, and its use in preparing drugs

The present application relates to novel indazole carboxamides, to methods for their preparation, to their use for treating and/or preventing diseases, and to their use for the preparation of drugs for treating and/or preventing diseases, in particular the following diseases: proliferative disorders, autoimmune and inflammatory disorders such as, for example, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), multiple sclerosis, endometriosis, and inflammation-induced or chronic pain and lymphoma.

IRAK4 plays a key role in the activation of the immune system, especially innate immunity. Innate immunity is based on the fact that microorganisms such as bacteria and viruses have certain inherent characteristics that can be recognized by the immune system, thereby causing the activation of the immune system. What is recognized are certain pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by pattern recognition receptors (PRRs) including toll-like receptors (TLRs) (Janeway and Medzhitov, Annu. Rev. Immunol., 2002). In humans, 10 different TLRs have been described. TLR1 and TLR6 are co-receptors of TLR2. TLR2 specifically recognizes lipoproteins and lipopeptides. TLR3 recognizes double-stranded RNA. TLR4 specifically recognizes LPS (lipopolysaccharides) of Gram-negative bacteria and lipoteichoic acid of Gram-positive bacteria. TLR5 recognizes flagellin. CpG motifs in bacterial DNA are recognized by TLR9 (Miggin, O'Neill, J.Leukoc.Biol., 2006). Other molecules can further change the recognition ability of TLRs (Akashi-Takamura and Miyake, Current Opinion in Immunology, 2008). In addition to recognizing PAMPs, TLRs can also recognize DAMPs (damage-associated molecular patterns). These are endogenous cell-derived molecules formed due to trauma, ischemia or other tissue damage processes in the absence of any obvious infection. DAMPs can be components of both the cytoplasm and the nucleus. They are secreted, such as HMGB1 (high-mobility group box 1 protein), which is recognized by TLR2 and TLR4. Other DAMPs are re-released or accumulated in, for example, the outer plasma membrane, such as HSP90 (heat shock protein 90), where they are recognized by TLR2 and TLR4. Others, for their part, are produced as final degradation products of the cell death process (Krysko, Garg, et al., Nat Rev Cancer, 2012).

In addition to TLRs, other components such as cytokines also play an important role in innate immunity. Here, the interleukin (IL) -1 family can be particularly mentioned, which includes interleukins IL-1, IL-18 and IL-33. They are produced and released by various immune cells in the presence of infection or cell stress or tissue stress. Then, by binding to the corresponding receptors, an immune response is triggered (Dinarello, Annu. Rev. Immunol., 2009).

TLRs (except TLR3) and receptors of the IL-1 family (IL-1R (receptor), IL-18R, and IL-33R) share a common signaling cascade that is activated by binding of the corresponding ligand to its receptor. Ligand-receptor binding results in the recruitment of the adaptor molecule MyD88 [myeloid differentiation factor primary response gene (88)] to the receptor via TIR/TIR domain interactions, which are components of both the receptor and MyD88. In addition to the TIR domain, MyD88 has an N-terminal "death domain" (DD) that interacts with the DD domain of interleukin-1 receptor-associated kinase-4 (IRAK4). IRAK4 belongs to the serine/threonine kinase family, which also includes the structurally similar kinases IRAK1, IRAK2, and IRAK-M (Cao et al., Science, 1996; Muzio et al., Science, 1997; Wesche, Gao, et al., Journal of Biological Chemistry, 1999; Li, Strelow, et al., PNAS, 2002). With the exception of IRAK-M, which is expressed only in monocytes and macrophages, IRAK4, IRAK1, and IRAK2 are ubiquitously expressed (Flannery and Bowie, Biochemical Pharmacology, 2010). During activation, several MyD88 and IRAK4 molecules form a multicomplex called the "myddosome" (Precious et al., J. Biol. Chem., 2009). The myddosome now interacts with IRAK1 or IRAK2 via DD-DD interactions, forming a larger complex in the process (Lin, Lo, et al., Nature, 2010). The formation of this complex then triggers autophosphorylation of IRAK4, which subsequently produces phosphorylation of IRAK1 or IRAK2. Due to the activation of IRAK1 or IRAK2, these kinases are autophosphorylated (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004). Activated IRAK1 or IRAK2 interacts with TRAF6 (tumor necrosis factor-receptor-associated factor 6)—which, together with the ubiquitin enzyme complex (E2), acts as a ubiquitin-protein ligase—which produces K62-associated ubiquitination of TRAF6. In turn, this process allows the formation of other complexes with other proteins. This complex induces the activation of TAK1 (Xia, Sun, et al., Nature, 2009). Activated TAK1 mediates the activation of the NF-κB (nuclear factor) signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway (Wang, Deng, et al., Nature, 2001). In the first signaling pathway, TAK1 activates the IKK complex, thereby inhibiting the phosphorylation and proteasomal degradation of the IκB protein. At this point, NF-κB, which has been blocked by IκB, translocates from the cytoplasm to the nucleus, where it binds to specific DNA motifs (κB motifs), resulting in the transcription of multiple genes (Gasparini and Feldmann, Curr Pharm Des, 2012).

In the MAPK signaling pathway, TAK1 phosphorylates multiple members of the MAPK family, such as MKK3, MKK4, MKK6, and MKK7 (Wang, Deng, et al., Nature, 2001). Activation of these kinases leads to activation of p38 and JNK (c-Jun N-terminal kinase) (Ono and Han, Cellular Signaling, 2000; Davis, Cell, 2000). Activation of both the NF-kB signaling pathway and the MAPK signaling pathway produces a variety of processes related to different immune processes. Consequently, this is the increased expression of a variety of inflammatory signaling molecules and enzymes (such as cytokines, chemokines, and COX-2), and the increased mRNA stability of certain genes (Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004). Furthermore, these processes may be accompanied by proliferation and differentiation of certain cell types (Wan, Chi, et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).

The central importance of IRAK4 in immune processes mediated by TLRs (except TLR3) and the IL-1 receptor family is demonstrated by IRAK4 deficiency. Cells isolated from patients with confirmed IRAK4 deficiency show no activity upon stimulation with various TLRs (except TLR3) and the IL-1β family (Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007). Furthermore, IRAK4-deficient mice show no response to stimulation with IL-1β or other TLRs except TLR3 (Suzuki, Suzuki, et al., Nature, 2002). The kinase activity of IRAK4, in particular, plays a key role here (Kim, Staschke, et al., JEM, 2007). In contrast, the absence of IRAK1 or IRAK2 results only in a loss of signaling pathway activity following stimulation (Thomas, Allen, et al., The Journal of Immunology, 1999; Swantek, Tsen, et al., The Journal of Immunology, 2000; Kawagoe, Sato, et al., Nat Immunol, 2008). Mice lacking IRAK2 and IRAK1, for their part, exhibit a phenotype similar to that of animals lacking IRAK4 (Kawagoe, Sato, et al., Nat Immunol, 2008). The central role of IRAK4 in the pathology of various inflammatory conditions associated with this signaling pathway has been demonstrated by direct comparison of wild-type (WT) mice with animals genetically modified with an inactive form of the IRAK4 kinase (IRAK4 KDKI). IRAK4 KDKI animals have improved clinical manifestations in animal models of multiple sclerosis, atherosclerosis, myocardial infarction, and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Cameron, Tse, et al., The Journal of Neuroscience, 2012). In addition, IRAK4 deficiency in animal models has been found to protect against viral-induced myocarditis by improving antiviral responses and simultaneously reducing systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013).

Due to the central role of IRAK4 in the signaling cascade mediated by TLRs (except TLR3) and MyD88 of the IL-1 receptor family, inhibition of IRAK4 can be used to prevent and/or treat disorders mediated by these receptors. TLR-dependent processes are associated with a large number of different disorders. Thus, TLRs have been found to be involved in the pathogenesis of multiple sclerosis, rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, leukemia and sepsis (Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Roger, Froidevaux, et al, PNAS, 2009; Gambuzza, Licata, et al., Journal of Neuroimmunology, 2011; Fresno, Archives Of Physiology And Biochemistry, 2011; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012; Li, Wang, et al., Pharmacology & Therapeutics, 2013). Skin disorders such as psoriasis, atopic dermatitis, acne inversa, and acne vulgaris are associated with IRAK4-mediated TLR signaling pathways.

The mentioned disorders are characterized by increased expression of specific TLRs, and their pathological immune responses are mediated by certain TLR-associated inflammatory processes (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; Dispenza, Wolpert, et al., J Invest Dermatol, 2012; Selway, Kurczab, et al., BMC Dermatology, 2013; Wollina, Koch, et al. Indian Dermatol Online, 2013).

Pulmonary disorders such as pulmonary fibrosis, COPD, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis, and pulmonary hypertension show associations with multiple TLR-mediated signaling pathways. The pathogenesis of pulmonary disorders can be infection-mediated or non-infection-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., International Journal of Inflammation, 2011). For example, HMGB1 (high-mobility group box 1), an endogenous ligand for TLR2 and TLR4, is elevated in patients with pulmonary fibrosis. Blockade of these TLR signaling pathways reduces inflammation in animal models (Yang, Cui, et al., The Journal of Immunology, 2009; Entezari, Weiss, et al., Mol Med, 2012). Recently, the involvement of TLR2-mediated processes in the pathogenesis of sarcoidosis has been demonstrated in in vitro and in vivo studies (Chen, Song, et al., American Journal of Respiratory and Critical Care Medicine, 2010; Gabrilovich, Walrath, et al., Clinical & Experimental Immunology, 2013).

TLRs are also involved in the pathogenesis of other inflammatory conditions, such as leukemia, gout, and transplant rejection, making IRAK4 inhibition a promising therapeutic approach (Liu-Bryan, Scott, et al., Arthritis & Rheumatism, 2005; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013). Lesion and peritoneal macrophages from endometriosis patients have enhanced immune responses following LPS (lipopolysaccharide) stimulation compared to healthy volunteers (Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Khan, Kitajima, et al., Journal of Obstetrics and Gynaecology Research, 2013).

Patients with lupus erythematosus and adult-onset Still's disease have elevated expression of TLR7, MyD88, and IRAK4 (Chen, Lin, et al., Arthritis Res Ther, 2013). In lupus disease models, inhibition of TLR7, 8, and 9 and the use of animals with TLR7 and/or TLR9 deletions have resulted in improved pathogenesis (Christensen, Shupe, et al., Immunity, 2006; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Zhu, Jiang, et al., Autoimmunity, 2013). Patients with chronic inflammatory bowel diseases such as ulcerative colitis or Crohn's disease have polymorphisms in multiple TLR genes. In various animal models, it has been shown that certain TLRs are also involved in the pathogenesis of these intestinal disorders (Rakoff-Nahoum, Hao, et al., Immunity, 2006; Heimesaat, Fischer, et al., PLoS ONE, 2007; Cario, Inflammatory Bowel Diseases, 2010; Walsh, Carthy, et al., Cytokine & Growth Factor Reviews, 2013).

In addition to the disorders already mentioned, IRAK4-mediated TLR processes have also been described in the pathogenesis of ocular disorders such as 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).

The role of TLRs in atherosclerosis is supported not only by the analysis of human samples but also by various animal models (Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013).

Due to the central role of IRAK4 in TLR-mediated processes, inhibition of IRAK4 allows for the treatment and/or prevention of cardiovascular and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension (Oyama, Blais, et al., Circulation, 2004; Timmers, Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med Sci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin Sci (Lond), 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013), as well as Alzheimer's disease, stroke and Parkinson's disease (Carty and Bowie, Biochemical Pharmacology, 2011; Lim, Kou, et al., The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Noelker, Morel, et al., Sci. Rep., 2013; Wang, Wang, et al., Stroke, 2013).

Neurons, as well as microglia and astrocytes, express most of the known TLRs.

In animal models, TLR7 deficiency prevents various triggers of itch (Nicotra, Loram, et al., Experimental Neurology, 2012; Liu and Ji, Pflugers Arch., 2013). In addition to the role of TLRs in itch, their involvement in pain has been demonstrated in various animal models (Kim, Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; Guerrero, Cunha, et al., European Journal of Pharmacology, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; David, Ratnayake, et al., Neurobiology of Disease, 2013). Studies in pain patients support these findings (Kwok, Hutchinson, et al., PLoS ONE, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013).

Since TLR signaling is mediated through IRAK4, therapeutic efficacy by inhibition of IRAK4 should be expected in the mentioned indications.

This also applies to some tumor conditions. Certain lymphomas harbor activating MyD88 mutations that are treatable with IRAK4 inhibitors (Ngo, Young, et al., Nature, 2011; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013). Chronic lymphocytic leukemia, melanoma, and hepatocellular carcinoma are also associated with MyD88 mutations or changes in MyD88 activity (Puente, Pinyol, et al., Nature, 2011; Srivastava, Geng, et al., Cancer Research, 2012; Liang, Chen, et al., Clinical Cancer Research, 2013). In addition, MyD88 plays an important role in ras-dependent tumors, so IRAK4 inhibitors are also suitable for treating these tumors (Kfoury, A., K.L. Corf, et al., Journal of the National Cancer Institute, 2013).

In addition to mediating MyD88-related processes and TLR (except TLR3)-related processes, IRAK4 also mediates signaling of the IL-1 receptor family. Inflammatory disorders are treated by blocking the IL-1 signaling pathway; therefore, IRAK4 inhibitors are also suitable for the treatment of the mentioned diseases, 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, adult Still's disease, Adamantiades-disease, rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca and syndrome (Narayanan, Corrales, et al. al., Cornea, 2008; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello, European Journal of Immunology, 2011; Gul, Tugal-Tutkun, et al., Ann Rheum Dis, 2012; Pettersson, Annals of MedicinePetterson, 2012; Ruperto, Brunner, et al., New England Journal ofMedicine, 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). IL-18 is particularly involved in the pathogenesis of rheumatoid arthritis, adult-onset Still's disease, type 1 diabetes, multiple sclerosis, and lupus erythematosus. Therefore, due to this mechanism of action, IRAK4 inhibitors are useful for treating and/or preventing these conditions (Volin and Koch, J Interferon Cytokine Res, 2011; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013; Yap and Lai, Nephrology, 2013). In addition, IRAK4 inhibitors are suitable for treating type 2 diabetes and post-myocardial infarction syndrome, as there are indications that inhibition of the IL-1 signaling pathway is a promising therapeutic approach (Abbate, Kontos, et al., The American Journal of Cardiology, 2010; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013). Several members of the IL-1 receptor family have been implicated in a variety of pulmonary disorders, including asthma, COPD, idiopathic interstitial pneumonia, and acute respiratory distress syndrome (ARDS), and their roles in the pathogenesis have been supported in various animal models (Kang, Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al., The Journal of Immunology, 2009; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke, et al., European Respiratory Journal, 2011; Yin, Li, et al., Clinical & Experimental Immunology, 2012; 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; Qiu, Li, et al., Immunology, 2013).

Furthermore, several studies have shown a relationship between the amount of IL-1β and its receptors, IL-18, and IL-33, and the condition endometriosis (Akoum, Lawson, et al., Human Reproduction, 2007; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology; Santulli, Borghese, et al., Human Reproduction, 2013). Furthermore, in animal models, the growth of human endometrial tissue can be blocked by administering the endogenous IL-1β inhibitor IL-1R2 (Khoufache, Bondza, et al., The American Journal of Pathology, 2012). IRAK4 inhibitors are also effective in this setting due to their mechanism of action. Chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis are associated with dysregulation of the IL-1 receptor family (Kobori, Yagi, et al., J Gastroenterol, 2010; Hao, Liu, et al., Curr Opin Gastroenterol, 2013). In addition to the indications mentioned, IRAK4 inhibitors are also suitable for the treatment and/or prevention of neurological disorders mediated by the IL-1 receptor family, such as stroke apoplexy, Alzheimer's disease, stroke, skull-brain trauma, and pain, such as cancer pain, postoperative pain, inflammation-induced pain and chronic pain (Wolf, Livshits, et al., Brain, Behavior, and Immunity, 2008; Brough, Tyrrell, et al., Trends in Pharmacological, 2011; Sciences Denes, Kitazawa, Cheng, et al., The Journal of Immunology, 2011; Pinteaux, et al., Cerebrovascular Diseases, 2011; del Rey, Apkarian, et al., Annals of the New York Academy of Sciences, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Han, Zhao, et al., Neuroscience, 2013; Zhao, Zhang, et al., Neuroscience, 2013. Because processes mediated by the IL1 receptor family propagate through IRAK4, IRAK4 inhibitors are active in skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis. The IL1 receptor family is implicated in the pathogenesis of these conditions (Viguier, Guigue, et al., Annals of Internal Medicine, 2010; Cevikbas, Steinhoff, J Invest Dermatol, 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Mattii, Ayala, et al., Experimental Dermatology, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013).

The association of IRAK4 with many different pathologies mediated by diverse signaling via TLRs (besides TLR3) and the IL1 receptor family suggests that a wide range of pathologies could be impacted in a positive manner by inhibiting IRAK4.

The compounds described in the present invention are able to inhibit IRAK4. This is also supported by the fact that the compounds of the present invention have inhibitory activity in TLR-mediated processes and IL1-mediated processes.

The object of the present invention is therefore to provide novel compounds which act as inhibitors of interleukin-1 receptor associated kinase-4 (IRAK4) in the manner described above. These novel IRAK4 inhibitors are particularly suitable for the treatment and prevention of proliferative and inflammatory disorders characterized by an overreactive immune system. In this context, particular mention is made of inflammatory skin disorders, cardiovascular disorders, pulmonary disorders, ocular disorders, autoimmune disorders, and neoplastic disorders.

Many IRAK4 inhibitors are known in the prior art. IRAK4 inhibitors are described, for example, in G.C. Harriman et al. US20130231328 and L.D. Romero et al. US20120283238.

IRAK4 modulators based on the pyrazolo[1,5a]pyrimidine skeleton were described by N. Arora et al. in US20120015962.

In addition, V.R. Paidi et al. reported thiazolyl-substituted pyridine derivatives or thiadiazolyl-substituted pyridine derivatives in WO2013106641, and S.D. Dodd et al. reported triazolyl-substituted pyridine derivatives in WO2013106614. Other pyridine derivatives are disclosed in WO2013106612.

Aminopyrimidone as an IRAK4 inhibitor was described by W.M.Seganish et al. in WO2013066729. In addition, W.T.Mcelroy et al. also described amidopyrazole as an IRAK inhibitor in WO2012129258.

G. Buckeley et al. reported imidazo[1,2-a]pyridines in Bioorg. Med. Chem. Lett. 18 (2008), 3291–3295 and Bioorg. Med. Chem. Lett. 18 (2008), 3656–3660. In addition, A. D. Frenkel et al. reported benzimidazole derivatives as IRAK4 inhibitors in US20070037803.

Other IRAK inhibitors having a 2-aminoimidazole or 2-aminobenzimidazole structure are claimed by A.D. Frenkel et al. in US 2007/0037803.

IRAK inhibitors, similar to the compounds of the present invention, are based on the indazole structure described by K. Guckian et al. in US Pat. No. 8,293,923. These are indazole derivatives substituted with a benzimidazol-2-ylamino group at the 3-position of the indazole. US Pat. No. 8,293,923 does not disclose 2-substituted indazoles.

Other indazole-based IRAK4 inhibitors were reported by C. Jorand-Lebrun et al. in US20130274241. These are indazole derivatives with a triazole-containing substituent at the 3-position of indazole. US20130274241 does not disclose any 2-substituted indazoles.

WO2011043371 describes oxazolecarboxamides linked to monocyclic aromatic heterocycles as IRAK4 inhibitors. Oxazolecarboxamides linked to indazoles, like the compounds of the present invention, are not described in WO2011043371.

Bicyclic heterocycles having a carboxamide structure as IRAK4 inhibitors, such as substance L1, are described by B. Anima et al. in WO 2013042137. However, only benzimidazole derivatives, benzoxazole derivatives, and benzothiazole derivatives are described, and no indazole derivatives are mentioned.

G.M. Buckley et al. reported carboxamide derivatives as IRAK4 inhibitors in Bioorg. Med. Chem. Lett. 18 (2008), 3211-3214. For example, molecules L2 and L3 are described. Indazole derivatives are not described.

In WO2009019167, A. Bombrun et al. describe 6-aminopyrimidine-4-carboxamides having a 2-substituted indazole structure, such as L4. These substances are reported to bind to the sphingosine-1-phosphate receptor. WO2009019167 does not describe an inhibitory effect on IRAK4 kinase.

US20080058341 describes azaindoles having a carboxamide structure as CCR1 antagonists, but does not disclose 2-substituted indazole derivatives having other carboxamide structures.

A.J. Souers et al. describe 2-substituted indazoles as MCH (melanin-concentrating hormone) antagonists in US20050137187. However, the 2-substituent of indazole does not include a carboxamide structure.

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

in:

R ⁰ represents hydrogen or C ₁ -C ₄ -alkyl, where the C ₁ -C ₄ -alkyl radical may optionally be mono- or polysubstituted by identical or different radicals selected from hydroxy and halogen;

R ¹ represents hydrogen, halogen, cyano, C(═O)OH, C(═O)OR ^a , C(═O)NH ₂ , C(═O)N(H) ^Ra , C(═O)N( ^Ra )R ^b , C(═O)R ^d , hydroxy or C ₁ -C ₆ -alkyl, where the C ₁ -C ₆ -alkyl radicals are optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of:

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 which is optionally mono- or polysubstituted by identical or different radicals selected from halogen, C ₃ -C ₈ -cycloalkoxy which is optionally mono- or polysubstituted by identical or different radicals selected from halogen, heterocycloalkyl which is optionally mono- or polysubstituted by identical or different radicals selected from R ^c , or represents C ₁ -C ₆ -alkoxy, where the C ₁ -C ₆ -alkoxy radical may be optionally mono- or polysubstituted by identical or different radicals selected from:

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 ₈ -cycloalkyl which is optionally mono- or polysubstituted by identical or different radicals selected from halogen, C ₁ -C ₆ -alkoxy which is optionally mono- or polysubstituted by identical or different radicals selected from halogen, C ₃ -C ₈ -cycloalkoxy which is optionally mono- or polysubstituted by identical or different radicals selected from halogen, heterocycloalkyl which is optionally mono- or polysubstituted by identical or different radicals selected from R ^c ,

an aryl group which is optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c , or a 5-membered or 6-membered heteroaryl group which is optionally monosubstituted or polysubstituted by the same or different groups selected from R ^c ,

or represents C ₃ -C ₈ -cycloalkoxy or heterocycloalkoxy which may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano and C ₁ -C ₆ -alkyl,

or represents aryloxy or 5-membered or 6-membered heteroaryloxy, where aryloxy and 5-membered or 6-membered heteroaryloxy may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy,

or represents C ₃ -C ₈ -cycloalkyl or heterocycloalkyl which may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano and C ₁ -C ₆ -alkyl,

or represents C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl,

or represents aryl, 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5-membered heteroaryl-C ₁ -C ₄ -alkyl or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, where aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, hydroxy, cyano, C(═O)OH, C(═O)OR ^a , C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl and C ₁ -C ₆ -alkoxy;

R ^a represents C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

wherein alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, hydroxy, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, heterocycloalkyl, —C(═O)OC ₁ -C ₆ -alkyl and S(═O) ₂ -C ₁ -C ₆ -alkyl;

R ^b represents C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl;

or ^Ra and ^Rb together with the nitrogen atom form a 5- or 6-membered heterocyclic ring, which may be optionally mono- or polysubstituted by identical or different groups selected from the group consisting of hydroxy, halogen, cyano and _C1 - _C6 -alkyl;

R ^c represents hydroxy, halogen, cyano, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -alkoxy;

R ^d represents hydrogen, C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl;

R ² represents hydrogen, C ₁ -C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl;

R ¹³ represents hydrogen or C ₁ -C ₆ -alkyl;

W represents a 5-membered heteroaryl group containing one to three heteroatoms selected from N, O and S and which may be optionally monosubstituted by R ³ and may be optionally monosubstituted or polysubstituted by identical or different groups R ⁴ , or

W represents pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl, which may be optionally monosubstituted by R ³ and may be optionally monosubstituted or polysubstituted by identical or different radicals R ⁴ ;

R ³ represents hydrogen, halogen, cyano, C(═O)R ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(═O)R ^a or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NH ₂ , NHR ^a , N(R ^a )R ^b , C ₁ -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkoxy,

where C ₁ -C ₆ -alkoxy and C ₃ -C ₈ -cycloalkoxy may optionally be mono- or polysubstituted by identical or different halogen groups;

or C ₁ -C ₆ -alkyl is optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of C ₃ -C ₆ -cycloalkyl and heterocycloalkyl,

wherein C ₃ -C ₆ -cycloalkyl and heterocycloalkyl may optionally be mono-, di- or trisubstituted by identical or different radicals selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy,

or C ₁ -C ₆ -alkyl is optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of aryl and 5- or 6-membered heteroaryl,

wherein aryl and 5-membered or 6-membered heteroaryl may be optionally mono-, di- or tri-substituted by identical or different substituents selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy,

or

R ³ represents a C ₁ -C ₆ -alkoxy group, wherein

C ₁ -C ₆ -alkoxy may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₃ -C ₈ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkoxy,

or represents C ₃ -C ₆ -cycloalkyl, heterocycloalkyl or C ₅ -C ₁₁ -spirocycloalkyl, where the cycloalkyl, heterocycloalkyl and spirocycloalkyl groups may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , C ₁ -C ₆ -alkyl and C ₁ -C ₄ -alkoxy;

or represents an aryl group or a 5- to 10-membered heteroaryl group, wherein

Aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, hydroxy, cyano, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, NO ₂ , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(═O)R ^a , C ₃ -C ₈ -cycloalkyl, C ₁ -C ₃ -alkoxy and C ₁ -C ₃ -alkyl, wherein

C ₁ -C ₃ -alkyl may optionally be mono- or polysubstituted by identical or different halogen groups;

R ⁴ represents halogen; hydroxy; cyano; or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may be optionally mono- or polysubstituted by identical or different radicals selected from halogen; C ₁ -C ₆ -alkoxy, where C ₁ -C ₆ -alkoxy may be optionally mono- or polysubstituted by identical or different radicals selected from halogen; C ₂ -C ₆ -alkenyl; C ₂ -C ₆ -alkynyl; C ₃ -C ₁₀ -cycloalkyl; 3- to 10-membered heterocycloalkyl and aryl, where aryl may be optionally mono- or polysubstituted by identical or different radicals R,

or

R ⁴ represents an aryl or heteroaryl group which may be optionally mono- or polysubstituted by identical or different radicals R,

or

R ⁴ represents C(=O)R ^a , C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , C(=O)OR ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(=O)R ^a , N(R ^a )C(=O)R ^a , N(H)C(=O)NH ₂ ^{. ​ ​ ​} _​ ^{​ ​ ​ ​ ​ ​ ​ ​} _​ ^{. ​ ​} _​ ^{​ ​} _​ ^{​ ​ ​ ​} _​ ^{​ ​ ​} , SH, SR ^a , S(=O)R ^a , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(=O) ₂ NHR ^a , S(=O) ₂ N(R ^a )R ^b or S(=O)(=NR ^a )R ^b ;

R represents halogen, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₁₀ -cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, C(═O)R ^a , C(═O)NH ₂ , C(═O)N(H)R a , C(═O)N(R a )R ^b , C( ^═O )OR ^a , NH ₂ , NHR ^a , ^N (R ^a )R ^b , N(H)C(═O)R ^a , N(R ^a )C(═O)R ^a , N(H)C(═O)NH ₂ , N(H)C(═O)NHR ^a , N(H)C(═O)N(R ^a )R ^b , N(R ^a )C(═O)NH ₂ , N(R ^a )C(=O)NHR ^a ,N(R ^a )C(=O)N(R ^a )R ^b ,N(H)C(=O)OR ^a ,N(R ^a )C(=O)OR ^a ,NO ₂ ,N(H)S(=O)R ^a ,N(R ^a )S(=O)R ^a ,N(H)S(=O) ₂ R ^a ,N(R ^a )S(=O) ₂ R ^a , N=S(=O)(R ^a )R ^b , OH, C ₁ -C ₆ -alkoxy, OC(=O)R ^a , OC(=O)NH ₂ , OC(=O)NHR ^a , OC(=O)N(R ^a )R ^b , SH, SR ^a , S(=O)R ^a , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(＝O) ₂ NHR ^a , S(=O) ₂ N(R ^a )R ^b or S(=O)(=NR ^a )R ^b ;

n represents 0 or 1;

Y represents a group selected from the following

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

R ⁵ represents hydrogen, C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy and C ₃ -C ₈ -cycloalkyl;

R ⁶ represents hydrogen or C ₁ -C ₆ -alkyl, where C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C ₃ -C ₁₀ -cycloalkyl, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy and C ₃ -C ₈ -cycloalkoxy,

or represents C ₃ -C ₁₀ -cycloalkyl, wherein

C ₃ -C ₁₀ -cycloalkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano and C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be substituted by hydroxy,

or represents a heterocycloalkyl group, wherein

Heterocycloalkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy,

or represents an aryl group or a 5-membered or 6-membered heteroaryl group, wherein

Aryl and 5- or 6-membered heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl, C ₁ -C ₃ -alkoxy, S(═O) ₂ NH ₂ , S(═O) ₂ NHR ^a and S(═O) ₂ N(R ^a )R ^b ;

R ^7a represents hydrogen, halogen, N(R ^a )R ^b , C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

R ^7b represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

or R ^7a and R ^7b together with the carbon atoms form C ₃ -C ₆ -cycloalkyl, which may optionally be identically or differently mono- or polysubstituted by radicals selected from hydroxy, halogen _, cyano and C _{1 -C 6} -alkyl,

or R ^7a and R ^7b together represent an oxo group;

R ^7c represents hydrogen, halogen, N(R ^a )R ^b , C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

R ^7d represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

or R ^7c and R ^7d together with the carbon atoms form C ₃ -C ₆ -cycloalkyl, which may be optionally mono- or polysubstituted by identical or different radicals selected from hydroxy, halogen _, cyano and C _{1 -C 6} -alkyl,

or R ^7c and R ^7d together represent an oxo group;

R ^8a represents hydrogen, halogen, N(R ^a )R ^b , C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

R ^8b represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

or R ^8a and R ^8b together with the carbon atoms form C ₃ -C ₆ -cycloalkyl, which may be optionally mono- or polysubstituted by identical or different radicals selected from hydroxy, halogen _, cyano and C _{1 -C 6} -alkyl,

R ^8c represents hydrogen, halogen, N(R ^a )R ^b , C ₁ -C ₆ -alkyl or C ₃ -C ₁₀ -cycloalkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

R ^8d represents hydrogen, halogen or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyl and heterocycloalkyl;

or R ^8c and R ^8d together with the carbon atoms form C ₃ -C ₆ -cycloalkyl, which may be optionally mono- or polysubstituted by identical or different radicals selected from hydroxy, halogen _, cyano and C _{1 -C 6} -alkyl,

or R ^8c and R ^8d together represent an oxo group;

o represents 0, 1 or 2,

p represents 0, 1 or 2,

q represents 0, 1, or 2,

r represents 0, 1 or 2,

s represents 0, 1 or 2,

Among them, o, p, q, r and s do not represent 0 at the same time;

Z represents a group selected from C(═O), CR ⁹ R ¹⁰ , NR ¹¹ , O, S, S(═O) and S(═O) ₂ ;

R ⁹ represents hydrogen or C ₁ -C ₆ -alkyl,

R ¹⁰ represents hydrogen, halogen, cyano, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , C(═O)NH ₂ , C(═O)N(H)R ^a , C(═O)N(R ^a )R ^b , N(H)C(═O)R ^a , N(R ^b )C(═O)R ^a , S(═O) ₂ R ^a , hydroxy, N(R ^a )R ^b and C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N(R ^a )R ^b , C ₁ -C ₄ -alkoxy and C ₃ -C ₈ -cycloalkoxy,

or represents a C ₁ -C ₆ -alkoxy group, wherein

C ₁ -C ₆ -alkoxy may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, N( ^Ra )R ^b , C ₃ -C ₈ -cycloalkyl, C ₁ -C ₄ -alkoxy, C ₃ -C ₈ -cycloalkyloxy, heterocycloalkyl, aryl or 5- or 6-membered heteroaryl, wherein

Aryl and 5- or 6-membered heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, cyano, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy,

or represents an aryloxy group or a 5-membered or 6-membered heteroaryloxy group, wherein

Aryloxy and 5- or 6-membered heteroaryloxy may be optionally mono- or disubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)OH, C(═O)OR ^a , C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy,

or represents C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, heterocycloalkyl or heterocycloalkyl-C ₁ -C ₄ -alkyl, which may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)R ^a , C(═O)OH, C(═O)OR ^a , C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, wherein

C ₁ -C ₆ -alkoxy may optionally be mono- or polysubstituted by identical or different halogen groups or oxo groups;

or represents C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl, or represents aryl, 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, wherein

Aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen, hydroxy, cyano, C(═O)OH, C(═O)OR ^a , NHR ^a , N( ^Ra )R ^b , C ₁ -C ₃ -alkyl, C ₃ -C ₈ -cycloalkyl and C ₁ -C ₃ -alkoxy;

or R ⁹ and R ¹⁰ together with the carbon atoms form a C ₃ -C ₈ -cycloalkyl or a 4- to 6-membered heterocyclic ring, wherein

The C ₃ -C ₈ -cycloalkyl radical or the 4- to 6-membered heterocycle may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C ₁ -C ₆ -alkyl, C(═O)R ^a and oxo;

R ¹¹ represents hydrogen, C(═O)R ^a , 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 N(R ^a )R ^b or C ₁ -C ₆ -alkyl, wherein

C ₁ -C ₆ -alkyl may optionally be mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C(═O)R ^a , C(═O)OR ^a , 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, N(R ^a )R ^b , C ₃ -C ₈ -cycloalkyl, C ₁ -C ₄ -alkoxy and C ₃ -C ₈ -cycloalkoxy, wherein

C ₃ -C ₈ -cycloalkyl, C ₁ -C ₄ -alkoxy and C ₃ -C ₈ -cycloalkoxy may optionally be mono- or polysubstituted by identical or different radicals selected from hydroxy and halogen,

or represents C ₃ -C ₈ -cycloalkyl, heterocycloalkyl or heterocycloalkyl-C ₁ -C ₄ -alkyl, which may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of hydroxy, halogen, cyano, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, whereby alkyl and alkoxy may be optionally mono- or polysubstituted by identical or different radicals selected from the group consisting of halogen and oxo,

or represents C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl,

or represents aryl, 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, wherein

Aryl and heteroaryl can optionally be mono- or polysubstituted by identical or different radicals selected from halogen, hydroxy, cyano, C(═O)OH, C(═O)OR ^a , C ₁ -C ₃ -alkyl, C ₃ -C ₈ -cycloalkyl and C ₁ -C ₃ -alkoxy.

In the synthetic intermediates and working examples of the present invention described below, if the compounds are given in the form of salts of the corresponding bases or acids, the exact stoichiometric composition of such salts obtained according to the respective preparation and/or purification methods is generally unknown. Unless otherwise specified, the supplementary names and structural formulas (such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF ₃ COOH", "x Na ⁺ ") should not be understood as the stoichiometric composition of such salts, but are merely descriptive symbols for the salt-forming components contained therein.

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

If the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of said salts, the compounds of the present invention are compounds of formula (I) and their salts, solvates and solvates of salts, compounds encompassed by formula (I) mentioned hereinafter and their salts, solvates and solvates of salts, as well as compounds encompassed by formula (I) and mentioned hereinafter as working examples and their salts, solvates and solvates of said salts.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention.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 mineral 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.

The compounds according to the invention may exist, depending on their structure, in different stereoisomeric forms, i.e. in the form of configurational isomers or optionally as conformers (enantiomers and/or diastereomers, including atropisomers). The present invention therefore encompasses the enantiomers and diastereomers and their respective mixtures. Stereoisomerically homogeneous components 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 comprises all tautomeric forms.

The present invention also includes all suitable isotopic variants of the compounds of the present invention. In this article, the isotopic variant of the compounds of the present invention is understood to mean such a compound: wherein at least one atom in the compound of the present invention is replaced by another atom with 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, in particular variants in which one or more radioactive isotopes have been incorporated, can be useful, for example, for studying the mechanism of action or distribution of the active compound 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, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention in some cases. 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 corresponding isotopic modifications of the respective reagents and/or starting compounds.

The present invention further provides all possible crystalline 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 such a compound: it may be biologically active or inactive, but is converted into a compound of the present invention during its residence in the body (for example, by metabolic or hydrolytic methods).

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-chain or branched alkyl group having a specified number of carbon atoms. Examples that may be mentioned are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl. Preference is given to methyl, ethyl, n-propyl, n-butyl and 1-methylpropyl as well as tert-butyl.

In the context of the present invention, alkenyl is a straight-chain or branched monovalent hydrocarbon radical which has at least one double bond and has the specific number of carbon atoms specified, typically 2 to 6 carbon atoms, preferably 2 to 4 and particularly preferably 2 or 3 carbon atoms.

In the case of multiple double bonds, these may be isolated or conjugated, with isolated double bonds being preferred.

Examples which may be mentioned are:

vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,

(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl,

(Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl,

Hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl,

(E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,

2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl,

(Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl,

3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl,

(E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl,

(Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl,

(E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl,

1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,

3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl,

(E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl,

(Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,

(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl,

(Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,

(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl,

(Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,

(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl,

(Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl,

(E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,

(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl,

2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl,

1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl,

(E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,

(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl,

(E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,

(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, buta-1,3-dienyl,

Penta-1,4-dienyl, hexa-1,5-dienyl, methylhexadienyl.

Particularly preferred are vinyl and allyl groups.

Alkynyl in the context of the present invention is a straight-chain or branched monovalent hydrocarbon radical which has at least one triple bond and has the specific number of carbon atoms specified, usually 2 to 6 carbon atoms, preferably 2 to 4 and particularly preferably 2 or 3 carbon atoms.

Examples which may be mentioned are:

ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl,

Pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl,

Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl,

3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl,

1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl,

1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl,

1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl,

2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or

3,3-Dimethylbut-1-ynyl.

Particular preference is given to ethynyl, prop-1-ynyl or prop-2-ynyl.

Cycloalkyl in the context of the present invention is a monocyclic saturated alkyl radical having in each case the indicated number of carbon atoms. Examples which may be mentioned as preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the context of the present invention, alkoxy is a straight-chain or branched alkoxy group having a specified number of carbon atoms. Preferably, it has 1 to 6 or 1 to 4 carbon atoms. Examples that may be mentioned are 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. Preferably, it has a straight-chain or branched alkoxy group having 1 to 4 carbon atoms. Examples that may be mentioned as preferred are methoxy, ethoxy, n-propoxy, 1-methylpropoxy, n-butoxy and isobutoxy.

Cycloalkoxy in the context of the present invention is a monocyclic saturated alkyl radical which has the specific number of carbon atoms indicated and is bonded via an oxygen atom. Examples which may be mentioned as preferred are: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.

Aryl in the context of the present invention is a monovalent monocyclic to tricyclic aromatic carbocyclic ring system having generally 6 to 14 carbon atoms. Examples which may be mentioned are: phenyl, naphthyl and phenanthrenyl. Phenyl is preferred.

Heterocyclyl or heterocycle (heterocyclus) or heterocycloalkyl in the context of the present invention is a monocyclic or polycyclic (preferably monocyclic or bicyclic), non-aromatic, saturated or partially unsaturated heterocycle, which generally has 3 to 10, preferably 3 to 7 ring atoms and up to 3, preferably up to 1 or 2 heteroatoms and/or heterogroups selected from N, O, S, SO and SO _2. Preference is given to 3- to 7-membered monocyclic saturated heterocyclyl groups, which have up to two heteroatoms selected from O, N and S. Examples that may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, dihydroindolinyl and dihydroisoindolinyl. Preference is given to: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

Heteroaryl is a monovalent aromatic monocyclic or bicyclic ring system, which generally has 5 to 10, preferably 5 to 6 ring atoms and preferably 1 to 3 heteroatoms. The heteroatoms can be nitrogen atoms, oxygen atoms and/or sulfur atoms. The binding valency can be on any aromatic carbon atom or on the nitrogen atom.

Heteroaryl groups having 5 ring atoms include, for example, the following ring:

thienyl, thiazolyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl and thiadiazolyl.

Heteroaryl groups having 6 ring atoms include, for example, the following ring:

pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Bicyclic heteroaryl groups of the present invention have 9 or 10 ring atoms.

Heteroaryl groups having 9 ring atoms include, for example, the following ring:

phthalidy, thiophthalidy, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, indolinyl.

Heteroaryl groups having 10 ring atoms include, for example, the following ring:

Isoquinolyl, quinolyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, 1,7-naphthyridinyl or 1,8-naphthyridinyl, pteridinyl, chromanyl.

_C5 - _C11 -spirocycloalkyl or heterospirocycloalkyl , in which 1 to 4 carbon atoms are replaced by nitrogen, oxygen and/or sulfur, including their two oxidized forms SO and _SO2 and their modified derivatives sulphoximine, are understood to mean fused bicyclic ring systems which share one common atom. Examples are spiro[2.2]pentane, spiro[2.3]hexane, azaspiro[2.3]hexane, spiro[3.3]heptane, azaspiro[3.3]heptane, oxazaspiro[3.3]heptane, thiazaspiro[3.3]heptane, oxazaspiro[5.3]nonane, oxazaspiro[4.3]octane, oxazaspiro[5.5]undecane, diazaspiro[3.3]heptane, thiazaspiro[3.3]heptane, oxazaspiro[5.3]nonane, oxazaspiro[4.3]octane, oxazaspiro[5.5]undecane, diazaspiro[3.3]heptane, thiazaspiro[3.3]heptane, oxazaspiro[5.3]nonane, oxazaspiro[4.3]octane, oxazaspiro[5.5]undecane, oxazaspiro[3.3]hept ... Spiro[3.3]heptane, thiazaspiro[4.3]octane, azaspiro[5.5]decane, and other homologous spiro[3.4], spiro[4.4], spiro[5.5], spiro[6.6], spiro[2.4], spiro[2.5], spiro[2.6], spiro[3.5], spiro[3.6], spiro[4.5], spiro[4.6] and spiro[5.6] systems, including variants modified by heteroatoms as defined.

Halogen in the context of the present invention is fluorine, chlorine and bromine, preferably fluorine and chlorine.

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

An oxo group in the context of the present invention is an oxygen atom which is attached to a carbon atom via a double bond.

The symbol * on a bond in a molecule indicates the point of attachment.

When a radical in the compounds of the invention is substituted, the radical may be monosubstituted or polysubstituted, unless otherwise stated. In the context of the present invention, all radicals occurring more than once are independent of one another in their meaning. Substitution by one, two or three identical or different substituents is preferred.

Preferred are compounds of formula (I), wherein

W represents a 5-membered heteroaryl group containing one to three heteroatoms selected from N, O and S and optionally monosubstituted by ^R and optionally monosubstituted or polysubstituted by identical or different radicals R, wherein the ^ring heteroatoms are adjacent to the ring carbon atom which is the point of attachment to the rest of the molecule

or

represents a pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl radical which may be optionally monosubstituted by R ³ and may be optionally monosubstituted or polysubstituted by identical or different radicals R ⁴ , wherein the ring heteroatoms are adjacent to the ring carbon atom which serves as the point of attachment of the radical to the remainder of the molecule.

Further preferred are compounds of formula (I), wherein

W represents a group selected from the following general formulae (III) to (IX):

in

R ¹² represents hydrogen, halogen, C ₁ -C ₆ -alkyl which is optionally mono- or polysubstituted by identical or different halogen groups, C ₃ -C ₆ -cycloalkyl which is optionally mono- or polysubstituted by identical or different halogen groups, aryl which is optionally mono- or polysubstituted by identical or different groups selected from R ^c , or 5- or 6-membered heteroaryl which is optionally mono- or polysubstituted by identical or different groups selected from R ^c , or represents NHR ^a ;

m represents 0, 1, 2, or 3, and

R ³ and R ⁴ have the meanings given above, and

*Represents the point of attachment of the group to the rest of the molecule.

Particular preference is further given to compounds of the general formula (I) in which W represents a group of the general formula (IX)

where m = 0 or 1, and

R ³ is a C ₁ -C ₆ -alkyl group which is optionally mono- or polysubstituted by halogen and/or hydroxy, halogen, cyano or a C ₃ -C ₆ -cycloalkyl group which is optionally mono- or polysubstituted by halogen and/or hydroxy.

Preferably, R ³ is a C ₁ -C ₃ -alkyl radical which is unsubstituted or mono- or polysubstituted by hydroxy and/or halogen.

For the purposes of the present invention, particularly preferred C ₁ -C ₃ -alkyl radicals for R ³ are methyl and ethyl. Preferably, R ³ is a C ₁ -C ₆ -alkyl radical which is optionally monosubstituted by hydroxy and/or mono- to trisubstituted by fluorine.

Particularly preferably, R ³ is a C ₁ -C ₃ -alkyl radical which is optionally monosubstituted by hydroxy and/or mono- to trisubstituted by fluorine.

Preferred substituted C ₁ -C ₃ -alkyl groups for R ³ are trifluoro-C ₁ -C ₃ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyprop-2-yl and 2,2,2-trifluoro-1-hydroxyethyl. In this context, the trifluoromethyl group is particularly preferred.

It is also preferred that R ³ is a cyclopropyl group.

As W, the following groups may be mentioned by way of example:

1-ethyl-1H-pyrazol-3-yl, 2,4'-bipyridin-6-yl, 2-(4-fluorophenyl)-1,3-thiazol-4-yl, 2-(4-methoxyphenyl)-1,3-thiazol-4-yl, 2-(azetidin-3-ylamino)-1,3-thiazol-4-yl, 2-(pyridin-3-yl)-1,3-thiazol-4-yl, 2-(pyridin-4-yl) -1,3-thiazol-4-yl, 2-(trifluoromethyl)-1,3-thiazol-4-yl, 2-bromo-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-methyl-1,3-oxazol-4-yl, 2-methyl-1,3-oxazol-5-yl, 2-phenyl-2H-1,2,3-triazol-4-yl, 2-{[1-(tert-butoxycarbonyl)nitrogen heterocyclobutane-3-yl]amino}-1,3-thiazol-4-yl, 4'-methyl-2,3'-bipyridin-6-yl, 4-(trifluoromethyl)-1,3-thiazol-2-yl, 5'-methyl-2,3'-bipyridin-6-yl, 5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 5-fluoropyridin-2-yl, 6'-acetamido-2, 3'-Bipyridin-6-yl, 6'-amino-2,3'-bipyridin-6-yl, 6'-methoxy-2,3'-bipyridin-6-yl, 6'-methyl-2,3'-bipyridin-6-yl, 6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(1-methyl-1H -pyrazol-5-yl)pyridin-2-yl, 6-(1H-1,2,4-triazol-1-yl)pyridin-2-yl, 6-(1H-pyrazol-1-yl)pyridin-2-yl, 6-(3-hydroxyazetidin-1-yl)pyridin-2-yl, 6-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(4-chloro-1H-pyrazol-1-yl)pyridin-2-yl -yl, 6-(4H-1,2,4-triazol-4-yl)pyridin-2-yl, 6-(azetidin-3-ylamino)pyridin-2-yl, 6-(cyclopropylmethoxy)pyridin-2-yl, 6-(dimethylamino)pyridin-2-yl, 6-(morpholin-4-yl)pyridin-2-yl, 6-(morpholin-4-yl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl , 6-[1-hydroxyethyl]pyridin-2-yl, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-yl, 6-[3-(methylsulfonyl)phenyl]pyridin-2-yl, 6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-2-yl, 6-acetamidopyridin-2-yl, 6-aminopyridin-2-yl, 6-bromopyridin-2 -yl, 6-chloropyridin-2-yl, 6-cyclopropylpyridin-2-yl, 6-ethoxypyridin-2-yl, 6-ethylpyridin-2-yl, 6-fluoropyridin-2-yl, 6-methoxypyridin-2-yl, 6-methylpyridin-2-yl, 6-{[(2S)-azetidin-2-ylmethyl]amino}pyridin-2-yl and 6-(2-hydroxypropan-2-yl)pyridin-2-yl.

As W, the following groups are preferred:

2-(4-Fluorophenyl)-1,3-thiazol-4-yl, 2-(4-methoxyphenyl)-1,3-thiazol-4-yl, 2-(azetidin-3-ylamino)-1,3-thiazol-4-yl, 2-(pyridin-4-yl)-1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(1H-1,2,4-triazol-1-yl)pyridin-2-yl, 6-(1H-pyrazol-4-yl)pyridin-2-yl 1-Hydroxypropylpyridin-2-yl, 6-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(azetidin-3-ylamino)pyridin-2-yl, 6-(dimethylamino)pyridin-2-yl, 6-(morpholin-4-yl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-[1-hydroxyethyl]pyridin-2-yl, 6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-2-yl, 6-cyclopropylpyridin-2-yl, 6-methylpyridin-2-yl, and 6-(2-hydroxypropan-2-yl)pyridin-2-yl.

If W represents a group of the general formula (IX) and m=1, R ⁴ is preferably positioned in the ortho position to R ³ :

If W represents a radical of the general formula (X), R ⁴ is preferably hydrogen, C ₁ -C ₃ -alkyl, fluorine, chlorine, bromine, cyano or trifluoromethyl.

Particularly preferably, W represents a group of the general formula (X) in which R ⁴ is hydrogen.

As W, the following groups are particularly preferred:

6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(1H-1,2,4-triazol-1-yl)pyridin-2-yl, 6-(1H-pyrazol-1-yl)pyridin-2-yl, 6-(3-methyl-1H-pyrazol-4-yl)pyridin-2-yl, 6-(azetidin-3-ylamino)pyridin-2-yl, 6-(dimethylamino)pyridin-2-yl, 6-(morpholin-4-yl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-[1-hydroxyethyl]pyridin-2-yl, 6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridin-2-yl, 6-cyclopropylpyridin-2-yl, 6-methylpyridin-2-yl, and 6-(2-hydroxypropan-2-yl)pyridin-2-yl.

Further preference is given to compounds in which R ¹ is hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, aryloxy or heteroaryloxy.

In ^a preferred embodiment, C ₁ -C ₆ -alkoxy is methoxy, ethoxy, isopropoxy or isobutoxy. C ₁ -C ₆ -alkoxy may be mono- or polysubstituted, preferably by one or more halogens or by C _{3 -C 8} -cycloalkyl which is mono- or polysubstituted _by the same or different halogens.

If R ¹ represents monohalogenated or polyhalogenated C ₁ -C ₆ -alkoxy, fluorine is preferred. Mention may be made here by way of example of trifluoromethoxy, difluoromethoxy and 2,2,2-trifluoroethoxy. Very particular preference is given to trifluoromethoxy and 2,2,2-trifluoroethoxy.

If R ¹ represents a C _{1 -C 6} -alkoxy radical which is mono- or polysubstituted by C ₃ -C ₈ -cycloalkyl, preferably C ₃ -C ₅ -cycloalkyl, particularly preferably cyclopropyl radicals, cyclopropylmethoxy may be mentioned as an example.

If R ¹ is a C ₁ -C ₆ -alkoxy group substituted by an aryl group, an aryl group having 6 carbon atoms is preferred, for example benzyloxy.

If R ¹ is a C ₁ -C ₆ -alkoxy group substituted by a heteroaryl group, a 6-membered heteroaryl group is preferred. In this context, mention may be made of the pyrimidinylmethoxy group as an example for R ¹ .

In the case of C ₁ -C ₆ -alkyl, further preferred embodiments of R ¹ are methyl or ethyl.

If R ¹ is halogen, it is preferably bromine, fluorine or chlorine, with chlorine being particularly preferred.

Furthermore, R ¹ may be a hydroxy-substituted C ₁ -C ₅ -alkyl group. In this context, particular mention is made of 2-hydroxypropan-2-yl or 3-hydroxypentan-3-yl. Preference is given to the 2-hydroxypropan-2-yl group.

If R ¹ is halogen, fluorine, chlorine and bromine are preferred, with chlorine being particularly preferred.

The invention further provides compounds of the general formula (I) in which W represents a group of the general formula (IX) or (X) and R ² represents hydrogen.

Furthermore, the present invention provides compounds of the general formula (I) in which W represents a group of the general formula (IX) or (X) and R ⁰ represents hydrogen or methyl.

The present invention further provides compounds of the general formula (I) in which W represents a group of the general formula (IX) or (X) and R ¹³ represents hydrogen or methyl.

Furthermore, the present invention provides compounds of the general formula (I) in which W represents a group of the general formula (IX) or (X) and n represents 0 or 1.

Furthermore, the present invention provides compounds of the general formula (I), in which W represents a group of the general formula (IX) or (X) and R ¹ represents hydrogen, cyano, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, isobutoxy, cyclopropylmethoxy, pyridin-2-ylmethoxy, benzyloxy, bromo, chloro, ethoxy, fluoro, hydroxy, methoxy or 2-hydroxyprop-2-yl.

Furthermore, the present invention provides compounds of the general formula (I), wherein W represents a group of the general formula (IX)

wherein m represents 0 or 1, R ³ is a C ₁ -C ₆ -alkyl group which is optionally mono- or polysubstituted by halogen and/or hydroxy, halogen, cyano or a C ₃ -C 6 -cycloalkyl group which is optionally mono- or polysubstituted by halogen and/or hydroxy, and R ⁴ is _a C ₁ -C ₃ -alkyl group, fluorine, chlorine, bromine, cyano or trifluoromethyl.

Furthermore, the present invention provides compounds of the general formula (I), wherein W represents a group of the general formula (X)

wherein R ⁴ is hydrogen, C ₁ -C ₃ -alkyl, fluorine, chlorine, bromine, cyano or trifluoromethyl, and R ³ is a C ₁ -C ₆ -alkyl group optionally mono- or polysubstituted by halogen and/or hydroxy, halogen, cyano or a C _{3 -C 6} -cycloalkyl group optionally mono- or polysubstituted by halogen and/or hydroxy.

Particular preference is given to compounds in which W represents a radical of the general formula (X) in which R ⁴ represents hydrogen and R ³ is an unsubstituted or mono- or polysubstituted C ₁ -C ₃ -alkyl radical by hydroxy and/or halogen.

In this context, very particular preference is given to compounds in which W represents a radical of the general formula (X) in which R ⁴ represents hydrogen and R ³ is a C ₁ -C ₃ -alkyl radical which is optionally monosubstituted by hydroxy and/or mono- to trisubstituted by fluorine.

In this context, particular preference is given to compounds in which R ⁴ represents hydrogen and R ³ is methyl, ethyl, trifluoro-C ₁ -C ₃ -alkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyprop-2-yl or 2,2,2-trifluoro-1-hydroxyethyl.

Especially preferably, R ⁴ is hydrogen and R ³ is a trifluoromethyl or cyclopropyl group.

Y represents a group

or representative group

If Y represents NR ⁵ R ⁶ as described above, R ⁵ is preferably C ₁ -C ₆ -alkyl, particularly preferably methyl or ethyl.

R ⁶ is likewise optionally mono- or polysubstituted C ₁ -C ₆ -alkyl, preferably mono- or polysubstituted by C ₃ -C ₁₀ -cycloalkyl.

Particular preference is given to R ⁶ methyl or ethyl, optionally substituted by C ₃ -C ₁₀ -cycloalkyl. In this context, cyclopropyl is particularly preferred.

As an example thereof, cyclopropylmethyl group can be mentioned.

Other preferred embodiments of R ⁶ are C ₃ -C ₁₀ -cycloalkyl, heterocycloalkyl, 5-membered or 6-membered heteroaryl or aryl.

In this context, pyridazinyl, phenyl, oxazolyl, piperidinyl and cyclohexyl are particularly preferred.

If Y represents NR ⁵ R ⁶ , the following groups may be mentioned as examples of Y: (3-sulfamoylphenyl)amino, [(3R)-piperidin-3-ylamino]ethyl, 1,2-oxazol-4-ylamino, [3-(dimethylsulfamoyl)phenyl]amino, [trans-4-(2-hydroxypropan-2-yl)cyclohexyl]amino, pyridazin-4-ylamino, (cyclopropylmethyl)(methyl)amino.

If Y represents a group of formula (II)

in

o = 0, 1, or 2;

p = 0, 1, 2, or 3;

q = 0 or 1,

where the sum of o, p, and q = 1, 2, or 3; and

r = 0 or 1;

s = 0 or 1; and

Z represents CR ⁹ R ¹⁰ , NR ¹¹ , O, S or S(═O) ₂ ,

Then for p, 0, 1 or 2 is preferred.

In this context, particular preference is given to compounds in which Y represents a group of the general formula (II)

in

o＝0，

p = 0 or 1,

q, r, and s = 1, and

Z represents CR ⁹ R ¹⁰ , NR ¹¹ , O, S or S(═O) ₂ .

If Y represents a radical of the formula (II) mentioned above, the following radicals may be mentioned by way of example:

4-Benzoylpiperazin-1-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl, 4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl, 4-(methoxyacetyl)piperazin-1-yl, 4-(2-hydroxypropan-2-yl)piperidin-1-yl, 4-(cyclopropylmethyl)piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(cyclopropylcarbonyl)piperazin-1-yl, morpholin-4-yl, 4-(ethoxycarbonyl)piperazin-1-yl, 3-(dimethylamino)azetidin-1-yl, 3-(piperidin-1-yl)azetidin-1-yl, 2-[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl, 4-hydroxy-1 , 4'-bipiperidin-1'-yl, 4-(dimethylamino)piperidin-1-yl, 4-(2,2,2-trifluoroethyl)piperazin-1-yl, 4-ethyl-3-oxopiperazin-1-yl, 4-(4-fluorobenzoyl)piperazin-1-yl, 4-(pyridin-2-yl)piperazin-1-yl, 4-cyclopentyl-3-oxopiperazin-1-yl, 3-oxo-4-phenylpiperazin-1-yl, 4-(2,2-dimethylpropionyl)piperazin-1-yl, 4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl, 4-(1-phenylethyl)piperazin-1-yl]ethyl, 4-(pyridin-3-ylcarbonyl)piperazin-1-yl, 4-isonicotinoylpiperazin-1-yl, 4-(Morpholin-4-ylcarbonyl)piperazin-1-yl, 4-[2-(methylamino)-2-oxoethyl]piperazin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl, 4-(1-hydroxyethyl)piperidin-1-yl, 2-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl, 6-acetyl-2,6-diazaspiro[3.3]hept-2-yl, 3-oxo-2,8-diazaspiro[4.5]dec-8-yl)ethyl, 6-methyl-2,6-diazaspiro[3.5]nonan-2-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 1,4'-bipiperidin-1'-yl, 2-[2-(hydroxymethyl)piperidin-2-yl] 4-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl, 4-[(4-methylpiperazin-1-yl)piperidin-1-yl, 4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl, 4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl, 3-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl, 4-[( ...4-methylpiperazin-1-yl)piperidin-1-yl, 4-[(2-(morpholin-4-yl)ethyl]piperidin-1-yl, 4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl, 3-(pyrrolidin-1-ylmethyl)piperidin-1-yl, 3-(pyrrolidin-1-ylmethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(morpholin-4-yl)ethyl]piperidin-1-yl, 3-(pyrrolidin-1-ylmethyl)piperidin-1-yl, 3-(hydroxymethyl)piperidin-1-yl, 3-(dimethylamino)piperidin-1-yl, 3-(morpholin-4-yl)ethyl]piperidin-1-yl, 3-(cyclopropylcarbonyl)amino]piperid 1-yl, 4-(methylsulfonyl)piperidin-1-yl, 4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl, 4-(phenylsulfonyl)piperidin-1-yl, 4-[isonicotinyl(methyl)amino]piperidin-1-yl, 4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl, 4-(1,1-dioxidotetrahydrothiophen-3-yl)piperazin-1-yl, 4-[(methoxyacetyl)(methyl)amino]piperidin-1-yl, 4-(cyclohexylcarbonyl)piperazin-1-yl, 4-[2-(cyclopropylamino)-2-oxoethyl]piperazin-1-yl ]piperazin-1-yl, 2-hydroxyethyl)piperidin-1-yl, 4-(1H-pyrrol-1-yl)piperidin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-carbamoylpiperazin-1-yl, 4-(2-oxopyrrolidin-1-yl)piperidin-1-yl, 4-(2-amino-2-oxoethyl)piperazin-1-yl, 1,1-dioxothiomorpholin-4-yl, 4-isopropylpiperazin-1-yl, 4-(2-thienylcarbonyl)piperazin-1-yl, 2-cyclopropyl-2-oxoethyl)piperazin-1-yl, 4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazin-1-yl, 4-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]piperazin-1-yl] 1-yl, 4-(2-furylmethyl)piperazin-1-yl, 4-(3-thienylmethyl)piperazin-1-yl, 4'-methyl-1,4'-bipiperidin-1'-yl, 6-methyl-2,6-diazaspiro[3.3]hept-2-yl, 4-cyclopentylpiperazin-1-yl, 4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl, 4-(pyridin-4-ylmethyl)piperazin-1-yl, 4-(dimethylsulfamoyl)piperazin-1-yl, 4-(pyridin-4-yl)piperazin-1-yl, 4-(methylsulfonyl)piperazin-1-yl, {4-[ 2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl, 4-(diethylsulfamoyl)piperazin-1-yl, 4-(pyridin-3-yl)piperazin-1-yl, 4-(piperidin-1-ylsulfonyl)piperazin-1-yl, 4-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl, 4-ethylpiperazin-1-yl, 4-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl, 4-(cyclobutylcarbonyl)piperazin-1-yl, 4-(cyclopentylcarbonyl)piperazin-1-yl, 4-[3-(methylsulfonyl)benzoyl]piperazin-1-yl and 4-[2-methoxy-5-(methylsulfonyl)benzoyl]piperazin-1-yl.

Particularly preferably, Y is 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl or morpholin-4-yl.

The present invention preferably provides compounds of the general formula (I), wherein W represents a group of the general formula (IX)

in

m represents 0 and R ² , R ⁰ and R ¹³ all represent hydrogen and R ³ represents trifluoromethyl, ethyl, methyl, cyclopropyl, 2,2,2-trifluoro-1-hydroxyethyl or 1-hydroxyethyl; Y represents 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl or morpholin-4-yl, n represents 0 and R ¹ represents cyclopropylmethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, chlorine, ethoxy or methoxy.

In this context, R ¹ particularly preferably represents cyclopropylmethoxy, methoxy or ethoxy.

In this context, particular preference is given to compounds in which R ³ is a trifluoromethyl or cyclopropyl group.

The present invention also provides the following compounds:

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

6-ethyl-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

5-Fluoro-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

N-(2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-(2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

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

N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-cyclopropylpyridine-2-carboxamide

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

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

6-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}pyridine-2-carboxamide

tert-Butyl 3-{[4-({2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamoyl)-1,3-thiazol-2-yl]amino}azetidine-1-carboxylate

N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-Bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-{6-Bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-cyclopropyl-1,3-oxazole-4-carboxamide

tert-Butyl 3-{[4-({6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamoyl)-1,3-thiazol-2-yl]amino}azetidine-1-carboxylate

2-(azetidin-3-ylamino)-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-1,3-thiazole-4-carboxamide

N-{6-cyano-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

6'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

5'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

4'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

6'-Methoxy-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

6'-acetamido-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6'-nitro-2,3'-bipyridine-6-carboxamide

6'-amino-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-Fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

N-{6-Fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{6-Fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(morpholin-4-yl)pyridine-2-carboxamide

N-{6-Fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide

N-{6-(Benzyloxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-isobutoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-isobutoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-isobutoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(cyclopropylmethoxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(cyclopropylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-[6-(Cyclopropylmethoxy)-2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(Morpholin-4-yl)-2-oxoethyl]-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-chloro-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

4-{[6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylic acid ethyl ester

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

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

N-(6-chloro-2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(6-chloro-2-{2-[3-(dimethylamino)azetidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(6-chloro-2-{2-oxo-2-[3-(piperidin-1-yl)azetidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(6-chloro-2-{2-[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-(4-hydroxy-1,4'-bipiperidin-1'-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

N-{6-ethoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-ethoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{6-ethoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-2-(pyridin-3-yl)-1,3-thiazole-4-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-2-(pyridin-4-yl)-1,3-thiazole-4-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

6-(azetidin-3-ylamino)-N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(pyridin-3-yl)-1,3-thiazole-4-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-4-yl)pyridine-2-carboxamide

6-(1,3-Dimethyl-1H-pyrazol-4-yl)-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide

6-ethyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

6-(1-methyl-1H-pyrazol-4-yl)-N-(2-{2-oxo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

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

N-{2-[2-(4-ethyl-3-oxopiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(pyridin-4-yl)-1,3-thiazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-chloropyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-methyl-1,3-oxazole-5-carboxamide

6-amino-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-methyl-1,3-oxazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methoxypyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-cyclopropyl-1,3-oxazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(4H-1,2,4-triazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-phenyl-2H-1,2,3-triazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-5-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(trifluoromethyl)-1,3-thiazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-1-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1-ethyl-1H-pyrazole-3-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(4-chloro-1H-pyrazol-1-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-4-(trifluoromethyl)-1,3-thiazole-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,4'-bipyridine-6-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-1,2,4-triazol-1-yl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-ethoxypyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(cyclopropylmethoxy)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-ethylpyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(4-methoxyphenyl)-1,3-thiazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-bromo-1,3-thiazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(4-fluorophenyl)-1,3-thiazole-4-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-fluoropyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-bromopyridine-2-carboxamide

N-(2-{2-[4-(4-Fluorobenzoyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyridin-2-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(Methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-cyclopentyl-3-oxopiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-oxo-2-(3-oxo-4-phenylpiperazin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-Oxo-2-(pyridazin-4-ylamino)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-isonicotinoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[2-(methylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyrazin-2-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{2-[2-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(6-Acetyl-2,6-diazaspiro[3.3]hept-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-oxo-2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-(2-{2-[2-(Hydroxymethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{2-[2-(4-Carbamoylpiperidin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

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

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

N-[2-(2-{4-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

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

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

N-(2-{2-oxo-2-[3-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{[3-(dimethylsulfamoyl)phenyl]amino}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(1,2-oxazol-4-ylamino)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-[2-(2-oxo-2-{4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}ethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-(2-{2-oxo-2-[(3-sulfamoylphenyl)amino]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[isonicotinyl(methyl)amino]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[2-(Isopropylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(1,1-dioxotetrahydrothiophen-3-yl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[(methoxyacetyl)(methyl)amino]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylic acid ethyl ester

N-(2-{2-[4-(cyclohexylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[2-(cyclopropylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

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

N-(2-{2-[4-(3-Hydroxypropyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

4-{[5-({[6-(Trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxamide

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

N-{2-[2-(Morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{2-[2-(4-Isopropylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(2-thienylcarbonyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(2-cyclopropyl-2-oxoethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N,N-Diethyl-4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxamide

N-{2-[2-Oxo-2-(thiomorpholin-4-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(2-Furylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(3-thienylmethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{2-[2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-cyclopentylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(dimethylsulfamoyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyridin-4-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(Methylsulfonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

Formic acid N-[2-(2-{4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1:1)

N-(2-{2-[4-(diethylsulfamoyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-oxo-2-[4-(pyridin-3-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-[2-(2-{4-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-(2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

6-(1-methyl-1H-pyrazol-4-yl)-N-(2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

N-{2-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-(2-{2-[4-(Dimethylamino)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide

N-(2-{2-[(Cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-ethoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

6-(azetidin-3-ylamino)-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

6-[(azetidin-2-ylmethyl)amino]-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(3-hydroxyazetidin-1-yl)pyridine-2-carboxamide

6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

N-[2-(2-{4-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-(6-chloro-2-{2-oxo-2-[(3R)-piperidin-3-ylamino]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-isopropoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-isopropoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-isopropoxy-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-6-isopropoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-Isopropoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-Isopropoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-(2-{2-[4-(cyclobutylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-(2-{2-[4-(cyclopentylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[3-(methylsulfonyl)benzoyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

N-[2-(2-{4-[2-methoxy-5-(methylsulfonyl)benzoyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

6-Bromo-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide

2-(4-Methoxyphenyl)-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-1,3-thiazole-4-carboxamide

2-(4-Fluorophenyl)-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-1,3-thiazole-4-carboxamide

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

6-Bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

6-Bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}pyridine-2-carboxamide

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-6-(4H-1,2,4-triazol-4-yl)pyridine-2-carboxamide

2-Bromo-N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1,3-thiazole-4-carboxamide

N-{6-hydroxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-[6-(Benzyloxy)-2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide

6-Bromo-N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{6-(Benzyloxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

2-(Azetidin-3-ylamino)-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1,3-thiazole-4-carboxamide

6-acetamido-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

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

6-(Dimethylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

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

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

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(methylsulfonyl)phenyl]pyridine-2-carboxamide

N-{2-[1-(4-Benzoylpiperazin-1-yl)-1-oxopropan-2-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-[6-chloro-2-(2-{[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]amino}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

6-(2-Hydroxypropan-2-yl)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{6-chloro-2-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-(6-chloro-2-{2-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

6-(Difluoromethyl)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{2-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxamide

N-{2-[2-(1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-methoxy-2-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(3-hydroxy-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

6-ethyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

6-Isobutyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

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

5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazole-6-carboxylic acid methyl ester

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(pyrrolidin-1-yl)pyridine-2-carboxamide

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide

6-(Cyclopropylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

6-(Butylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(propylamino)pyridine-2-carboxamide

6-(Isobutylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

R-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxamide

S-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxamide

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

6-(Cyclopropylamino)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(propylamino)pyridine-2-carboxamide

6-(Isobutylamino)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

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

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

N-{6-(Benzyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

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

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

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

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

5-Fluoro-N-(2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide

N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(3-cyanopropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(Morpholin-4-yl)-2-oxoethyl]-6-(2,2,2-trifluoroethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(cyclohexylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(Morpholin-4-yl)-2-oxoethyl]-6-(tetrahydrofuran-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(cyclopentyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(cyanomethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

({2-[2-(Morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)acetic acid

N-{6-(cyclobutylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-[2-(pyrrolidin-1-yl)ethoxy]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-[2-(morpholin-4-yl)ethoxy]-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

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

N-{6-(3-Hydroxypropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(2-hydroxypropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(2-hydroxyethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-(2-methoxyethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Ethyl ({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)acetate

Methyl 4-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)butanoate

Ethyl 2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propanoate

Ethyl 3-methyl-2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)butanoate

2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propanoic acid

N-{6-(2-hydroxypropan-2-yl)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide

N-{6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide.

The present invention also provides a method for preparing an intermediate of general formula (III) from a compound of formula (II)

wherein R ¹⁴ is methyl or ethyl.

The conversion of the intermediate of formula (II) into the intermediate of formula (III) is carried out by a Grignard reaction. Preferably, the Grignard reaction is carried out using an alkylmagnesium bromide. For this purpose, methylmagnesium bromide or ethylmagnesium bromide is preferably used.

Therefore, the present invention also provides intermediates of general formula (II).

The present invention also provides an intermediate of the general formula (III), wherein R ¹⁴ represents a methyl group or an ethyl group.

The compounds of the general formula (I) of the present invention act as IRAK4 kinase inhibitors and have an unexpectedly useful spectrum of pharmacological activities.

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.

The compounds of the present invention are suitable for the prevention and/or treatment of various disorders and disease-related conditions, in particular disorders mediated by TLRs (except TLR3) and/or the IL-1 receptor family and/or disorders whose pathology is directly mediated by IRAK4. IRAK4-related disorders that may be mentioned are multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, virus-induced myocarditis, gout, psoriasis and arthritis.

The compounds of the present invention can also be used to prevent and/or treat conditions mediated by MyD88 and TLRs (except TLR3). These include multiple sclerosis, rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, syndrome, sepsis, skin conditions such as psoriasis, atopic dermatitis and acne vulgaris, and 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 according to the invention are suitable for the prevention and/or treatment of TLR-mediated disorders: gout, endometriosis, transplant rejection, lupus erythematosus, adult Still's disease and chronic inflammatory bowel disorders such as ulcerative colitis and Crohn's disease.

In addition to the disorders already listed, the compounds according to the invention are also suitable for use in 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 arteriosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's disease, stroke and Parkinson's disease.

Furthermore, the compounds according to the invention can be used for the prevention and/or treatment of itching and pain.Due to their mechanism of action, the compounds according to the invention are suitable for the prevention and/or treatment of tumor disorders such as lymphomas, chronic lymphocytic leukemias, melanomas and hepatocellular carcinomas and Ras-dependent tumors.

Furthermore, the compounds according to the invention are suitable for the treatment and/or prevention of disorders which are mediated via the IL-1 receptor family. These conditions include: 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; adult-onset Still's disease; Adamantiades disease; rheumatoid arthritis; osteoarthritis; keratoconjunctivitis sicca and syndrome; multiple sclerosis; lupus erythematosus; type 1 diabetes mellitus; type 2 diabetes mellitus and post-myocardial infarction syndrome. The following diseases are associated with dysregulation of the IL-1 receptor family and are suitable for therapeutic and/or prophylactic use of the compounds of the present invention: pulmonary disorders such as asthma, COPD, idiopathic interstitial pneumonias and ARDS; endometriosis; chronic inflammatory bowel disorders such as Crohn's disease and ulcerative colitis.

The compounds of the present invention can also be used to treat and/or prevent neurological disorders mediated by the IL-1 receptor family, such as stroke, Alzheimer's disease, infarction, craniocerebral trauma, pain disorders such as cancer pain, postoperative pain, inflammation-induced pain and chronic pain, and skin disorders such as psoriasis, atopic dermatitis, allergic contact dermatitis.

Particularly preferred is the use of the IRAK4 inhibitors of the present invention for the treatment and/or prevention of inflammatory skin disorders, cardiovascular disorders, lung disorders, eye disorders, autoimmune disorders and tumor disorders.

The present invention further provides a method for the treatment and/or prevention 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 condition and/or the symptoms of said condition. The term "therapy" is understood herein to be synonymous with the term "treatment".

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

A disease, disorder, condition, 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 compounds. The present invention therefore also provides medicaments, in particular for the treatment and/or prevention of the aforementioned conditions, comprising at least one compound according to the invention and one or more other active ingredients. Preferred examples of active compounds suitable for combination include:

Active compounds which may generally be mentioned are: 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, tacrolimus, rapamycin, mycophenolate mofetil, mofetil), interferon, corticosteroids (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, there may be mentioned, by way of example and not limitation, immunotherapies, antiproliferative substances, such as trastuzumab, rituximab, tositumomab, aromatase inhibitors (e.g. letrozole, anastrozole), antiestrogens (e.g. tamoxifen), topoisomerase I inhibitors (e.g. irinotecan, topotecan), topoisomerase II inhibitors (e.g. daunorubicin, idarubicin), substances that regulate cell differentiation processes such as 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., methotrexate, 5-fluorouracil, cladribine, fludarabine), platinum compounds (e.g., carboplatin, cisplatin, cisplatinum); antiangiogenic compounds (e.g., bevacizumab), antiandrogenic compounds (e.g., flutamide, nilutamide, bicalutamide, cyproterone acetate), acetate), proteasome inhibitors (e.g., bortezomib, carfilzomib, oprozomib, ONYX0914), gonadotropin-releasing hormone agonists and antagonists (e.g., goserelin, triptorelin, degarelix), methionine aminopeptidase inhibitors (e.g., bengamide derivatives, TNP-470, PPI-2458), acetylcholinesterase inhibitors (e.g., acetylcholinesterase inhibitors ... 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, etc.); hydrochloride), IPI-493, AUY922, BIIB028, STA-9090, KW-2478), kinesin spindle protein inhibitors (e.g., SB715992, SB743921, pentamidine/chlorpromazine), MEK (mitogen-activated protein kinase kinase) inhibitors (e.g., trametinib, BAY 86-9766, AZD6244), kinase inhibitors (e.g., sorafenib, regorafenib, lapatinib, sutent, dasatinib, cetuximab BMS-908662, GSK2118436, AMG 706), 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, BAY80-6946, 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), bisphosphonates (e.g., etridonate, clodronate salt, tiludronate, pamidronate, alendronic acid, ibandronate, risedronate, zoledronate), rituximab, cyclophosphamide, doxorubicin, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone.

For tumor therapy, also suitable is the combination of non-drug therapy such as chemotherapy, radiotherapy or phototherapy with the IRAK4 inhibitor of the present invention along with drug therapy, or the supplementation of the IRAK4 inhibitor of the present invention with drug therapy after the completion of non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy.

In addition to the active compounds mentioned above, the IRAK4 inhibitors of the present invention can also be combined with the following active compounds:

Active compounds for the treatment of Alzheimer's disease, for example, acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, 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., entacapone), Dopamine agonists (e.g., ropinrol, pramipexol, bromocriptine), MAO-B (monoaminooxidase-B) inhibitors (e.g., selegiline), anticholinergics (e.g., trihexyphenidyl), and NMDA antagonists (e.g., amantadin); beta-interferon (IFN-β) (e.g., IFNβ-1b, IFNβ-1a, and IFNβ-2b) for the treatment of multiple sclerosis, glatiramer acetate, and dapoxetine. acetate), immunoglobulins, natalizumab, fingolimod, and immunosuppressive drugs such as mitoxantrone, azathioprine, and cyclophosphamide; substances used to treat 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 used to treat osteoarthritis such as nonsteroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, methotrexate and biological agents (eg rituximab, abatacept) for B-cell and T-cell therapy may be mentioned for rheumatoid disorders such as rheumatoid arthritis and juvenile idiopathic arthritis. Neurotrophic substances such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoamine oxidase) inhibitors (e.g. selegiline), interferons and antispasmodics (e.g. gabapentin); active compounds for the treatment of cardiovascular disorders such as beta-blockers (e.g. metoprolol), ACE inhibitors (e.g. benazepril), diuretics (e.g. hydrochlorothiazide), calcium channel blockers (e.g. nifedipine), statins (e.g. simvastatin); antidiabetic drugs such as metformin and glibenclamide, sulfonylureas (e.g. tolbutamide) and insulin therapy for the treatment of diabetes and metabolic syndrome. Active compounds 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, antidiarrheals such as loperamide, or laxatives (bisacodyl). Immunosuppressants used to treat lupus erythematosus, such as glucocorticoids and nonsteroidal anti-inflammatory substances (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide, by way of example and not limitation, 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 disorders such as, for example, calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, ciclosporine, methotrexate, efalizumab.

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

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

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

Suitable dosage forms for oral administration are dosage forms which act according to the prior art and release the compound of the invention quickly and/or in a sustained manner, containing the compound of 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 for controlled release of the compound of 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 inhalable pharmaceutical forms (including powder inhalers, sprays), nasal drops, solutions or sprays, tablets, films/papers or capsules for lingual, 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), milks, pastes, foams, sprinkling powders, implants or stents.

Oral or parenteral administration is preferred, especially oral administration.

The compounds of the invention can be converted into the mentioned administration forms. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients 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. polyvinyl pyrrolidone), 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 scent correctors.

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 appropriate 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 serve to illustrate the present invention. The present 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:

Intermediate 0 shown in Synthesis Scheme 1 can be prepared, for example, from 4-substituted 2-fluoro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzaldehyde in a manner similar to literature and patent methods, or is commercially available. For the preparation, 4-substituted 2-fluoro-5-nitrobenzaldehyde is reacted with hydrazine (J. Med. Chem., 2013, 56, 4343). The resulting 5-nitroindazole (intermediate 0) can be reduced, for example, by hydrogenation with palladium on carbon (US201228984, WO200671940, US2003153596, EP2045253) or transfer hydrogenation (Eur.J.Med.Chem., 2010, 45, 5520) or by reaction with iron (J.Chem.Soc., 1955, 2412) or tin(II) chloride (Bioorg.Med.Chem., 2004, 12, 2115, US201215962) to give the corresponding 5-aminoindazole. Intermediate 1a can be converted to intermediate 1b. The group ^R2 can be introduced in a variety of ways, for example, via alkylation with an alkyl halide (Bioorg. Med. Chem., 2010, 18, 4801) or an alkyl sulfonate or via reductive amination by reaction with an aldehyde (WO2009102498) or a ketone (EP140325). Suitable reducing agents are various hydride donors such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. Alternatively, the aniline nitrogen of intermediate 1a can be first acylated with an acyl halide or a carboxylic anhydride, and then the amide can be reduced with a suitable reducing agent to obtain the corresponding amine, which also gives intermediate 1b. Suitable reducing agents are, for example, lithium aluminum hydride (J. Am. Chem. Soc., 1954, 76, 1384), a complex of borane and dimethyl sulfide (Synthetic Communications, 1991, 21, 1579) or tetrahydrofuran (Org. and Biomol. Chem., 2012, 10, 8692) or sodium bis(2-methoxyethoxy)aluminum hydride (WO200873461).

The aniline nitrogen of intermediates 1a and 1b can be provided with known protecting groups described in the literature (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme, Chapter 8; Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience, Chapter 7), thereby obtaining intermediate 2. A preferred protecting group is a tert-butoxycarbonyl group (BOC protecting group). The BOC protecting group is preferably introduced using di-tert-butyl dicarbonate in the presence of a base (e.g., N,N-diisopropylethylamine or triethylamine).

Intermediate 2 can be reacted with a halogenated carboxylate in the carboxylic acid moiety under basic conditions to give a mixture of the corresponding regioisomeric 1-alkylated and 2-alkylated indazole compounds, such as methyl bromoacetate, ethyl bromoacetate, tert-butyl bromoacetate, benzyl bromoacetate, ethyl 3-bromopropionate, or ethyl 2-bromopropionate (Organic Letters, 2009, 11, 5054; WO200474284; US2009286800; WO200919167; WO201297744; J. Med. Chem., 2007, 50, 3101; Molecules, 2006, 11, 86). In this context, the reaction with N,N-dicyclohexylmethylamine in tetrahydrofuran or N,N-dimethylformamide at 25° C. to 100° C. is preferred (J. Org. Chem. 2006, 71, 5392). Also preferred is the reaction in N,N-dimethylformamide in the presence of potassium carbonate. A mixture of regioisomeric 1-alkylated indazole compounds and 2-alkylated indazole compounds can be separated by column chromatography or preparative HPLC to give the 2-alkylated indazole compound (Intermediate 3).

The conversion of intermediate 3 to intermediate 4 can be carried out under known conditions (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme, Chapter 6; Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience, Chapter 5; WO200919167A1). In this context, hydrolysis with lithium hydroxide or lithium hydroxide monohydrate in a mixture of tetrahydrofuran and water is preferred (J. Med. Chem., 2012, 55, 1318, Bioorg. Med. Chem., 2009, 17, 7113). Optionally, ethanol or methanol may also be added.

Intermediate 4 can react with an amine to obtain the corresponding intermediate 5. In this article, various coupling reagents known in the literature can be used (Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 3-Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiley, Chapter 12-Peptide-Coupling Reagents, 407-442; Chem. Soc. Rev., 2009, 38, 606). Preferably, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride combined with 1-hydroxy-1H-benzotriazole hydrate is used (WO2012107475; Bioorg. Med. Chem. Let., 2008, 18, 2093).

Intermediate 5 obtained in this manner can be converted to intermediate 6. Removal of the protecting group on the aniline nitrogen can be carried out under known reaction conditions (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme, Chapter 8; Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience, Chapter 7). Preferably, the tert-butoxycarbonyl protecting group is removed using trifluoroacetic acid in dichloromethane (Bioorg. Med. Chem. Lett., 2011, 21, 6274; J. Med. Chem., 2008, 51, 1904; WO201353051).

Intermediate 6 can be reacted with a heterocyclic carboxylic acid to give compounds of general formula (I) using coupling reagents known in the literature and mentioned for the preparation of intermediate 5. In this context, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in combination with 1-hydroxy-1H-benzotriazole hydrate is also preferably used (US2006194801).

Synthesis Scheme 1:

(PG means protecting group; ^Rd represents C ₁ -C ₆ -alkyl or benzyl.)

Alternatively, as shown in Synthesis Scheme 1a, Intermediate 5 can also be obtained directly from Intermediate 2. The reagent used is a halogenated carboxamide. The reaction conditions are the same as those for preparing Intermediate 3 from Intermediate 2. Preferably, the reaction with 2-bromoacetamide in the presence of a base, N,N-dicyclohexylmethylamine, is used. The reaction with 2-bromo-1-(morpholin-4-yl)ethanone is particularly preferred.

Synthesis Scheme 1a:

As shown in Synthesis Scheme 2, intermediate 3 can also be first converted to intermediate 7 (J.Am.Chem.Soc., 2009, 131, 3342; EP2522657). If PG represents tert-butoxycarbonyl, trifluoroacetic acid in dichloromethane is preferably used (WO201062171). Intermediate 7 can be reacted with a heterocyclic carboxylic acid to obtain intermediate 8. In this article, as in Synthesis Scheme 1, a coupling reagent is used. The coupling reagent used is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in combination with 1-hydroxy-1H-benzotriazole hydrate.

Intermediate 8 can be hydrolyzed analogously to Synthesis Scheme 1, preferably in a mixture of tetrahydrofuran and water using lithium hydroxide or lithium hydroxide monohydrate. Optionally, ethanol or methanol can also be added.

The intermediate 9 formed in this way can be converted into a compound of the general formula (I). Coupling with an amine can be carried out analogously to synthesis scheme 1 using coupling reagents known from the literature. Preference is given to using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in combination with 1-hydroxy-1H-benzotriazole hydrate.

Synthesis Scheme 2:

(PG means protecting group; ^Rd represents C ₁ -C ₆ -alkyl or benzyl.)

Intermediate 2b can be prepared according to Synthesis Scheme 3. Intermediate 1a is reacted with an excess of di-tert-butyl dicarbonate to give a mixture of intermediates 10 and 11, which can be selectively hydrolyzed at positions 1 and 2, respectively, to give intermediate 2b. The hydrolysis is preferably carried out using sodium carbonate in a mixture of N,N-dimethylformamide and water at 50°C to 100°C for 12-36 hours (Tet. Lett., 2006, 47, 8575).

Synthesis Scheme 3:

Intermediate 8a can be prepared in a multi-step synthetic sequence from intermediate 1a, for example, where R ¹ = Cl, as described in Synthesis Scheme 4. To this end, one nitrogen atom in the indazole ring is first protected, preferably at position 1 (WO200958924). A preferred protecting group is the tert-butyloxycarbonyl group (BOC protecting group). The BOC protecting group is preferably introduced using di-tert-butyl dicarbonate in the presence of a base, such as N,N-diisopropylethylamine or triethylamine.

Intermediate 12 can be acylated with a heterocyclic carboxylic acid under the coupling conditions mentioned above to give intermediate 13. Preferably, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in combination with 1-hydroxy-1H-benzotriazole hydrate is used.

The protecting group on the indazole ring in Intermediate 13 can be removed under reaction conditions known in the literature (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme, Chapter 8; Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience, Chapter 7). Trifluoroacetic acid in dichloromethane is preferably used to remove the BOC protecting group. Intermediate 14 can be converted to a mixture of the corresponding regioisomeric 1-alkylated and 2-alkylated indazole compounds. Separation of the regioisomers affords the desired 2-alkylated indazole derivative (Intermediate 8a) (J. Org. Chem. 2006, 71, 5392). Herein, the same reaction conditions (Synthetic Scheme 1) are used to prepare Intermediate 3 from Intermediate 2. Preferably, N,N-dicyclohexylmethylamine is used in tetrahydrofuran or N,N-dimethylformamide.

Synthesis Scheme 4:

(PG means protecting group; ^Rd represents C ₁ -C ₆ -alkyl or benzyl.)

In some cases, intermediate 14 is also prepared according to Synthesis Scheme 5. Intermediate 1a is regioselectively acylated at the aniline nitrogen using a heterocyclic carboxylic acid. In this case, the coupling reagents mentioned above are used. Preferably, a combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy-1H-benzotriazole hydrate in the presence of triethylamine is used (EP1403255; WO200582890; US2006194801; Bioorg. Med. Chem. Lett., 2007, 17, 3550).

Synthesis Scheme 5:

According to Synthesis Scheme 5-1, intermediate 14a (wherein R ^1c = -CO ₂ Me or -CO ₂ Et, preferably -CO ₂ Me) can be converted into intermediate 14b (wherein R ^1d = -C(CH _{3 ) 2 OH or -C(CH 2 CH 3} ) ₂ OH) by using methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium bromide or ethylmagnesium chloride in a Grignard reaction (Organikum, 19th Edition, _Johann Ambrosius Barth Leipzig _{, pp. 515-520). Reaction with methylmagnesium bromide preferably yields intermediates with R 1d = -C(CH 3 ) 2 OH} ^. _{Intermediates of} formula 14b can then be converted into compounds of the present invention, where R ¹ = -C(CH ₃ ) ₂ OH or -C(CH ₂ CH ₃ ) ₂ OH, by analogy to Synthesis Scheme 4 and then according to Synthesis Scheme 2. Alternatively, preferably, intermediate 14b can also be converted into a compound of formula (I) according to the present invention, wherein R ¹ = -C(CH ₃ ) ₂ OH or -C(CH ₂ CH ₃ ) ₂ OH, by reaction with 2-chloroacetamide or 2-bromoacetamide. Here, the same reaction conditions as in Synthesis Scheme 1a can be used. Preferably, N,N-dicyclohexylmethylamine is used in tetrahydrofuran or N,N-dimethylformamide. Particularly preferred is 2-bromo-1-(morpholin-4-yl)ethanone.

Synthesis Scheme 5-1:

(R ^1c represents –CO ₂ Me or –CO ₂ Et

R ^1d represents a methyl group or an ethyl group)

A subset of the compounds of the present invention can be prepared as shown in Scheme 6. The starting material of general formula (Ia) is reacted with an organometallic compound that transfers the group R ^1b in the presence of a palladium catalyst. The radical R ^1b represents C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, heterocycloalkyl-C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, which may be optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of protected hydroxy, halogen, cyano, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, protected NH ₂ , protected NHR ^a or N(R ^a )R ^b . A suitable reaction is a known coupling reaction: at a temperature of 40-200° C., using a base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, potassium hexamethyldisilazane, tripotassium phosphate, cesium carbonate), in a solvent (e.g., N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether), in the presence of a palladium compound (e.g., palladium(II) acetate, tetrakis(triphenylphosphine)palladium, allyl chloride(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)palladium, tris(dibenzylidene)imidazol-2-ylidene)palladium, The reaction was carried out using an organomagnesium compound (Kumada et al., 2004) in the presence of a ligand (e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 1,1'-bis(di-o-tolylphosphino)ferrocene). reaction: J. Organomet. Chem., 2002, 653, 288; Handbook of Organopalladium Chemistry for Organic Synthesis, 2002, 1, 335; Top. Curr. Chem., 2002, 219, 1), organoboron compounds (Suzuki reaction: Pure Appl. Chem., 1985, 57, 1749; Chem. Rev., 1995, 95, 2457; Advances in Metal-Organic Chemistry, 1998, 6, 187; Angew. Chem., Int. Ed. Engl., 2004, 43, 2201, Top. Curr. Chem., 2002, Vol. 219, 248), organotin compounds (Stille reaction: Angew. Chem., 1986, 98, 504; Synthesis, 1992, 803; Org. React., 1997, 50, 1; Angew. Chem., Int. Ed. Engl., 2004, 43, 4704; J. Organomet. Chem., 2002, 653, 50) or organic zinc compounds (Negishi reaction:Acc.Chem.Res.,1982,15,340;Metal-Catalyzed Cross-couplingReactions,F.Diedrich,PJStang,Wiley-VCH,1998,1;Aust.J.Chem.2004,57,107;Handbook of Organopalladium Chemistry for Organic Synthesis, E.-I. Negishi, Y. Dumond, 2002, Vol. 1, 767). The temperature depends in particular on the solvent. As an alternative to the palladium compounds mentioned above, other palladium compounds known as pre-catalysts (e.g., chloro[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) or (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride) can also be used. In the reaction, preference is given to using tetrakis(triphenylphosphine)palladium, palladium(II) acetate, and 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl or 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene or allylchloro(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)palladium. Tetrakis(triphenylphosphine)palladium is particularly preferred. In this context, the groups ^Ra and ^Rb may be defined as described for the general formula (I). In the case where the electrophile carries a protected hydroxyl function or a protected _NH2 or ^NHRa , this protecting group can be removed again in an additional synthesis step by conventional literature methods (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme; Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience).

When R ^1b represents cyanide, the reaction of the starting material of general formula (Ia) can be carried out at a temperature of 40-200°C in the presence of a palladium compound as described above and in the presence of zinc cyanide in a solvent as described above. In this context, the reaction mixture can be heated thermally or in a microwave. In this context, the use of tetrakis(triphenylphosphine)palladium in N,N-dimethylformamide at a temperature of 150°C in a microwave is particularly preferred.

Furthermore, the starting materials of the general formula (Ia) can also be reacted with primary or secondary amines or with alkoxides (Buchwald-Hartwig reaction: Chemtracts: Inorg. Chem., 1996, 8, 1; Chem. Org. Chem. 1997, 1, 287; Synlett 1997, 329; Angew. Chem., Int. Ed. Engl., 1998, 37, 2046; Pure Appl. Chem. 1999, 71, 1425; Top. Curr. Chem. 2002, 219, 131), which allows to obtain compounds of the general formula (Ib) in which R ^1b ═NHR ^a , NR ^a R ^b , NHC(═O)R ^a or OR ^a . The reaction is carried out under the following conditions: at a temperature of 40-200° C., using a base (e.g., sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate) in a solvent (e.g., N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether) in the presence of a palladium compound (e.g., palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(II)). )), ligands (e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl, 1,1'-bis(di-o-tolylphosphino)ferrocene). The temperature depends, among other things, on the solvent. As an alternative to the palladium compounds mentioned above, other palladium compounds known as precatalysts (e.g., chloro[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) or (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride) may also be used. In this context, the reaction preferably uses the latter-mentioned precatalyst.

Synthesis Scheme 6:

(R ^1a represents chlorine, bromine, iodine, [(trifluoromethyl)sulfonyl]oxy or [(nonafluorobutyl)sulfonyl]oxy.

R ^1b represents a) C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, heterocycloalkyl-C ₁ -C ₄ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, aryl, 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, which may optionally be identically or differently mono- or polysubstituted by substituents selected from the group consisting of protected hydroxy, halogen, cyano, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, protected NH ₂ , protected NHR ^a or N(R ^a )R ^b ,

b) cyanide, c) NHR ^a , NR ^a R ^b , NHC(═O)R ^a or OR ^a .

A subset of the compounds of the present invention can be prepared by reacting starting materials of general formula (Ic) with an electrophilic reagent Re- ^X , such as an alkyl halide, alkyl sulfonate, aryl halide, aryl sulfonate, heteroaryl halide or heteroaryl sulfonate, as _shown in Synthesis Scheme 7. X has the meaning of chlorine, bromine, _iodine , O(S=O) _2CH3 , _{O(S=O)2C6H4CH3 or O} (S=O _{)2CF3 ,} wherein X is preferably chlorine, bromine or iodine and particularly preferably bromine.

R ^e represents C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, heterocycloalkyl-C ₁ -C ₄ -alkyl, C 2 -C _{6 -alkenyl, C 2 -C 6 -alkynyl , aryl} , 5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, which may be optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxy (optionally protected), halogen, cyano, C (= O) OR ^a , S (= O) ₂ -C ₁ -C ₆ -alkyl, protected NH ₂ , protected NHR ^a or NR ^a R ^b . In this context, the radicals R ^a and R ^b may be defined as described for the general formula (I). In the case that the electrophile carries a protected hydroxyl function or a protected NH ₂ or NHR ^a , this protecting group can be removed again in an additional synthetic step by customary literature methods (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme; Greene's Protective Groups in Organic Synthesis, Peter G. M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience). If R ^e -X means an alkyl halide or an alkyl sulfonate, a suitable base such as, for example, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, potassium hexamethyldisilazane, tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate ( WO2003101379 A2 ; Bioor. Med. Chem., 2008, 16, 1966 ; J. Med. Chem., 2012, 55, 7141 ) can be used for the alkylation. In addition, other additives (e.g., sodium iodide, potassium iodide, cesium iodide) can be used. The reaction with activated aryl halides, aryl sulfonates, heteroaryl halides or heteroaryl sulfonates (electron withdrawing groups or heteroatoms in the ortho and/or para positions of the halide or sulfonate) can be carried out by electrophilic aromatic substitution on the activated aryl halide, aryl sulfonate, heteroaryl halide or heteroaryl sulfonate, and a suitable base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, potassium hexamethyldisilazane potassium salt, tripotassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate) can also be used in the reaction (WO200795124 A2, EP2103620 A1). In addition, the arylation or heteroarylation of the starting material of the general formula (Ic) in Synthesis Scheme 7 can be carried out by reacting with an aryl halide, an aryl sulfonate, a heteroaryl halide or a heteroaryl sulfonate under the following conditions: at a temperature of 40-200° C., in a solvent (e.g., N,N-dimethylformamide, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether), in the presence of a suitable base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, potassium hexamethyldisilazane potassium salt). , tripotassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate) and ligands (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, 1,1'-bis(diphenylphosphino)ferrocene, 1,1'-bis(di-o-tolylphosphino)ferrocene, 1,3-di-tert-butyl-2-chloro-1,3,2-diazaphospholidine, 2'-(dicyclohexylphosphino)-N,N 1-dimethylbenzyl-2-amine) in the presence of a copper-based transition metal catalyst known in the literature (e.g., copper (I) iodide, copper (I) oxide, copper (II) acetate) (Russ. Chem. Rev., 1974, 43, 1443; Tetrahedron, 2000, 56, 5054; Synlett, 2003, 2428; Angew. Chem., Int. Ed. Engl., 2003, 42, 5 400; Angew. Chem., Int. Ed. Engl., 2004, 43, 1043) or palladium (e.g., palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0)) (Acc. Chem. Res., 1998, 31, 852; Angew. Chem., Int. Ed. Engl., 1998, 37, 2046; Top. Cur. Chem., 2002, 219, 131). Preferably, 6-hydroxyindazole is reacted with an alkyl halide using a base of potassium carbonate and a solvent of N,N-dimethylformamide. The reaction is preferably carried out in a microwave at 70-150°C for 1-24 hours.

Synthesis Scheme 7

(R ^e represents C ₁ -C ₆ -alkyl, C ₃ -C ₈ -cycloalkyl, heterocycloalkyl, C ₃ -C ₈ -cycloalkyl-C ₁ -C ₄ -alkyl, heterocycloalkyl-C ₁ -C ₄ -alkyl, C 2 -C _{6 -alkenyl, C 2 -C 6} -alkynyl, aryl, _5- to 10-membered heteroaryl, aryl-C ₁ -C ₄ -alkyl or 5- or 6-membered heteroaryl-C ₁ -C ₄ -alkyl, which may be optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxy (optionally protected), halogen, cyano, C(═O)OR ^a , S(═O) ₂ -C ₁ -C ₆ -alkyl, protected NH ₂ , protected NHR ^a or NR ^a R ^b .)

Pyridinecarboxylic acids (intermediates 19), used as starting materials for synthesizing a subset of the compounds of the present invention, are commercially available or can be prepared according to synthetic scheme 8 by routes known in the literature. Some intermediates 19 can be prepared from carboxylic acid esters (intermediates 17) by hydrolysis or, in the case of tert-butyl esters, by reaction with an acid such as, for example, hydrogen chloride or trifluoroacetic acid. Intermediates 19 can optionally be prepared as salts (e.g., as potassium salts). Intermediates 17 are commercially available, can be prepared by routes known in the literature, or can be obtained from intermediates 16 (which carry chlorine, bromine, or iodine as X ¹ ) by reaction in a carbon monoxide atmosphere, optionally under superatmospheric pressure, in the presence of a phosphine ligand (e.g., 1,3-bis(diphenylphosphino)propane), a palladium complex (e.g., palladium(II) acetate), and a base (e.g., triethylamine), with the addition of ethanol or methanol, in a solvent (e.g., dimethyl sulfoxide).

In this context, the radical R ³ represents cyano, substituted or unsubstituted C ₁ -C ₆ -alkyl, substituted or unsubstituted C ₁ -C ₆ -alkoxy, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl, heterocycloalkyl, C ₅ -C ₁₁ -spirocycloalkyl, substituted or unsubstituted C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl, substituted or unsubstituted aryl, 5-membered to 10-membered heteroaryl, NH ₂ , NHR ^a , N(R ^a )R ^b or N(H)C(═O)R ^a .

In the specific case where R ³ represents substituted or unsubstituted C ₁ -C ₆ -alkoxy, NH ₂ , NHR ^a or N( ^Ra )R ^b , R ³ can be introduced by heating the corresponding dihalogenated intermediate 15 (wherein X ¹ and X ² independently represent chlorine, bromine or iodine) with an alcohol or an amine to give intermediate 16.

If R ³ represents a substituted or unsubstituted C ₁ -C ₆ -alkyl group ( Eur. J. of Org. Chem., 2002, 327 ), a substituted or unsubstituted C ₃ -C ₆ -cycloalkyl group, a heterocycloalkyl group, a C ₅ -C ₁₁ -spirocycloalkyl group, or a substituted or unsubstituted C ₃ -C ₆ -cycloalkyl-C ₁ -C ₄ -alkyl group, R ³ can be introduced by reacting the intermediate 15 with a suitable organometallic compound. Suitable for this purpose are organolithium compounds ( Green Chemistry, 2011, 13, 1110 ), organomagnesium compounds, or organocopper compounds ( Angew. Chem., 2013, 125, 6397 ). In the case of amino- or hydroxy-substituted radicals R ^<3> , the functional groups in the organometallic compound carry protecting groups which are known in the literature and which are suitable according to the opinion of the person skilled in the art (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme; Greene's Protective Groups in Organic Synthesis, Peter G. M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience). These protecting groups can be removed again in additional synthetic steps by customary literature methods (Protecting Groups, Philip J. Kocienski, 3rd Revised Edition (9th February 2005), Thieme; Greene's Protective Groups in Organic Synthesis, Peter G. M. Wuts, Theodora W. Greene, 4th Edition (8th December 2006), Wiley-Interscience). Alternatively, if R ³ is a substituted or unsubstituted aryl or 5- to 10-membered heteroaryl group, the group R ³ can also be introduced via palladium-catalyzed Suzuki coupling (Pure Appl. Chem., 1985, 57, 1749; Chem. Rev., 1995, 95, 2457; Advances in Metal-Organic Chemistry, 1998, 6, 187; Angew. Chem., Int. Ed. Engl., 2004, 43, 2201, Top. Curr. Chem., 2002, Vol. 219, 248). In this context, R ³ is introduced via the corresponding organoboron compound under the following conditions: at a temperature of 25-200 ° C, in the presence of a palladium compound (such as palladium acetate (II), tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium), a ligand (such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9,9-dimethyl In the presence of xanthene, 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, and 1,1′-bis(di-o-tolylphosphino)ferrocene, a base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, sodium hydroxide) is used in a solvent (e.g., N,N-dimethylformamide, acetonitrile, toluene, xylene, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, water), and optionally lithium chloride is added. Tetrakis(triphenylphosphine)palladium is preferably used.

Alternatively, intermediate 17 can also be prepared from intermediate 18. To introduce the group R ³ , the above-mentioned Suzuki reaction using an appropriate organoboron compound is employed.

Synthesis Scheme 8:

( ^X1 represents chlorine, bromine or iodine.

X ² represents chlorine, bromine or iodine.

R ^d represents C ₁ -C ₆ -alkyl or benzyl.

R ³ , R ⁴ and m have the same meanings as described in the general formula (I).

According to Synthesis Scheme 9, intermediate 20, which can be prepared according to Synthesis Scheme 2, can be reacted with primary and secondary alkylzinc reagents in the presence of a palladium catalyst in a Negishi reaction (Acc. Chem. Res., 1982, 15, 340; Metal-Catalyzed Cross-coupling Reactions, F. Diedrich, PJ Stang, Wiley-VCH, 1998, 1; Aust. J. Chem. 2004, 57, 107; Handbook of Organopalladium Chemistry for Organic Synthesis, E.-I. Negishi, Y. Dumond, 2002, Vol. 1, 767). This allows the preparation of a subset of compounds of the present invention (Ie) wherein ^Rg = primary _C1 - _C6 -alkyl or secondary _C1 - _C6 -alkyl. Preferably, the reaction is with diethylzinc bromide or 2-methylpropylzinc bromide.

Synthesis Scheme 9

( ^Rg represents a primary _C1 - _C6 -alkyl group or a secondary _C1 - _C6 -alkyl group)

Other intermediates can be obtained according to Synthetic Scheme 10: Intermediate 9 can be reacted in an amide coupling as described in Synthetic Scheme 1 to provide intermediate 21. Preferably, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride combined with 1-hydroxy-1H-benzotriazole hydrate is used. Intermediate 21 can then be converted to intermediate 22 by reaction with trifluoroacetic acid, which can be reacted in an amide coupling reaction similar to the method described in Synthetic Scheme 1 to provide exemplary compounds.

Synthesis Scheme 10:

Intermediates of type 2b can be obtained according to Synthetic Scheme 11: Intermediate 12b is reacted with benzyl chloroformate and N-ethyl-N-isopropylpropane-2-amine in THF to give intermediate 23. Reaction with trifluoroacetic acid in dichloromethane subsequently gives intermediate 2b, which is further reacted according to Synthetic Scheme 1 to give the compounds of the present invention.

Synthesis Scheme 11:

abbreviation

method

Analytical HPLC method:

Method A1: UPLC (ACN-HCOOH):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; mobile phase A: water + 0.1 vol% formic acid (99%), mobile phase B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate: 0.8 ml/min; temperature: 60°C; injection volume: 2 μl; DAD scan: 210-400 nm; ELSD.

Method A2: UPLC (ACN-NH3):

Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 50×2.1 mm; mobile phase A: water + 0.2 vol% ammonia (32%), mobile phase B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate: 0.8 ml/min; temperature: 60°C; injection volume: 2 μl; DAD scan: 210-400 nm; ELSD.

Method A3: (LC-MS)

Instrument: Agilent 1290 Infinity LC; Column: Acquity UPLC BEH C18 1.7 50×2.1 mm; Mobile phase A: water + 0.05 vol% formic acid, Mobile phase B: acetonitrile + 0.05 vol% formic acid; Gradient: 0-1.7 min 2-90% B, 1.7-2.0 min 90% B; Flow rate: 1.2 ml/min; Temperature: 60°C; Injection volume: 2 μl; DAD scan: 190-390 nm; MS: Agilent TOF 6230.

Method A4: (LC-MS)

Instrument: Waters Acquity; Column: Kinetex (Phenomenex), 50×2 mm; Mobile phase A: water + 0.05 vol% formic acid, Mobile phase B: acetonitrile + 0.05 vol% formic acid; Gradient: 0-1.9 min 1-99% B, 1.9-2.1 min 99% B; Flow rate: 1.5 ml/min; Temperature: 60°C; Injection volume: 0.5 μl; DAD scan: 200-400 nm.

Preparative HPLC method:

Method P1: System: Waters automated purification system: pump 2545, sample manager 2767, CFO, DAD 2996, ELSD 2424, SQD; column: XBridge C18 5μm 100×30mm; mobile phase: A: water + 0.1% by volume formic acid, mobile phase 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 P2: System: Waters automated purification system: pump 254, sample manager 2767, CFO, DAD 2996, ELSD2424, SQD 3100; column: XBridge C18 5μm 100×30mm; mobile phase: A: water + 0.2% by volume ammonia (32%), mobile phase B: methanol; gradient: 0-8min 30-70% B; flow rate: 50ml/min; temperature: room temperature; detection: DAD scanning range 210–400nm; MS ESI+; ESI-, scanning range 160-1000m/z; ELSD.

Method P3: System: Labomatic, Pump: HD-5000, Fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; Column: XBridge C18 5 μm 100×30 mm; Mobile phase A: Water + 0.2% by volume of ammonia (25%), Mobile phase B: Acetonitrile; Gradient: 0-1 min 15% B, 15-55% B from 1-6.3 min, 55-100% B from 6.3-6.4 min, 100% B from 6.4-7.4 min; Flow rate: 60 ml/min; Temperature: Room temperature; Solution: Maximum 250 mg/2 ml DMSO; Injection volume: 2×2 ml; Detection: UV 218 nm; Software: SCPA PrepCon5.

Method P4: System: Agilent: Prep 1200, 2×Prep pumps, DLA, MWD, Prep FC; Column: Chiralpak IA 5 μm 250×20 mm; Mobile phase A: methanol, Mobile phase B: ethanol; Gradient: isocratic 50% B; Flow rate: 15 ml/min; Temperature: room temperature; Detection: UV 254 nm

Method P5: System: Labomatic, Pump: HD-5000, Fraction collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1S; Column: Chromatorex RP C18 10 μm 125×30 mm, Mobile phase: A: water + 0.1% by volume formic acid, Mobile phase B: acetonitrile; Gradient: 0-15 min 65-100% B; Flow rate: 60 ml/min; Temperature: Room temperature; Solution: Maximum 250 mg/2 ml DMSO; Injection volume: 2×2 ml; Detection: UV 254 nm; Software: SCPA PrepCon5.

microwave

CEM Discover S-Class; Autosampler: CEM Explorer; Software: CEM Synergy; Method: Dynamic heating mode, 300 W, 18 bar maximum.

intermediates

2-Fluoro-5-nitro-4-(trifluoromethoxy)benzaldehyde

20.9 g (100.4 mmol) of 2-fluoro-4-(trifluoromethoxy)benzaldehyde were dissolved in 100 ml of sulfuric acid (w=96%) and cooled to -15°C in a three-necked flask equipped with a mechanical stirrer, dropping funnel, and internal thermometer. Nitrating acid (28 ml of sulfuric acid (w=96%) in 14 ml of nitric acid (w=65%)) which had been prepared and cooled previously was added dropwise to this solution over 60 minutes. During the addition, the internal temperature fluctuated between -15°C and -12°C. After the addition was complete, stirring was continued for a further hour (internal temperature -13°C). The reaction mixture was poured into ice and extracted three times with 150 ml of ethyl acetate each time. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. This gave 25.4 g (100% of theory) of the title compound.

¹ H NMR (400MHz, CHLOROFORM-d) δ = 7.34 (dd, 1H), 8.57 (d, 1H), 10.34 (s, 1H).

Intermediate 0-2

5-Nitro-6-(trifluoromethoxy)-1H-indazole

First, 25.4 g (100.4 mmol) of 2-fluoro-5-nitro-4-(trifluoromethoxy)benzaldehyde were added to 200 ml of anhydrous ethanol, and 25 ml (513.6 mmol) of hydrazine hydrate were added. The color of the solution deepened. The reaction mixture was heated under reflux for 2 h. The reaction mixture was then added to 1.4 L of water and stirred vigorously for 10 minutes. The resulting precipitate was filtered off with suction and washed three times with 40 ml of water each time. The resulting solid was dried overnight in a vacuum drying oven at +50°C. This gave 19.4 g (78% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.03 min

MS (ESIpos): m/z＝248 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6) δ = 7.86 (s, 1H), 8.46 (s, 1H), 8.82 (s, 1H), 13.87 (br.s., 1H).

Intermediate 0-3

6-(Benzyloxy)-5-nitro-1H-indazole

First, 20.0 g (111.6 mmol) of 5-nitro-1H-indazole-6-ol (CAS No. 1082041-56-2) was added to 750 ml of tetrahydrofuran, and 13.9 ml (134.0 mmol) of benzyl alcohol and 35.1 g (134.0 mmol) of triphenylphosphine were added. The solution was cooled to 0°C and 26.03 ml (134.0 mmol) of diisopropyl azodicarboxylate were added. The reaction mixture was stirred at 0°C for 1 hour and then at 25°C for 24 hours. Water was then added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and concentrated. The residue was dissolved in dichloromethane, HM-N (Biotage) was added, and the residue was adsorbed onto Isolute during the concentration process. Isolute was applied to a column (750 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 200 ml/min; gradient: isocratic 88:12 (1 CV), 88:12->20:80 (10 CV), isocratic 20:80 (2 CV)). The combined product fractions were concentrated and dried. 18.908 g (63% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.09 min

MS (ESIpos): m/z＝270 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6) δ = 5.35 (s, 2H), 7.25-7.57 (m, 6H), 8.20 (s, 1H), 8.45 (s, 1H), 13.38 (br.s., 1H).

Intermediate 0-4

6-Ethoxy-5-nitro-1H-indazole

First, 100 mg (0.56 mmol) of 5-nitro-1H-indazole-6-ol (CAS No. 1082041-56-2) was added to 668 μl of N,N-dimethylformamide, and 93 mg (0.67 mmol) of potassium carbonate and 54 μl (0.67 mmol) of iodoethane were added. The solution was heated at 60 ° C for 1 h in a microwave. Water was then added and the reaction mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was dissolved in dichloromethane, HM-N (Biotage) was added, and the residue was adsorbed onto Isolute during the concentration process. Isolute was applied to a column (25 g; KP-Sil) pre-equilibrated with hexane and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 25 ml/min; gradient: isocratic 88:12 (1 CV), 88:12->0:100 (10 CV), isocratic 0:100 (2 CV)). The combined product fractions were concentrated and dried. 89 mg (77% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t = 0.89 min

MS (ESIpos): m/z＝208 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6) δ = 1.37 (t, 3H), 4.23 (q, 2H), 7.19 (s, 1H), 8.17 (s, 1H), 8.40 (s, 1H), 13.31 (br.s., 1H).

Intermediate 0-5

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

4.60 g (26.1 mmol) of methyl 1H-indazole-6-carboxylate were dissolved in 120 ml of sulfuric acid (w=96%) and cooled to -15°C in a three-necked flask equipped with a mechanical stirrer, dropping funnel, and internal thermometer. Nitrating acid (9.2 ml of sulfuric acid (w=96%) in 4 ml of nitric acid (w=65%)) which had been prepared and cooled beforehand was added dropwise to this solution over a period of 15 minutes. During the addition, the internal temperature fluctuated between -15°C and -12°C. After the addition was complete, stirring was continued for a further hour (internal temperature -5°C). The reaction mixture was poured into ice, and the resulting precipitate was filtered off with suction, washed with water, and dried under reduced pressure in a drying cabinet at 50°C. This gave 5.49 g (91% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.21 min

MS (ESIpos): m/z = 471 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 3.85 (s, 3H) 6.01 (s, 2H) 6.98 (s, 1H) 7.79-7.91 (m, 1H) 7.99 (s, 1H) 12.84 (br.s., 1H).

Intermediate 1-1

6-(Trifluoromethoxy)-1H-indazol-5-amine

10.0 g (40.5 mmol) of 5-nitro-6-(trifluoromethoxy)-1H-indazole (Intermediate 0-2) was dissolved in 400 ml of methanol. The solution was then degassed and flushed with nitrogen (this process was repeated twice). 2.48 g (2.0 mmol) of palladium on activated carbon were added. The flask was evacuated and flushed with hydrogen. The reaction mixture was hydrogenated under standard hydrogen pressure at room temperature for 5 hours. The reaction mixture was filtered through a PTFE filter with Celite and concentrated. This gave 7.2 g (74% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.75 min

MS (ESIpos): m/z＝218 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6) δ = 4.91 (s, 2H), 7.04 (s, 1H), 7.32 (s, 1H), 7.83 (s, 1H), 12.72 (br.s., 1H).

Intermediate 1-2

5-Amino-1H-indazol-6-ol

Analogously to Intermediate 1-1, 6.5 g (36.3 mmol) of 5-nitro-1H-indazol-6-ol (CAS No. 1082041-56-2) were dissolved in 1.5 L of methanol and hydrogenated with 193 mg (1.8 mmol) of palladium on activated carbon at standard hydrogen pressure at 25° C. for 5 h. This gave 5.28 g (98% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.26 min

MS (ESIpos): m/z＝150(M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 4.37 (br.s., 2H) 6.71-6.78 (m, 2H) 7.59 (s, 1H) 12.17 (br.s., 1H).

Intermediates 1-3

6-(Benzyloxy)-1H-indazol-5-amine

18.5 g (68.7 mmol) of 6-(benzyloxy)-5-nitro-1H-indazole (Intermediate 0-3) was dissolved in 500 ml of ethanol and first added to a 1 L three-necked flask with a mechanical stirrer and a reflux condenser, followed by 100 ml of water. 19.2 g (343.5 mmol) of iron powder and 1.84 g (34.35 mmol) of ammonium chloride were subsequently added. The brown suspension was heated under reflux for 4 h. The reaction mixture was cooled to 25° C. in a water bath and filtered through Celite (clear filtrate). The filter cake was washed with ethanol. The filtrate was concentrated until approximately 200 ml of solvent remained. The reaction mixture was added to 2 L of water. The suspension was cooled and the resulting precipitate was then filtered off with suction. The filter cake was washed twice with water (150 ml each) and twice with ether (100 ml each). The precipitate was dried in a vacuum drying cabinet at 50° C. for 5 h and then hydrogenated for a further 5 h at 25° C. using 193 mg (1.81 mmol) of palladium on activated carbon under standard hydrogen pressure. This gave 15.28 g (92% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.66 min

MS (ESIpos): m/z＝240 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 4.54 (s, 2H), 5.19 (s, 2H), 6.84 (s, 1H), 6.91 (s, 1H),7.22-7.45(m,3H),7.48-7.57(m,2H),7.66(s,1H),12.43(br.s.,1H).

Intermediates 1-4

6-Isopropoxy-1H-indazol-5-amine

10 g (45.2 mmol) of 6-isopropoxy-5-nitro-1H-indazole (CAS No. 1082041-56-2) was dissolved in 200 ml of ethanol and hydrogenated with 1.20 g (1.13 mmol) of palladium on activated carbon at 25° C. under standard hydrogen pressure for 24 h. The reaction mixture was filtered through Celite, the filter cake washed with ethanol, and the filtrate concentrated. The residue was incipiently dissolved in a small amount of ethanol in an ultrasonic bath. Ether was added and the residue was further digested in an ultrasonic bath. The solid was filtered off with suction and washed with small amounts of ether and hexane to give 4.69 g (54%) of the product. The filtrate was concentrated and applied to a Biotage SNAP column (100 g; KP-Sil) pre-equilibrated with hexane. Chromatography was performed using a flash purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient: 90:10 -> 35:65 (9.2 CV), isocratic 35:65 (1 CV)). The combined product fractions were concentrated, and the residue was then digested with a mixture of hexane and dichloromethane (2:1) in an ultrasonic bath. The solid formed was filtered off. This gave a further 2.36 g (27% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.75 min

MS (ESIpos): m/z＝192(M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.31 (s, 3H), 1.33 (s, 3H), 4.43 (s, 2H), 4.57-4.68 (m, 1H), 6.81 (s, 1H), 6.83 (s, 1H), 7.64 (s, 1H), 12.34 (br.s., 1H).

Intermediates 1-5

6-Ethoxy-1H-indazol-5-amine

Analogously to Intermediate 1-1, 65 mg (0.31 mmol) of 6-ethoxy-5-nitro-1H-indazole (Intermediate 0-4) were dissolved in 4.1 ml of methanol and hydrogenated with 33 mg (0.03 mmol) of palladium on activated carbon under standard hydrogen pressure at 25° C. for 5 h. This gave 54 mg (97% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.64 min

MS (ESIpos): m/z＝178 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.40 (t, 3H), 4.07 (q, 2H), 4.47 (br.s., 2H), 6.81 (s, 2H), 7.65 (s, 1H), 12.39 (br.s., 1H).

Intermediates 1-6

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

Analogously to Intermediate 1-1, 5.48 g (24.8 mmol) of methyl 5-nitro-1H-indazole 6-carboxylate (Intermediate 0-9) were dissolved in 293 ml of methanol and hydrogenated with 1.32 g (1.24 mmol) of palladium on activated carbon under standard hydrogen pressure at 25° C. for 3 h. This gave 4.52 g (91% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.75 min

MS (ESIpos): m/z = 222 (M+H ⁾

¹ H NMR (500MHz, DMSO-d6): δ = 3.85 (s, 3H), 6.05 (br.s., 2H), 6.99 (d, 1H), 7.85 (d, 1H), 8.00 (s, 1H), 12.83 (br.s., 1H).

Intermediate 2-1

tert-Butyl (6-methyl-1H-indazol-5-yl)carbamate

10.3 g (70.0 mmol) of 6-methyl-1H-indazol-5-amine (CAS No: 81115-45-9) was suspended in 150 ml of tetrahydrofuran, 13.4 ml (80.0 mmol) of N,N-diisopropylethylamine was added, and the mixture was cooled to 0°C. After 5.52 g (25.3 mmol) of di-tert-butyl dicarbonate was added at 0°C, the mixture was stirred at 25°C for 18 hours. The mixture was concentrated to obtain 17.6 g of crude product, which was used without purification.

UPLC-MS (Method A1): R _t =1.01min

MS (ESIpos): m/z=248(M+H) ⁺ .

Intermediate 2-2

tert-Butyl (6-methoxy-1H-indazol-5-yl)carbamate

4.0 g (24.5 mmol) of 6-methoxy-1H-indazol-5-amine (CAS No. 749223-61-8) were dissolved in 30 ml of tetrahydrofuran, and 5.35 g (24.5 mmol) of di-tert-butyl dicarbonate were added. The reaction mixture was stirred at 25° C. for 18 h. The mixture was then concentrated and the residue was suspended in 20 ml of dichloromethane. 200 ml of hexane were added and the resulting suspension was stirred for 25 minutes while cooling in an ice bath. The precipitate was filtered off with suction, washed twice with 25 ml of hexane, and dried. This gave 4.83 g (75% of theory) of the title compound.

UPLC-MS (Method A2): R _t =1.08 min

MS (ESIpos): m/z＝264 (M+H) ⁺

¹ H NMR (400MHz, CHLOROFORM-d) δ = 1.56 (s, 9H), 3.95 (s, 3H), 6.88 (s, 1H), 7.12 (br.s., 1H), 7.94 (d, 1H), 8.40 (br.s., 1H).

Intermediate 2-3

tert-Butyl [6-(trifluoromethoxy)-1H-indazol-5-yl]carbamate

5.0 g (23.0 mmol) of 6-(trifluoromethoxy)-1H-indazol-5-amine (Intermediate 1-1) was suspended in 100 ml of tetrahydrofuran, 4.81 ml (27.6 mmol) of N,N-diisopropylethylamine was added, and the mixture was cooled to 0°C. 5.52 g (25.3 mmol) of di-tert-butyl dicarbonate was added at 0°C, and the mixture was stirred at 25°C for 18 h. 3.52 g (16.1 mmol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at 25°C for a further 24 h. The reaction mixture was heated under reflux for a further 24 h. The reaction mixture was then concentrated, dissolved in ethyl acetate, and washed with 0.5 M hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The combined organic phases were dried over sodium sulfate, filtered, and the solution concentrated. The residue was dissolved in dichloromethane, and HM-N (Biotage) was added. During the concentration process, the residue was adsorbed onto Isolute. Isolute was applied to a Biotage SNAP column (340 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient: isocratic 90:10 (3CV), 90:10->80:20 (2CV), isocratic 80:20 (7CV), 80:20->75:25 (1CV), isocratic 75:25 (7CV)). The combined product fractions were concentrated and the brown solid was dried under reduced pressure. 3.48 g (48% of theory) of the title compound were obtained.

UPLC-MS (Method A2): R _t =1.15 min

MS (ESIpos): m/z＝318 (M+H) ⁺

1H NMR (300MHz, DMSO-d6) δ = 1.44 (s, 9H), 7.51 (s, 1H), 7.83 (s, 1H), 8.11 (s, 1H), 8.80 (s, 1H).

Intermediates 2-4

tert-Butyl (6-hydroxy-1H-indazol-5-yl)carbamate

8.05g (36.8mmol) of di-tert-butyl dicarbonate are suspended in 125ml of tetrahydrofuran, and 5.0g (33.5mmol) of 5-amino-1H-indazole-6-ol (intermediate 1-2) are added in small amounts each time under stirring. The reaction mixture is stirred at 25°C for 24h. The reaction mixture is subsequently concentrated, the residue is dissolved in methanol, and 2ml of 1M sodium hydroxide solution and 2ml of water are added. The mixture is stirred for another 30min, and then methanol is distilled off. 1M hydrochloric acid is added to the residue until pH 7 is reached. The mixture is then extracted with dichloromethane, and the combined organic phases are dried over sodium sulfate, filtered and concentrated. Obtain 7.50g (90% of theoretical value) of the title compound.

UPLC-MS (Method A2): R _t = 0.95 min

MS (ESIpos): m/z＝250 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 1.47 (s, 9H) 6.88 (s, 1H) 7.66 (s, 1H) 7.82 (s, 1H) 7.91 (s, 1H) 10.19 (br.s., 1H) 12.50 (s, 1H).

Intermediates 2-5

tert-Butyl (6-fluoro-1H-indazol-5-yl)carbamate

Analogously to Intermediate 2-2, 4.96 g (32.8 mmol) of 6-fluoro-1H-indazol-5-amine (CAS No.: 709046-14-0), 7.16 g (32.8 mmol) of di-tert-butyl dicarbonate, and 6.28 ml (36 mmol) of N,N-diisopropylethylamine were dissolved in 51 ml of tetrahydrofuran and stirred at 25° C. for 20 h. This gave 5.72 g (69% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.01min

MS (ESIpos): m/z＝252(M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.45 (s, 9H), 7.35 (d, 1H), 7.81 (m, 1H), 8.03 (s, 1H), 8.80 (s, 1H), 13.08 (s, 1H).

Intermediates 2-6

tert-Butyl (6-bromo-1H-indazol-5-yl)carbamate

A mixture of 7.05 g (17.1 mmol) of tert-butyl 6-bromo-5-[(tert-butoxycarbonyl)amino]-1H-indazole-1-carboxylate and tert-butyl 6-bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazole-2-carboxylate (Intermediates 10 and 11) was dissolved in 141 ml of dimethylformamide, and 2.17 g (20.5 mmol) of sodium carbonate dissolved in 71 ml of water were added. The reaction mixture was heated at 85° C. for 24 h. Dichloromethane was added, and the reaction mixture was washed with 0.5 M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate, and concentrated. The product was dried under reduced pressure. 5.35 g (98% of theory) of product were obtained.

UPLC-MS (Method A2): R _t = 1.09 min

MS (ESIneg): m/z=310(M( ^79Br )-H) ⁺

¹ H NMR (400MHz, CHLOROFORM-d) δ = 1.57 (s, 9H) 7.01 (br.s., 1H) 7.83 (s, 1H) 8.07 (s, 1H) 8.50 (s, 1H).

Intermediates 2-7

tert-Butyl [6-(Benzyloxy)-1H-indazol-5-yl]carbamate

7.50 g (30.1 mmol) of tert-butyl (6-hydroxy-1H-indazol-5-yl)carbamate (Intermediate 2-4) was dissolved in 150 ml of N,N-dimethylformamide, and 5.66 g (33.1 mmol) of benzyl bromide and 8.32 g (60.2 mmol) of potassium carbonate were added with stirring. The reaction mixture was stirred at 25°C for 24 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, phase separated, and filtered through a hydrophobic filter. The residue was dissolved in dichloromethane and adsorbed onto Isolute during concentration. Isolute was applied to a Biotage SNAP column (340 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient 100:0->60:40 (10 CV), isocratic 60:40 (9 CV)). The combined product fractions were concentrated and dried under reduced pressure to give 3.46 g (34% of theory) of product.

UPLC-MS (Method A2): R _t =1.27 min

MS (ESIpos): m/z＝340 (M+H) ⁺

¹ H NMR (300MHz, CHLOROFORM-d): δ = 1.55 (s, 9H) 5.20 (s, 2H) 6.92 (s, 1H) 7.14 (s, 1H) 7.36-7.49 (m, 5H) 7.94 (d, J = 0.75Hz, 1H) 8.44 (s, 1H).

Intermediate 2-8

tert-Butyl 1H-indazol-5-ylcarbamate

First, 25.5 g (191.5 mmol) of 1H-indazol-5-amine (CAS No. 19335-11-6) was added to 300 ml of tetrahydrofuran. 37 ml of N,N-diisopropylethylamine was added, and 41.8 g (191.5 mmol) of di-tert-butyl dicarbonate was added in small portions. The mixture was stirred at 25° C. for 24 hours. The mixture was concentrated to give 44.6 g (95% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.96 min

MS (ESIpos): m/z=234(M+H) ⁺ .

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.44 (s, 9H), 7.24-7.46 (m, 2H), 7.84 (s, 1H), 7.92 (s, 1H), 9.24 (br.s., 1H), 12.86 (br.s., 1H).

Intermediate 2-9

tert-Butyl (3-methyl-1H-indazol-5-yl)carbamate

1.00 g (6.8 mmol) of 3-methyl-1H-indazol-5-amine was similarly reacted with 1.48 g (6.8 mmol) of di-tert-butyl carbonate and 1.3 ml (7.5 mmol) of N,N-diisopropylethylamine in 15 ml of THF overnight. Concentration afforded 1.70 g of the title compound as a crude product.

UPLC-MS (Method A1): R _t =1.01min

MS (ESIpos): m/z=248(M+H) ⁺ .

Intermediate 2-10

tert-Butyl (6-isopropoxy-1H-indazol-5-yl)carbamate

Analogously to Intermediate 2-2, 2.2 g (11.6 mmol) of 6-isopropoxy-1H-indazol-5-amine (Intermediate 1-4) was reacted with 2.52 g (11.6 mmol) of di-tert-butyl dicarbonate and 2.21 ml (12.7 mmol) of N,N-diisopropylethylamine to give 2.72 g (81% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.20

MS (ESIpos): m/z＝292(M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.34 (d, 6H), 1.47 (s, 9H), 4.63-4.74 (m, 1H), 6.98 (s, 1H), 7.68 (s, 1H), 7.88 (s, 1H), 7.94 (s, 1H), 12.68 (s, 1H).

Intermediate 2-11

Benzyl (6-chloro-1H-indazol-5-yl)carbamate

6.1 ml of trifluoroacetic acid was added to 4.61 g of tert-butyl 5-{[(benzyloxy)carbonyl]amino}-6-chloro-2H-indazole-2-carboxylate (Intermediate 23-1, crude product) in 40 ml of dichloromethane, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, and the solid was filtered off with suction, washed with water and ether, and dried. 2.11 g of a light brown solid (crude product) was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ , selected signal): δ [ppm]=5.13 (s, 2H), 7.69 (s, 1H), 7.83 (s, 1H), 8.07 (s, 1H), 9.13 (br. s., 1H), 13.15 (br. s., 1H).

Intermediate 3-1

Ethyl {5-[(tert-Butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetate

At 70 ° C, 10.0 g (40.4 mmol) (6-methyl-1H-indazol-5-yl) tert-butyl carbamate (intermediate 2-1) was stirred with 9.00 ml (80.9 mmol) of ethyl bromoacetate in 75 ml of tetrahydrofuran in the presence of 17.1 ml (80.9 mmol) of N, N-dicyclohexylmethylamine for 24 hours. The precipitated solid was filtered off and washed twice with ethyl acetate. Water was added to the filtrate, and the organic phase was separated and then extracted twice with ethyl acetate. The combined organic phases were washed with 1M hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution and concentrated. The residue was dissolved in dichloromethane and HM-N (Biotage) was added. During the concentration process, the residue was adsorbed onto Isolute. Isolute was applied to a Biotage SNAP column (340 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 100 ml/min; gradient: isocratic 100:10 (1 CV), 100:0->50:50 (20 CV), isocratic 50:50 (0.2 CV)). The combined product fractions were concentrated and dried. 8.90 g (42% of theory) of the title compound were obtained.

In a second experiment, 213 mg of the title compound were obtained analogously by the following reaction: 2.00 g of tert-butyl (6-methyl-1H-indazol-5-yl)carbamate was dissolved in N,N-dimethylformamide at 80° C. using 2.24 g of potassium carbonate instead of N,N-dicyclohexylmethylamine and purified twice successively on silica gel (hexane/ethyl acetate).

UPLC-MS (Method A1): R _t =1.14 min

MS (ESIpos): m/z＝334 (M+H) ⁺

¹ H-NMR (600MHz, DMSO-d6): δ = 1.21 (t, 3H), 1.46 (s, 9H), 2.28 (s, 3H), 4.16 (q, 2H), 5.34 (s, 2H), 7.38 (d, 1H), 7.57 (s, 1H), 8.25 (d, 1H), 8.40 (s, 1H).

Intermediate 3-2

Benzyl {5-[(tert-Butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetate

Analogously to Intermediate 3-1, 4.17 g (15.8 mmol) of tert-butyl (6-methoxy-1H-indazol-5-yl)carbamate (Intermediate 2-2) was stirred in 50 ml of THF with 2.51 ml (15.8 mmol) of benzyl bromoacetate and 3.36 ml (15.8 mmol) of N,N-dicyclohexylmethylamine at 65° C. for 4 h, then 2.51 ml (15.8 mmol) of benzyl bromoacetate and 3.36 ml (15.8 mmol) of N,N-dicyclohexylmethylamine were added and the mixture was stirred at 65° C. for a further 18 h. Work-up and purification by column chromatography using a flash purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 100 ml/min; gradient: isocratic 100:10 (5 min), 100:0->75:25 (20 min), isocratic 75:25 (5 min), 75:25->50:50 (15 min), isocratic 50:50 (5 min), 50:50->20:80 (6 min)) gave 3.22 g (47% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.37 min

MS (ESIpos): m/z = 412 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 1.47 (s, 9H), 3.86 (s, 3H), 5.20 (s, 2H), 5.37 (s, 2H),6.97(s,1H),7.28-7.42(m),7.79(s,1H),7.94(br.s.,1H),8.21(s,1H).

Intermediate 3-3

Ethyl {5-[(tert-butoxycarbonyl)amino]-6-(trifluoromethoxy)-2H-indazol-2-yl}acetate

Analogously to Intermediate 3-1, 3.17 g (10.0 mmol) of tert-butyl [6-(trifluoromethoxy)-1H-indazol-5-yl]carbamate (Intermediate 2-3), 5.54 ml (50 mmol) of ethyl bromoacetate and 10.7 ml (50 mmol) of N,N-dicyclohexylmethylamine were heated in 20 ml of tetrahydrofuran at 70° C. for 24 h. Workup and purification by column chromatography using a flash purification system (Biotage) (mobile phase: hexane/dichloromethane/ethyl acetate; gradient: isocratic 90:5:5 (5CV), 90:5:5->85:7.5:7.5 (5CV), isocratic 85:7.5:7.5 (11CV), 85:7.5:7.5->80:10:10 (3CV), isocratic 80:10:10 (9CV)) gave 512 mg (13% of theory) of product.

UPLC-MS (Method A2): R _t =1.29 min

MS (ESIpos): m/z = 404 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6) δ = 1.22 (t, 3H), 1.44 (s, 9H), 4.18 (q, 2H), 5.42 (s, 2H), 7.58 (s, 1H), 7.82 (s, 1H), 8.44 (d, 1H), 8.75 (s, 1H).

Intermediate 3-4

Ethyl {6-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate

Analogously to Intermediate 3-1, 3.46 g (10.2 mmol) of tert-butyl [6-(benzyloxy)-1H-indazol-5-yl]carbamate (Intermediate 2-7), 2.26 ml (20.3 mmol) of ethyl bromoacetate, and 4.36 ml (20.3 mmol) of N,N-dicyclohexylmethylamine were heated in 50 ml of tetrahydrofuran for 2 h at 70° C. 2.26 ml (20.3 mmol) of ethyl bromoacetate and 4.36 ml (20.3 mmol) of N,N-dicyclohexylamine were further added, and the mixture was stirred at 70° C. for a further 22 h. Workup and purification by column chromatography using a flash purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient: 90:10->65:35 (10CV), isocratic 65:35 (5CV), 65:35->50:50 (5CV), isocratic 50:50 (5CV)) gave 2.37 g (55% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.43 min

MS (ESIpos): m/z = 426 (M+H) ⁺

¹ H NMR (400MHz, CHLOROFORM-d): δ = 1.28 (t, 3H), 1.54 (s, 9H), 4.25 (q, 2H), 5.09 (s, 2H), 5.19(s,2H),7.03(s,1H),7.25(s,1H),7.32-7.49(m,5H),7.82(s,1H),8.30(s,1H).

Intermediates 3-5

Ethyl {5-[(tert-Butoxycarbonyl)amino]-6-fluoro-2H-indazol-2-yl}acetate

Analogously to Intermediate 3-1, 5.44 g (21.6 mmol) of tert-butyl (6-fluoro-1H-indazol-5-yl)carbamate (Intermediate 2-5), 4.80 ml (43.3 mmol) of ethyl bromoacetate, and 9.18 ml (43.3 mmol) of N,N-dicyclohexylmethylamine were stirred in 30 ml of tetrahydrofuran for 72 h. An additional 0.96 ml (8.6 mmol) of ethyl bromoacetate and 1.84 ml (8.6 mmol) of N,N-dicyclohexylmethylamine were added after 24 h and 48 h, respectively. The mixture was concentrated, dissolved in dichloromethane, washed with water, dried, and concentrated. Workup and purification by column chromatography using a flash purification system (Biotage) (mobile phase: hexane/dichloromethane/ethyl acetate; isocratic 40:48:12 (8 CV)) gave 3.75 g (47% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.15 min

MS (ESIpos): m/z＝338 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.21 (t, 3H), 1.46 (s, 9H), 4.17 (q, 2H), 5.36 (s, 2H), 7.37 (d, 1H), 7.84 (d, 1H), 8.36 (s, 1H), 8.80 (s, 1H).

Intermediates 3-6

Ethyl {6-bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate

Similar to Intermediate 3-1, 4.85 g (15.5 mmol) of tert-butyl (6-bromo-1H-indazol-5-yl)carbamate (Intermediate 2-6), 6.89 ml (62.1 mmol) of ethyl bromoacetate, and 13.3 ml (62.1 mmol) of N,N-dicyclohexylmethylamine were stirred in 50 ml of tetrahydrofuran at 70°C for 24 h. Workup and purification by column chromatography using a Biotage flash purification system (mobile phase: hexane/dichloromethane/ethyl acetate; gradient: isocratic 80:10:10 (16 CV), 80:10:10 -> 75:12.5:12.5 (1 CV), isocratic 75:12.5:12.5 (8 CV)) gave 2.01 g (32% of theory) of the title compound.

UPLC-MS (Method A2): R _t =1.27 min

MS(ESIpos):m/z＝398(M( ^79Br )+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.21 (t, 3H), 1.45 (s, 9H), 4.17 (q, 2H), 5.40 (s, 2H), 7.78 (s, 1H), 7.96 (s, 1H), 8.41 (d, 1H), 8.54 (s, 1H).

Intermediates 3-7

Ethyl {5-[(tert-Butoxycarbonyl)amino]-2H-indazol-2-yl}acetate

10.5 g (76.3 mmol) of potassium carbonate and 4.67 ml (42.0 mmol) of ethyl bromoacetate were added to 8.90 g (38.1 mmol) of tert-butyl 1H-indazol-5-ylcarbamate (intermediate 2-8) in 80 ml of N,N-dimethylformamide, and the mixture was stirred at 80 ° C for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated, and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate). 2.4 g of the title compound were obtained as the main component, which was in the form of a mixture containing tert-butyl 1H-indazol-5-ylcarbamate (starting material).

¹ H-NMR (500 MHz, CHLOROFORM-d, selected signal): δ=1.28 (t, 3H), 4.25 (q, 1H), 5.16 (s, 2H), 7.03 (dd, 1H), 7.62 (d, 1H).

Intermediates 3-8

Ethyl {5-[(tert-Butoxycarbonyl)amino]-3-methyl-2H-indazol-2-yl}acetate

At 80 ° C, a mixture of 1.70 g (3-methyl-1H-indazole-5-yl) tert-butyl carbamate (intermediate 2-9) (crude product) and 842 μl (7.6 mmol) ethyl bromoacetate and 1.90 g (13.7 mmol) potassium carbonate was stirred in 10 ml N, N-dimethylformamide for 5 hours. The mixture was diluted with water and extracted three times with ethyl acetate, and the extract was washed with water and saturated sodium chloride solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate). 436 mg of the title compound was obtained as a crude product.

UPLC-MS (Method A1): R _t =1.12 min

MS (ESIpos): m/z=334(M+H) ⁺ .

Intermediates 3-9

Ethyl 3-{5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}propanoate

1.0 g (4.3 mmol) of tert-butyl 1H-indazol-5-ylcarbamate (Intermediate 2-8), 656 μl (5.1 mmol) of ethyl bromopropionate, and 1.30 g (9.4 mmol) of potassium carbonate were heated in 6.4 ml of N,N-dimethylformamide at 80° C. for 90 min. Workup and purification by column chromatography using a flash purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient 100:0 -> 80:20 (5 CV), 80:20 -> 70:30 (5 CV), 70:30 -> 60:40 (5 CV)) gave 640 mg (45% of theory) of the product.

UPLC-MS (Method A1): R _t =1.12 min

MS (ESIpos): m/z＝334 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.13 (t, 3H), 1.48 (s, 9H), 3.00 (t, 2H), 4.04 (q, 2H), 4.60 (t,2H),7.17–7.24(m,1H),7.43-7.50(m,1H),7.82(s,1H),8.21(s,1H),9.23(s,1H).

Intermediate 3-10

Ethyl {5-[(tert-Butoxycarbonyl)amino]-6-isopropoxy-2H-indazol-2-yl}acetate

Analogously to Intermediate 3-5, 2.72 g (9.3 mmol) of tert-butyl (6-isopropoxy-1H-indazol-5-yl)carbamate (Intermediate 2-10) were reacted with 3.10 ml (28.0 mmol) of ethyl bromoacetate to give 1.84 g (52% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.32 min

MS (ESIpos): m/z＝378 (M+H) ⁺

¹ H NMR (600MHz, DMSO-d6): δ = 1.21 (t, 3H), 1.34 (d, 6H), 1.48 (s, 9H), 4.16 (q, 2H), 4. 68–4.75(m,1H),5.27(s,2H),6.98(s,1H),7.63(s,1H),7.97(s,1H),8.17(s,1H).

Intermediate 3-11

Ethyl 2-{5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}propanoate

A mixture of 15.0 g (64.3 mmol) of tert-butyl 1H-indazol-5-ylcarbamate (Intermediate 2-8), 9.21 ml (70.7 mmol) of ethyl 2-bromopropionate, and 17.8 g (128.6 mmol) of potassium carbonate in 100 ml of N,N-dimethylformamide was stirred at 80° C. for 24 h. The mixture was diluted with water and extracted with ethyl acetate, which was washed with saturated sodium chloride solution and concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate). This gave 6.10 g (28% of theory) of the title compound.

^1H NMR (400MHz, DMSO-d6): δ = 1.14 (t, 3H), 1.49 (s, 9H), 1.77 (d, 3H), 4.07-4.17 (m, 2H), 5.52(q,1H),7.23(dd,1H),7.49(d,1H),7.85(br.s.,1H),8.32(s,1H),9.22(s,1H).

Intermediate 3-12

tert-Butyl (5-{[(Benzyloxy)carbonyl]amino}-6-chloro-2H-indazol-2-yl)acetate

First, 2.11g (6-chloro-1H-indazole-5-yl) benzyl carbamate (intermediate 2-11) was added to 20ml THF, 1.5ml tert-butyl bromoacetate and 2.2ml N, N-dicyclohexylmethylamine were added, and the mixture was stirred at 65°C overnight. 0.75ml tert-butyl bromoacetate and 1.1ml N, N-dicyclohexylmethylamine were added, and the mixture was stirred at 70°C overnight. The solid was filtered out, the filter cake was washed with ethyl acetate, water was added to the filtrate, the mixture was extracted with ethyl acetate, and the extract was washed with 1M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel. 950mg of the title compound was obtained as a yellow foam.

¹ H NMR (400MHz, DMSO-d6): δ = 1.43 (s, 9H), 5.14 (s, 2H), 5.29 (s, 2H), 7.29–7.47 (m, 5H), 7.80 (s, 1H), 7.84 (s, 1H), 8.41 (s, 1H), 9.09 (s, 1H).

Intermediate 4-1

{5-[(tert-Butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid

10.7 g (254 mmol) of lithium hydroxide monohydrate dissolved in 50 ml of water was added to 10.6 g (25.4 mmol, 80%) of ethyl {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetate (Intermediate 3-1) in 100 ml of tetrahydrofuran and 10 ml of ethanol, and the mixture was stirred. A solid precipitated. After 18 h, the reaction mixture was diluted with water and acidified to pH 4 with 2M hydrochloric acid. The solid was then filtered off, washed with water and diethyl ether, and dried. This gave 6.98 g (87% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.92 min

MS (ESIpos): m/z＝306 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.44 (s, 9H), 2.25 (s, 3H), 4.78 (s, 2H), 7.32 (s, 1H), 7.49 (s, 1H), 8.10 (s, 1H), 8.35 (s, 1H).

Intermediate 4-2

{5-[(tert-Butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid

In analogy to Intermediate 4-1, 1.91 g of the title compound was obtained from 3.2 g of benzyl {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetate (Intermediate 3-2).

UPLC-MS (Method A1): R _t =1.04 min

MS (ESIpos): m/z＝322 (M+H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 1.47 (s, 9H), 3.86 (s, 3H), 5.16 (s, 2H), 6.96 (s, 1H), 7.78 (s, 1H), 7.93 (br.s., 1H), 8.16 (d, 1H), 13.13 (br.s., 1H).

Intermediate 4-3

{5-[(tert-Butoxycarbonyl)amino]-6-(trifluoromethoxy)-2H-indazol-2-yl}acetic acid

Analogously to Intermediate 4-1, 530 mg (1.31 mmol) of ethyl {5-[(tert-butoxycarbonyl)amino]-6-(trifluoromethoxy)-2H-indazol-2-yl}acetate (Intermediate 3-3) was suspended in 20 ml of tetrahydrofuran, and a solution of 157 mg (6.57 mmol) of lithium hydroxide monohydrate in 2.4 ml of water was added, and the mixture was stirred at 25° C. for 24 h. Work-up gave 437 mg (81% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.10 min

MS (ESIpos): m/z＝376 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.44 (s, 9H), 5.29 (s, 2H), 7.57 (s, 1H), 7.81 (s, 1H), 8.41 (d, 1H), 8.74 (s, 1H).

Intermediate 4-4

{6-Bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid

Analogously to Intermediate 4-1, 1.00 g (2.5 mmol) of ethyl {6-bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (Intermediate 3-6) was dissolved in 50 ml of tetrahydrofuran, and a solution of 301 mg (12.6 mmol) of lithium hydroxide monohydrate in 4.5 ml of water was added, and the mixture was stirred at 25° C. for 24 h. Work-up gave 844 mg (82% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.64 min

MS(ESIpos):m/z＝370(M( ^79Br )+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 1.45 (s, 9H), 3.35 (s br, 1H), 5.28 (s, 2H), 7.76 (s, 1H), 7.95 (s, 1H), 8.38 (s, 1H), 8.52 (s, 1H).

Intermediate 4-5

{5-[(tert-Butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid

Analogously to Intermediate 4-1, 5.00 g (15.6 mmol) of ethyl {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (Intermediate 3-7) was dissolved in 50 ml of tetrahydrofuran and 5 ml of ethanol, and a solution of 6.57 g (15.6 mmol) of lithium hydroxide monohydrate in 20 ml of water was added, and the mixture was stirred at 25° C. for 24 h. Work-up gave 4.1 g (89% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.90 min

MS (ESIpos): m/z=292(M+H) ⁺ .

Intermediates 4-6

{5-[(tert-Butoxycarbonyl)amino]-3-methyl-2H-indazol-2-yl}acetic acid

Analogously to Intermediate 4-1, 436 mg (1.3 mmol) of ethyl {5-[(tert-butoxycarbonyl)amino]-3-methyl-2H-indazol-2-yl}acetate was dissolved in 5 ml of tetrahydrofuran and 1 ml of ethanol. 549 mg (13.1 mmol) of lithium hydroxide monohydrate in 2.5 ml of water were then added, and the mixture was stirred at 25° C. for 24 h. Addition of citric acid gave a solid, which was filtered off, washed with water and diethyl ether, and dried. This gave 320 mg (70% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.92 min

MS (ESIpos): m/z=306(M+H) ⁺ .

Intermediates 4-7

2-{5-[(tert-Butoxycarbonyl)amino]-2H-indazol-2-yl}propanoic acid

Analogously to Intermediate 4-1, 5.77 g (17.3 mmol) of ethyl 2-{5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}propanoate (Intermediate 3-8) was dissolved in 50 ml of tetrahydrofuran and 5 ml of ethanol. A solution of 7.26 g (17.3 mmol) of lithium hydroxide monohydrate in 40 ml of water was then added, and the mixture was stirred at 25° C. for 24 h. Acidification with 1 M hydrochloric acid solution gave a solid, which was filtered off, washed with water and diethyl ether, and dried. This gave 4.2 g (79% of theory) of the title compound.

¹ H-NMR (300MHz, DMSO-d6): δ = 1.45 (s, 9H), 1.72 (d, 3H), 5.33-5.41 (m, 1H), 7.18 ( dd,1H),7.45(d,1H),7.82(s,1H),8.26(s,1H),9.20(s,1H),13.13(br.s.,1H).

Intermediates 4-8

{6-(Benzyloxy)-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid

Analogously to Intermediate 4-1, 14.15 g (33.3 mmol) of ethyl {6-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (Intermediate 3-4) was dissolved in 250 ml of tetrahydrofuran and 25 ml of ethanol. 3.98 g (166.3 mmol) of lithium hydroxide monohydrate in 30 ml of water were then added, and the mixture was stirred at 25° C. for 72 h. After acidification to pH 3 with 1 M hydrochloric acid solution, the reaction mixture was concentrated, water was added, and the resulting solid was filtered off, washed with water and diethyl ether, and dried. This gave 13.05 g (33% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.25 min

MS (ESIpos): m/z＝398 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.45 (s, 9H), 4.93 (s, 2H), 5.20 (s, 2H), 7.01 (s, 1H), 7.26-7.45 (m, 3H), 7.53 (d, 2H), 7.80-7.91 (m, 2H), 8.11 (s, 1H).

Intermediates 4-9

(5-{[(Benzyloxy)carbonyl]amino}-6-chloro-2H-indazol-2-yl)acetic acid

1.7 ml of trifluoroacetic acid was added to a mixture of 940 g of tert-butyl (5-{[(benzyloxy)carbonyl]amino}-6-chloro-2H-indazol-2-yl)acetate (Intermediate 3-12) in 10 ml of dichloromethane, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added, and the precipitate was filtered off with suction, washed with water and ethyl acetate, and dried. This yielded 766 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 4.66 (s, 2H), 5.12 (s, 2H), 7.26-7.45 (m, 5H), 7.69 (s, 1H), 7.75 (s, 1H), 8.22 (s, 1H), 9.01 (s, 1H).

Intermediate 5-1

tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}carbamate

First, 181 mg (0.59 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid (Intermediate 4-1) and 169 mg (0.89 mmol) of phenyl(piperazin-1-yl)methanone were added to 5 ml of tetrahydrofuran and 0.5 ml of N,N-dimethylformamide. 91 mg (0.59 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 227 mg (1.19 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 0.25 ml (1.79 mmol) of triethylamine were added, and the mixture was stirred at 25° C. for 18 h. The mixture was diluted with water and ethyl acetate, and the precipitated solid was filtered off, washed with water and diethyl ether, and dried under reduced pressure. This gave 248 mg (85% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.07 min

MS (ESIpos): m/z＝478 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 1.42 (s, 9H), 2.24 (s, 3H), 3.32-3.82 (m, 8H), 5.41 (br.s. ,2H),7.33(s,1H),7.38-7.48(m,5H),7.52(s,1H),8.12-8.16(m,1H),8.35(s,1H).

Intermediate 5-2

tert-Butyl (6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 2.00 g (6.55 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid (Intermediate 4-1) was reacted with 1.31 g (8.52 mmol) of 4-(pyrrolidin-1-yl)piperidine to give 2.59 g (90% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.77 min

MS (ESIpos): m/z = 442 (M+H) ⁺

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.18-1.52 (m, 11H, containing a singlet at 1.45 ppm), 1.66 (br. s., 4H), 1.83 (t, 2H), 2.16-2.30 (m, 4H), 2.76-2.90 (m, 1H), 3.08-3.22 (m, 1H), 3.80-3.92 (m, 1H), 4.01-4.14 (m, 1H), 5.31-5.46 (m, 2H), 7.35 (s, 1H), 7.53 (s, 1H), 8.15 (s, 1H), 8.39 (s, 1H).

Intermediate 5-3

tert-Butyl (2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 300 mg (0.98 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid (Intermediate 4-1) was reacted with 238 mg (1.28 mmol) of 3-hydroxy-2,2-dimethyl-1-(piperazin-1-yl)propan-1-one. This gave 216 mg (46% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.96 min

MS (ESIpos): m/z = 474 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 1.16 (s, 6H), 1.45 (s, 9H), 2.26 (s, 3H), 3.39-3.68 (m, 10 H),4.59(t,1H),5.42(s,2H),7.35(s,1H),7.54(s,1H),8.15(s,1H),8.37(s,1H).

Intermediate 5-4

tert-Butyl (2-{2-[4-(methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 300 mg (0.98 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid (Intermediate 4-1) was reacted with 248 mg (1.28 mmol) of 2-methoxy-1-(piperazin-1-yl)ethanone hydrochloride (1:1) to give 144 mg of the title compound as a crude product.

UPLC-MS (Method A2): R _t = 0.93 min

MS (ESIpos): m/z=446(M+H) ⁺ .

Intermediate 5-5

tert-Butyl (2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 266 mg (0.83 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was reacted with 154 mg (1.08 mmol) of 2-(piperidin-4-yl)propan-2-ol in 10 ml of tetrahydrofuran to give 382 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 1.10 min

MS (ESIpos): m/z=447(M+H) ⁺ .

Intermediate 5-6

tert-Butyl (2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 250 mg (0.78 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was reacted with 164 mg (1.17 mmol) of 1-(cyclopropylmethyl)piperazine to give 402 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.85 min

MS (ESIpos): m/z=444(M+H) ⁺ .

Intermediates 5-7

tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 548 mg (1.71 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was reacted with 389 mg (2.05 mmol) of phenyl(piperazin-1-yl)methanone to give 808 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t =1.14 min

MS (ESIpos): m/z=494(M+H) ⁺ .

Intermediates 5-8

tert-Butyl {2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamate

350 mg (0.85 mmol) of tert-butyl {2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamate (Intermediate 4-3), 130 mg (0.85 mmol) of 1-hydroxy-1H-benzotriazole hydrate, and 325 mg (1.70 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 3.5 ml of N,N-dimethylformamide and 473 μl (3.40 mmol) of triethylamine at 25° C. for 30 min. Then, 103 μl (0.93 mmol) of 1-methylpiperazine (CAS No.: 109-01-3) was added, and the mixture was stirred at 25° C. for 24 h. The mixture was poured into 50 ml of water, filtered with suction, washed with water, and dried. This gave 305 mg (78% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 1.12 min

MS (ESIpos): m/z＝376 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ=1.44(s,9H),2.23(s,3H),2.28-2.38(m,2H),2.41(br.s.,2H),3.47(br.s.,2 H),3.55(br.s.,2H),5.49(s,2H),7.54(s,1H),7.80(s,1H),8.34(d,1H),8.73(s,1H),9.93(br.s.,1H).

Intermediates 5-9

tert-Butyl {6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-8, 800 mg (1.97 mmol) of {6-bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-4) were reacted with 246 μl (2.17 mmol) of 1-methylpiperazine to give 824 mg (93% of theory) of the title compound.

UPLC-MS (Method A2): R _t =1.07 min

MS(ESIpos):m/z＝452(M( ^79Br )+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=1.45(s,9H),2.20(s,3H),2.25-2.34(m,2H),2.34-2.40(m,2H),3.43- 3.49(m,2H),3.50-3.55(m,2H),5.47(s,2H),7.75(s,1H),7.93(s,1H),8.31(s,1H),8.54(s,1H).

Intermediates 5-10

tert-Butyl (2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 2.00 g (4.3 mmol, 62%) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-5) was reacted with 1.14 g (6.0 mmol) of cyclopropyl(piperazin-1-yl)methanone hydrochloride (1:1) to give 2.3 g of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.97 min

MS (ESIpos): m/z=428(M+H) ⁺ .

Intermediates 5-11

tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 2.53 mg (8.7 mmol) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-5) were reacted with 1.98 g (10.4 mmol) of phenyl(piperazin-1-yl)methanone to give 3.8 g (93% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.05 min

MS (ESIpos): m/z＝464(M+H) ⁺ .

¹ H-NMR (400MHz, DMSO-d ₆ ): δ=1.45(s,9H),3.30-3.78(m,8H),5.41(br.s.,2H),7.18(dd,1H),7.35-7.50(m,6H),7.82(br.s.,1H),8.11(s,1H),9.18(s,1H).

Intermediates 5-12

tert-Butyl {2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 1.00 g (3.4 mmol) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-5) was reacted with 0.41 g (4.1 mmol) of 1-methylpiperazine to give 916 mg (71% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.73 min

MS (ESIpos): m/z=374(M+H) ⁺ .

Intermediate 5-13

tert-Butyl (2-{2-oxo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)carbamate

Analogously to Intermediate 5-1, 1.01 g (3.5 mmol) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-5) was reacted with 1.00 g (4.2 mmol) of 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride to give 634 g (42% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.11 min

MS (ESIpos): m/z=442(M+H) ⁺ .

Intermediates 5-14

tert-Butyl {2-[2-(4-ethyl-3-oxopiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to intermediate 5-1, 2.38 g (3.5 mmol, 62%) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (intermediate 4-5) was reacted with 1.00 g (6.1 mmol) of 1-ethylpiperazin-2-one hydrochloride (1:1) to give 1.92 g (71% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.92 min

MS (ESIpos): m/z=402(M+H) ⁺ .

Intermediate 5-15

tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 160 mg (0.52 mmol) of {5-[(tert-butoxycarbonyl)amino]-3-methyl-2H-indazol-2-yl}acetic acid (crude product) (Intermediate 4-6) was reacted with 150 mg (0.79 mmol) of phenyl(piperazin-1-yl)methanone. Addition of water and ethyl acetate gave a solid precipitate, which was washed with water and diethyl ether and dried. This gave 130 mg (52% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.07 min

MS (ESIpos): m/z=478(M+H) ⁺ .

Intermediates 5-16

tert-Butyl {6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 1.00 g (3.11 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was reacted with 407 μl (4.67 mmol) of 1-methylpiperazine. The reaction mixture was added to water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated, and dried. This gave 1.16 g (95% of theory) of the title compound.

UPLC-MS (Method A2): R _t =1.03 min

MS (ESIpos): m/z＝391(M+H) ⁺

¹ H NMR (300MHz, CHLOROFORM-d): δ = 1.55 (s, 9H), 3.58 (s, 4H), 3.66 (s, 4H), 3.93 ( s,3H),5.18(s,2H),6.94(s,1H),7.22(s,1H),7.81-7.90(m,1H),8.25(s,1H).

Intermediate 5-17

tert-Butyl {6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-16, 1.00 g (3.11 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was reacted with 530 μl (4.67 mmol) of 1-methylpiperazine. Workup gave 1.21 g (96% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.82 min

MS (ESIpos): m/z = 404 (M+H) ⁺

^1H NMR (300MHz, CHLOROFORM-d): δ = 1.55 (s, 9H), 2.28 (s, 3H), 2.30-2.34 (m, 2H), 2.34-2.41 (m, 3H), 3.52-3.6 1(m,2H),3.62-3.71(m,2H),3.93(s,3H),5.18(s,2H),6.94(s,1H),7.22(s,1H),7.85(s,1H),8.24(s,1H).

Intermediate 5-18

tert-Butyl (2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate

Similar to Intermediate 5-1, 250 mg (0.78 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetic acid (Intermediate 4-2) was stirred with 86 mg (1.01 mmol) of 1-cyclopropyl-N-methylmethanamine at 25° C. for 24 h. The mixture was diluted with water and extracted three times with ethyl acetate, and the extracts were washed with saturated sodium chloride solution and concentrated. 353 mg of crude product was obtained.

UPLC-MS (Method A1): R _t =1.19 min

MS (ESIpos): m/z=389(M+H) ⁺ .

Intermediate 5-19

tert-Butyl {2-[1-(4-benzoylpiperazin-1-yl)-1-oxopropan-2-yl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 2.00 g (6.55 mmol) of {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}propanoic acid (Intermediate 4-6) and 1.50 g (7.86 mmol) of phenyl(piperazin-1-yl)methanone were stirred at 25° C. for 24 h to obtain 3.7 g of the title compound as a crude product.

UPLC-MS (Method A1): R _t =1.11 min

MS (ESIpos): m/z=448(M+H) ⁺ .

Intermediate 5-20

tert-Butyl {6-(benzyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to Intermediate 5-1, 3.50 g (8.81 mmol) of {6-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetic acid (Intermediate 4-8) and 1.14 ml (13.2 mmol) of morpholine were reacted at 25° C. for 24 h. Workup gave 3.67 g (89% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.25 min

MS (ESIpos): m/z = 467 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 1.45 (s, 9H), 3.41-3.48 (m, 2H), 3.51-3.60 (m, 4H), 3.61-3.66 (m, 2H), 5.21 (s, 2H), 5.35(s,2H),7.01(s,1H),7.29-7.37(m,1H),7.38-7.44(m,2H),7.50-7.57(m,2H),7.87(s,2H),8.11(s,1H).

Intermediate 5-21

Benzyl {6-chloro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

Analogously to the preparation of Intermediate 5-1, 387 mg of (5-{[(benzyloxy)carbonyl]amino}-6-chloro-2H-indazol-2-yl)acetic acid (Intermediate 4-9) was reacted with 140 mg of 1-methylpiperazine. After the reaction, the mixture was diluted with water and ethyl acetate and saturated sodium chloride solution were added. The precipitated solid was filtered, washed with water and diethyl ether, and dried. This yielded 302 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=2.19(s,3H),2.23-2.41(m,4H),3.41-3.48(m,2H),3.48-3.56(m,2H),5.13(s, 2H),5.46(s,2H),7.28-7.45(m,5H),7.75(s,1H),7.81(s,1H),8.32(d,1H),9.07(s,1H).

Intermediate 5-22

Benzyl {6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate

First, 400 mg of (6-chloro-1H-indazole-5-yl) benzyl carbamate (intermediate 2-11) was added to 5.0 ml of cyclopentyl methyl ether. 265 mg of 2-bromo-1-(morpholin-4-yl) ethanone and 0.22 ml of N-ethyl-N-isopropylpropan-2-amine were added, and the mixture was stirred at 100° C. for 20 h. Water was added, and a solid was obtained by scraping off the oily residue from the edge of the flask. The solid was filtered off with suction, washed with water and ether, ground with ethyl acetate, and dried. 254 mg of the title compound was obtained.

¹ H-NMR (500MHz, DMSO-d6): δ [ppm] = 3.47 (d, 2H), 3.56 (d, 2H), 3.58-3.61 (m, 2H), 3.65 (d, 2H), 5. 15(s,2H),5.49(s,2H),7.28-7.48(m,5H),7.76(s,1H),7.83(s,1H),8.33(s,1H),9.07(s,1H).

Intermediate 6-1

2-(5-amino-6-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone

0.3 ml (3.89 mmol) of trifluoroacetic acid was added to 247 mg (0.52 mmol) of tert-butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}carbamate (Intermediate 5-1) in 5 ml of dichloromethane, and the mixture was stirred at 25°C for 18 hours. An additional 0.3 ml (3.89 mmol) of trifluoroacetic acid was then added, and the mixture was stirred for 18 hours, poured into saturated sodium bicarbonate solution, and extracted several times with dichloromethane. Concentration afforded 223 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.61 min

MS (ESIpos): m/z＝378 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 2.15 (s, 3H), 3.29–3.75 (m, 8H), 4.53 (s, 2H), 5.28 (br.s.,2H),6.63(s,1H),7.17(s,1H),7.37-7.47(m,5H),7.75-7.79(m,1H).

Intermediate 6-2

2-(5-amino-6-methyl-2H-indazol-2-yl)-1-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethanone

First, 2.59 g (5.87 mmol) of tert-butyl (6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)carbamate (Intermediate 5-2) were added to 30 ml of dichloromethane, 4.5 ml (58.7 mmol) of trifluoroacetic acid were added, and the mixture was stirred at 25° C. for 78 h. The reaction mixture was concentrated, and toluene was added twice, again requiring concentration of the mixture after each addition. The residue was purified by HPLC according to Method P2 (gradient: 0-0.5 min 25 ml/min to 70 ml/min 25% B; 0.5-5.5 min 25-55% B; flow rate: 70 ml/min). This gave 1.04 g (53% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.81 min

MS (ESIpos): m/z＝342 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ=1.16-1.47(m,2H),1.66(br.s.,4H),1.82(br.s.,2H),2.12-2.28(m,4H),2.74–2.89(m,1H),3.05– 3.20(m,1H),3.79–3.92(m,1H),4.02–4.14(m,1H),4.58(br.s.,2H),5.18-5.33(m,2H),6.65(s,1H),7.19(s,1H),7.78(d,1H).

Intermediate 6-3

1-{4-[(5-amino-6-methyl-2H-indazol-2-yl)acetyl]piperazin-1-yl}-3-hydroxy-2,2-dimethylpropan-1-one

0.34 ml (4.37 mmol) of trifluoroacetic acid was added to 207 mg (0.44 mmol) of tert-butyl (2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)carbamate (Intermediate 5-3) in 5 ml of dichloromethane, and the mixture was stirred at 25° C. for 2 days. The mixture was poured into saturated sodium bicarbonate solution and extracted three times with dichloromethane, and the extract was concentrated. 184 mg of the title compound was obtained as a crude product.

UPLC-MS (Method A1): R _t = 0.52 min

MS (ESIpos): m/z=374(M+H) ⁺ .

Intermediate 6-4

2-(5-amino-6-methyl-2H-indazol-2-yl)-1-[4-(methoxyacetyl)piperazin-1-yl]ethanone

0.25 ml (3.23 mmol) of trifluoroacetic acid was added to 144 mg (0.32 mmol) of tert-butyl (2-{2-[4-(methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)carbamate (Intermediate 5-4) in 3 ml of dichloromethane, and the mixture was stirred at 25° C. for 24 h. The mixture was concentrated to give 219 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.46 min

MS (ESIpos): m/z=346(M+H) ⁺ .

Intermediate 6-5

2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]ethanone

261 μl (3.38 mmol) of trifluoroacetic acid were added to 382 mg (0.86 mmol) of tert-butyl (2-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate (Intermediate 5-5) in 5 ml of dichloromethane, and the mixture was stirred at 25° C. for 18 h. A further 609 μl (7.90 mmol) of trifluoroacetic acid were added, and stirring was continued at 25° C. until the reaction was complete. The mixture was concentrated, and toluene was added three times, each time being removed under reduced pressure. 735 mg of the title compound was obtained as a crude product.

UPLC-MS (Method A1): R _t = 0.57 min

MS (ESIpos): m/z=347(M+H) ⁺ .

Intermediate 6-6

2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-[4-(cyclopropylmethyl)piperazin-1-yl]ethanone

Analogously to Intermediate 6-5, 402 mg (0.86 mmol) of tert-butyl (2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate (Intermediate 5-6) was reacted with 663 μl (8.61 mmol) of trifluoroacetic acid in 5 ml of dichloromethane. 822 mg of the title compound was obtained as a crude product.

Intermediates 6-7

2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-3, 808 mg (1.64 mmol) of tert-butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}carbamate (Intermediate 5-7) was stirred with 1.26 ml (16.37 mmol) of trifluoroacetic acid in 10 ml of dichloromethane at 25° C. for 18 h. Workup gave 649 mg (99% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.63 min

MS (ESIpos): m/z＝394 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ=3.33–3.79(8H),3.81(s,3H),4.60(s,2H),5.27(br.s.,2H),6.62(s,1H),6.78(s,1H),7.39-7.50(m,5H),7.76(s,1H).

Intermediates 6-8

2-[5-amino-6-(trifluoromethoxy)-2H-indazol-2-yl]-1-(4-methylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-4, 484 mg (1.06 mmol) of tert-butyl {2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamate (Intermediate 5-8) was reacted with 815 μl of trifluoroacetic acid in 5 ml of dichloromethane. Workup gave 320 mg (85% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.79 min

MS (ESIpos): m/z＝357 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ=2.16-2.24(m,3H),2.28(t,2H),2.32-2.40(m,2H),3.41-3.49(m ,2H),3.49-3.56(m,2H),4.95(s,2H),5.36(s,2H),6.88(s,1H),7.39(s,1H),7.98(s,1H).

Intermediates 6-9

2-(5-Amino-6-bromo-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-4, 293 mg (0.65 mmol) of tert-butyl {6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-9) was reacted with 499 μl (6.48 mmol) of trifluoroacetic acid in 3 ml of dichloromethane. Workup gave 210 mg (93% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.70 min

MS(ESIpos):m/z＝352(M( ^79Br )+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 2.20 (s, 3H), 2.27 (t, 2H), 2.31-2.40 (m, 2H), 3.41-3.48 (m, 2 H),3.49-3.56(m,2H),4.91(s,2H),5.34(s,2H),6.92(s,1H),7.77(s,1H),7.95(d,1H).

Intermediates 6-10

2-(5-amino-2H-indazol-2-yl)-1-[4-(cyclopropylcarbonyl)piperazin-1-yl]ethanone

Analogously to Intermediate 6-4, 2.3 g (5.38 mmol) of tert-butyl (2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)carbamate (Intermediate 5-10) was reacted with 4.1 ml (53.8 mmol) of trifluoroacetic acid in 25 ml of dichloromethane to give 1.09 g (62% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.47 min

MS (ESIpos): m/z=328(M+H) ⁺ .

Intermediates 6-11

2-(5-amino-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-4, 4.20 g (9.06 mmol) of tert-butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-11) was reacted with 6.98 ml (90.6 mmol) of trifluoroacetic acid to give 3.27 g (99% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.57 min

MS (ESIpos): m/z＝364 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d ₆ ): δ=3.36–3.80(m,8H),4.78(s,2H),5.33(br.s.,2H),6.55(d,1H),6.74(dd,1H),7.30(d,1H),7.38-7.53(m,5H),7.81(s,1H).

Intermediate 6-12

2-(5-amino-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-4, 916 mg (2.45 mmol) of tert-butyl {2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-12) was stirred with 1.89 ml (24.5 mmol) of trifluoroacetic acid in dichloromethane at 25°C for 24 h. The mixture was concentrated, and the crude product was dissolved in 10 ml of tetrahydrofuran and 1 ml of N,N-dimethylformamide. The precipitated solid was filtered and washed with diethyl ether. The solid was dissolved in methanol, and the solution was concentrated to dryness. 1.2 g of the title compound was obtained as a crude product.

Intermediate 6-13

2-(5-amino-2H-indazol-2-yl)-1-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethanone

Analogously to Intermediate 6-4, 1.1 ml (14.4 mmol) of trifluoroacetic acid was added to 634 mg (1.43 mmol) of tert-butyl (2-{2-oxo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)carbamate (Intermediate 5-13) in 5 ml of dichloromethane, and the mixture was stirred at 25° C. for 24 h. The mixture was concentrated, toluene was added twice, and the mixture was evaporated. 1.0 g of crude product was obtained.

UPLC-MS (Method A1): R _t = 0.59 min

MS (ESIpos): m/z=342(M+H) ⁺ .

Intermediates 6-14

4-[(5-amino-2H-indazol-2-yl)acetyl]-1-ethylpiperazin-2-one

Analogously to Intermediate 6-4, 2.8 ml (35.9 mmol) of trifluoroacetic acid were added to 1.92 g (3.59 mmol, 75%) of tert-butyl {2-[2-(4-ethyl-3-oxopiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-14) in 15 ml of dichloromethane, and the mixture was stirred at 25°C for 24 h. Saturated sodium bicarbonate solution was added, the mixture was filtered, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. A precipitate formed in the aqueous phase; it was filtered off with suction and washed with water and diethyl ether. Drying gave 636 mg (44% of theory) of the title compound as a crude product.

Intermediate 6-15

2-(5-amino-3-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone

0.21 ml (2.72 mmol) of trifluoroacetic acid was added to 130 mg (0.27 mmol) of tert-butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}carbamate in 3 ml of dichloromethane, and the mixture was stirred at 25° C. for 24 hours and concentrated to obtain 204 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.61 min

MS (ESIpos): m/z=378(M+H) ⁺ .

Intermediate 6-16

2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-(morpholin-4-yl)ethanone

Analogously to Intermediate 6-4, 1.16 g (2.97 mmol) of tert-butyl {6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-16) was stirred with 2.29 ml (29.7 mmol) of trifluoroacetic acid in 20 ml of dichloromethane at 25° C. for 24 h. 1.15 ml (14.9 mmol) of trifluoroacetic acid was then added, and the mixture was stirred at 25° C. for a further 24 h. The reaction mixture was concentrated three times with toluene. The residue was dissolved in tetrahydrofuran and diethyl ether was added. The resulting precipitate was filtered off with suction, washed with diethyl ether, and dried. This gave 759 mg (88% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.60 min

MS (ESIpos): m/z＝291(M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 3.45 (br.s., 2H), 3.51-3.71 (m, 6H), 3.93 (s, 3H), 5.40 (s, 2H), 7.10 (s, 1H), 7.52 (s, 1H), 8.21 (s, 1H).

Intermediate 6-17

2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone

Analogously to Intermediate 6-16, 1.25 g (3.10 mmol) of tert-butyl {6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-17) was stirred with 2.39 ml (31.0 mmol) of trifluoroacetic acid in 25 ml of dichloromethane for 5 h at 25° C. Workup gave 534 mg (57% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.61 min

MS (ESIpos): m/z＝304 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 2.19 (s, 3H), 2.24-2.30 (m, 2H), 2.30-2.37 (m, 2H), 3.41-3.48 (m, 2H), 3. 49-3.54(m,2H),3.82(s,3H),4.61(br.s.,2H),5.23(s,2H),6.63(s,1H),6.79(s,1H),7.76(s,1H).

Intermediate 6-18

2-(5-amino-6-methoxy-2H-indazol-2-yl)-N-(cyclopropylmethyl)-N-methylacetamide

Analogously to Intermediate 6-4, 353 mg (0.86 mmol, 95%) of tert-butyl (2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)carbamate (Intermediate 5-18) were first added to 10 ml of dichloromethane. 665 μl (8.63 mmol) of trifluoroacetic acid were added, and the mixture was stirred at 25° C. for 24 h. 200 μl of trifluoroacetic acid were then added, and the mixture was stirred for 3 h. The mixture was concentrated, and toluene was added twice, again concentrating the mixture after each addition. 750 mg of crude product were obtained.

UPLC-MS (Method A1): R _t = 0.61 min

MS (ESIpos): m/z=289(M+H) ⁺ .

Intermediate 6-19

2-(5-amino-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)propan-1-one

Analogously to Intermediate 6-4, 3.70 g (7.75 mmol) of tert-butyl {2-[1-(4-benzoylpiperazine-1-yl)-1-oxopropyl-2-yl]-2H-indazole-5-yl}carbamate (Intermediate 5-19) (crude product) was first added to 40 ml of dichloromethane. 6.0 ml (77.4 mmol) of trifluoroacetic acid was added, and the mixture was stirred at 25° C. for 24 h. The mixture was carefully poured into a saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated. The crude product was triturated with ether. 2.4 g (75% of theory) of the title compound were obtained as a light brown solid.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.59 (d, 3H), 2.9–3.7 (broad signal, superposition), 4.78 (s, 2H), 5.74 (br.s, 1H), 6.52 (s, 1H), 6.71 (dd, 1H), 7.25-7.47 (m), 7.91 (s, 1H).

Intermediate 6-20

2-[5-amino-6-(benzyloxy)-2H-indazol-2-yl]-1-(morpholin-4-yl)ethanone

Analogously to Intermediate 6-4, 3.65 g (7.82 mmol) of tert-butyl {6-(benzyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-20) were first added to 50 ml of dichloromethane. 6.0 ml (78.2 mmol) of trifluoroacetic acid were added, and the mixture was stirred at 25° C. for 24 h. The mixture was carefully poured into saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution and concentrated. This gave 2.72 g (95% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.85 min

MS (ESIpos): m/z＝312 (M+H) ⁺

¹ H-NMR (400MHz, CHLOROFORM-d): δ = 3.59 (s, 4H), 3.65 (d, 4H), 5.15 (s, 4H), 6.78 (s,1H),6.98(s,1H),7.34-7.44(m,3H),7.46-7.50(m,2H),7.71-7.74(m,1H).

Intermediate 6-21

2-(5-Amino-6-chloro-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone

5.0ml of glacial trifluoroacetic acid was added to 299mg of {6-chloro-2-[2-(4-methylpiperazine-1-yl)-2-oxoethyl]-2H-indazole-5-yl} benzyl carbamate (intermediate 5-21), and the mixture was stirred at room temperature for 3 days. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. A solid was obtained by preparative HPLC purification (method P2), which was ground with ether. Drying gave 101mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ[ppm]=2.18(s,3H),2.22-2.39(m,4H),3.38-3.56(m),4.96(s,2H),5.33(s,2H),6.88(s,1H),7.57(s,1H),7.94(d,1H).

Intermediate 6-22

2-(5-Amino-6-chloro-2H-indazol-2-yl)-1-(morpholin-4-yl)ethanone

Analogously to the preparation of Intermediate 6-21, 254 mg of benzyl {6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamate (Intermediate 5-22) was stirred with 3 ml of trifluoroacetic acid at room temperature for 6 days. A similar aqueous workup gave 137 mg of the title compound as a crude product.

UPLC-MS (Method A1): Rt=0.60 min (UV detector: TIC). Mass measured 294.00.

Intermediate 7-1

Ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate

Analogously to Intermediate 6-4, 1.1 g (3.3 mmol) of ethyl {5-[(tert-butoxycarbonyl)amino]-6-fluoro-2H-indazol-2-yl}acetate (Intermediate 3-5) was reacted with 1.92 ml (24.9 mmol) of trifluoroacetic acid in 11 ml of dichloromethane. Workup gave 790 mg (100% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.67 min

MS (ESIpos): m/z＝238 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.21 (t, 3H), 4.16 (q, 2H), 4.93 (s, 2H), 5.24 (s, 2H), 6.81 (d, 1H), 7.21 (d, 1H), 8.80 (s, 1H).

Intermediate 7-2

Ethyl [5-amino-6-(benzyloxy)-2H-indazol-2-yl]acetate

Analogously to Intermediate 6-4, 2.37 g (5.56 mmol) of ethyl {6-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (Intermediate 3-4) was reacted with 3.24 ml (41.8 mmol) of trifluoroacetic acid in 25 ml of dichloromethane. Workup gave 1.79 g (99% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.91 min

MS (ESIpos): m/z＝326 (M+H) ⁺

^1H NMR (400MHz, CHLOROFORM-d): δ = 1.29 (t, 3H), 4.25 (q, 2H), 5.07 (s, 2H), 5.15 (s, 2 H),6.81(s,1H),7.01(s,1H),7.31-7.45(m,3H),7.45-7.52(m,2H),7.67(s,1H).

Intermediate 7-3

Ethyl (5-amino-2H-indazol-2-yl)acetate

Analogously to Intermediate 6-4, 9.0 ml (117.4 mmol) of trifluoroacetic acid was added to 5.00 g (15.7 mmol) of tert-butyl {5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}acetate (Intermediate 3-7) in 75 ml of dichloromethane, and the mixture was stirred at 25° C. for 24 h. The mixture was poured into saturated sodium bicarbonate solution, the organic phase was separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with sodium chloride solution, dried, and concentrated. 3.4 g of the title compound were obtained as a brown solid.

UPLC-MS (Method A1): R _t = 0.47 min

MS (ESIpos): m/z＝220 (M+H) ⁺

¹ H-NMR (400MHz, DMSO-d ₆ ): δ=1.18(t,3H),2.49(br.s.,1H),4.12(q,2H),4.80(s,2H),5.20(s,2H),6.52(dd,1H),6.73(dd,1H),7.26-7.32(m,1H),7.87(d,1H).

Intermediate 7-4

Ethyl 3-(5-amino-2H-indazol-2-yl)propanoate

Analogously to Intermediate 7-1, 640 mg (1.92 mmol) of ethyl 3-{5-[(tert-butoxycarbonyl)amino]-2H-indazol-2-yl}propanoate (Intermediate 3-9) was reacted with 1.1 ml (14.4 mmol) of trifluoroacetic acid to give 391 mg (87% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.50 min

MS (ESIpos): m/z=234(M+H) ⁺ .

Intermediate 7-5

Ethyl (5-amino-6-isopropoxy-2H-indazol-2-yl)acetate

Analogously to Intermediate 7-1, 1.8 g (4.84 mmol) of ethyl {5-[(tert-butoxycarbonyl)amino]-6-isopropoxy-2H-indazol-2-yl}acetate (Intermediate 3-10) was reacted with 2.8 ml (36.3 mmol) of trifluoroacetic acid to give 1.3 g (100% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.69 min

MS (ESIpos): m/z＝278 (M+H ⁾

¹ H-NMR (300MHz, DMSO-d6): δ = 1.21 (t, 3H), 1.32 (d, 6H), 4.15 (q, 2H), 4.59 (s, 1H),4.60–4.69(m,1H),5.16(s,2H),6.64(s,1H),6.81(d,1H),7.83(s,1H).

Intermediate 7-6

Benzyl (5-amino-6-methoxy-2H-indazol-2-yl)acetate

Analogously to Intermediate 7-1, 25.7 g (60.1 mmol) of benzyl {5-[(tert-butoxycarbonyl)amino]-6-methoxy-2H-indazol-2-yl}acetate (Intermediate 3-2) was reacted with 23.1 ml (300.3 mmol) of trifluoroacetic acid to give 20.5 g (98% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.85 min

MS (ESIpos): m/z＝312 (M+H) ⁺

Intermediate 8-1

Ethyl [6-fluoro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

221 mg (1.16 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 177 mg (1.16 mmol) of 1-hydroxy-1H-benzotriazole hydrate, and 444 mg (2.32 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 5.5 ml of dimethylformamide at 25° C. for 30 minutes. 250 mg (1.05 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1) were added, and the mixture was stirred at 25° C. for 30 minutes. The mixture was poured into 150 ml of water, filtered with suction, washed with water, and dried. This gave 366 mg (84% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.23 min

MS (ESIpos): m/z = 411 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.22 (t, 3H), 4.18 (q, 2H), 5.41 (s, 2H), 7.55 (d, 1H), 8.21 (m, 1H), 8.36–8.51 (m, 4H), 10.27 (m, 1H).

Intermediate 8-2

Ethyl (6-fluoro-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate

Analogously to Intermediate 8-1, 159 mg (1.16 mmol) of 6-methylpyridine-2-carboxylic acid were reacted with 250 mg (1.05 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1). Workup gave 316 mg (84% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.17 min

MS (ESIpos): m/z=357(M+H) ⁺ .

Intermediate 8-3

Ethyl [6-fluoro-5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-1, 235 mg (1.16 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid was reacted with 250 mg (1.05 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1). Workup gave 364 mg (82% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.05 min

MS (ESIpos): m/z=423(M+H) ⁺ .

Intermediate 8-4

Ethyl [6-fluoro-5-({[5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-1, 235 mg (1.0 mmol) of 5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Intermediate 19-5) was reacted with 250 mg (1.05 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1). Workup gave 326 mg (76% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.13 min

MS (ESIpos): m/z=442(M+H) ⁺ .

Intermediate 8-5

Ethyl [6-fluoro-5-({[6-(morpholin-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-1, 222 mg (0.97 mmol) of 6-(morpholin-4-yl)pyridine-2-carboxylic acid were reacted with 230 mg (0.97 mmol) of ethyl (5-amino-6-fluoro-2H-indazol-2-yl)acetate (Intermediate 7-1). Workup gave 414 mg (100% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.12 min

MS (ESIpos): m/z=428(M+H) ⁺ .

Intermediate 8-6

Ethyl [6-(benzyloxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

1.79 g (5.5 mmol) of ethyl [5-amino-6-(benzyloxy)-2H-indazol-2-yl]acetate (Intermediate 7-2), 1.26 g (6.6 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid, 842 mg (5.5 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 2.11 g (11.0 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 2.3 ml (16.5 mmol) of triethylamine were stirred in 75 ml of tetrahydrofuran at 25° C. for 24 h. The reaction mixture was concentrated, and water was added to the residue. The resulting solid was filtered off with suction, washed twice with water and twice with diethyl ether. The yellow solid was dried under reduced pressure. 2.44 g (89% of theory) of product were obtained.

UPLC-MS (Method A1): R _t =1.42 min

MS (ESIpos): m/z＝499 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ=1.23(t,3H),4.18(q,2H),5.31(s,2H),5.33(s,2H),7.32(s,1H),7.34-7.47( m,3H),7.54-7.61(m,2H),8.18(d,1H),8.32-8.42(m,2H),8.43-8.52(m,1H),8.81(s,1H),10.47(s,1H).

Intermediate 8-7

Ethyl [6-hydroxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

1.0 g (2.01 mmol) of ethyl [6-(benzyloxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-6) was dissolved in 40 ml of ethanol, and the flask was evacuated and then flushed with nitrogen (this step was repeated twice more). 213 ml (0.2 mmol) of palladium on carbon were added, and the flask was evacuated and then flushed with hydrogen. The reaction mixture was hydrogenated under standard hydrogen pressure at 25° C. for 6 h. The reaction mixture was then filtered through a PTFE filter containing Celite and concentrated. This gave 783 mg (96% of theory) of product.

UPLC-MS (Method A1): R _t =1.08 min

MS (ESIpos): m/z = 409 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.22 (t, 3H), 4.17 (q,, 2H), 5.28 (s, 2H) 6.92 (s, 1H) 8.21 (d, 1H),8.27(s,1H),8.40(t,1H),8.47(d,1H),8.70(s,1H),10.55(s,1H),10.72(s,1H).

Intermediate 8-8

Ethyl [6-isobutoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

200 mg (0.49 mmol) of ethyl [6-hydroxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-7) were dissolved in 1.5 ml of N,N-dimethylformamide, and 203 mg (1.47 mmol) of potassium carbonate were added with stirring. The suspension was stirred at 25° C. for 10 minutes, and then 80 μl (0.73 mmol) of 1-bromo-2-methylpropane were added. The reaction mixture was stirred at 100° C. in a microwave for 1 hour. The reaction mixture was then diluted with water, and ethyl acetate was added. A solid was formed, which was filtered off with suction, washed twice with water and twice with diethyl ether. The pale green solid was dried in a drying cabinet for 3 hours. This gave 200 mg (88% of theory) of product.

UPLC-MS (Method A1): R _t =1.45 min

MS (ESIpos): m/z = 465 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=1.12(d,6H),1.22(t,3H),2.19(dt,1H),3.96(d,2H),4.17(q,2H),5.32(s,2H) ,7.09(s,1H),8.22(d,1H),8.32(s,1H),8.37-8.45(m,1H),8.46-8.51(m,1H),8.78(s,1H),10.58(s,1H).

Intermediates 8-9

Ethyl [6-(cyclopropylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-5, 200 mg (0.49 mmol) of ethyl [6-hydroxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-7) was reacted with 71 μl (0.73 mmol) of (bromomethyl)cyclopropane. Workup gave 223 mg (99% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.38 min

MS (ESIpos): m/z = 463 (M+H) ⁺

¹ H NMR (300MHz, CHLOROFORM-d): δ = 0.38-0.50 (m, 2H), 0.69-0.84 (m, 2H), 1.30 (t, 3H), 1.45 (br.s., 1H), 3.98 (d, 2H), 4. 27(q,2H),5.15(s,2H),6.98(s,1H),7.87(d,1H),7.93(s,1H),8.13(t,1H),8.51(d,1H),8.88(s,1H),10.91(s,1H).

Intermediates 8-10

Ethyl [6-(pyridin-2-ylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

200 mg (0.49 mmol) of ethyl [6-hydroxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-7) were dissolved in 6.6 ml of N,N-dimethylformamide and 270 mg (1.96 mmol) of potassium carbonate were added with stirring. The suspension was stirred at 25° C. for 10 minutes, and then 185 mg (0.73 mmol) of 2-(bromomethyl)pyridine hydrobromide were added. The reaction mixture was stirred at 100° C. for 1 hour in a microwave. The reaction mixture was then diluted with water and ethyl acetate was added. A solid was formed, which was filtered off with suction, washed twice with water and twice with diethyl ether. The pale green solid was dried in a drying cabinet for 3 hours. This gave 160 mg (65% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.24 min

MS (ESIpos): m/z＝500 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.23 (t, 3H), 4.18 (q, 2H), 5.34 (s, 2H), 5.36 (s, 2H), 7.70 (d, 1H), 7.82-7.91 (m, 1H), 8.15-8.21(m,1H),8.36(s,1H),8.37-8.43(m,1H),8.45-8.50(m,1H),8.62(d,1H),8.82(s,1H),10.50(s,1H).

Intermediates 8-11

Ethyl [5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-1, 1.00 g of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (Intermediate 19-2) (crude product) and 961 mg (4.39 mmol) of ethyl (5-amino-2H-indazol-2-yl)acetate (Intermediate 7-3) were stirred in 10 ml of tetrahydrofuran at 25° C. for 24 h. Water was added, the mixture was concentrated, and the precipitated solid was filtered off with suction, washed with water and diethyl ether, and dried under reduced pressure. This gave 1.45 g (80% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.01min

MS (ESIpos): m/z=405(M+H) ⁺ .

Intermediates 8-12

Ethyl [6-ethoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Similar to Intermediate 3-1, 1.30 g (3.71 mmol) of N-(6-ethoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-3), 826 μl (7.42 mmol) of ethyl bromoacetate, and 1.54 ml (7.42 mmol) of N,N-dicyclohexylmethylamine were stirred in 20 ml of tetrahydrofuran at 65°C for 18 h. 413 μl (3.71 mmol) of ethyl bromoacetate and 770 μl (3.71 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 65°C for an additional 6 h. Workup afforded 143 mg of the title compound as a crude product.

A further 637 mg of the title compound were obtained by adding water to the reaction filtrate, extracting with ethyl acetate, washing the organic phase with 1 M hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, drying, concentrating and triturating the residue with ethyl acetate.

UPLC-MS (Method A1): R _t =1.31 min

MS (ESIpos): m/z＝437 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.23 (t, 3H), 1.51 (t, 3H), 4.14-4.27 (m, 4H), 5.31 (s, 2H), 7.10 (s, 1H), 8.18-8.23(m,1H),8.31(s,1H),8.37-8.44(m,1H),8.45-8.49(m,1H),8.73(s,1H),10.74(s,1H).

Intermediates 8-13

Ethyl 3-[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]propanoate

Analogously to Intermediate 8-1, 194 mg (0.83 mmol) of ethyl 3-(5-amino-2H-indazol-2-yl)propanoate (Intermediate 7-4) was reacted with 175 mg (0.91 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid to give 285 mg (84% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.17 min

MS (ESIpos): m/z=407(M+H) ⁺ .

Intermediates 8-14

tert-Butyl [6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

First, 4.48 g (12.2 mmol) of N-(6-chloro-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-1) was added to 40 ml of tetrahydrofuran. 3.61 ml (24.5 mmol) of tert-butyl bromoacetate and 5.19 ml (24.5 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 70°C for 5.5 h. 3.61 ml (24.5 mmol) of tert-butyl bromoacetate and 5.19 ml (24.5 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 65°C for 18 h. 1.81 ml (12.3 mmol) of tert-butyl bromoacetate and 2.60 ml (12.3 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 65°C for an additional 6 h. The mixture was filtered, water was added to the filtrate, the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution and concentrated. The crude product was triturated with ethyl acetate and, after drying, 1.45 g (26% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.43 min

MS (ESIpos): m/z＝455 (M+H) ⁺

¹ H-NMR (400MHz, DMSO-d6): δ = 1.45 (s, 9H), 5.32 (s, 2H), 7.95 (s, 1H), 8.23 (d, 1H) ),8.38-8.44(m,1H),8.45-8.49(m,1H),8.49(s,1H),8.66(s,1H),10.5(s,1H).

Intermediates 8-15

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

2.00 g (5.95 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-2) was dissolved in 40 ml of tetrahydrofuran, and 4.39 ml (29.7 mmol) of tert-butyl bromoacetate and 6.37 ml (29.7 mmol) of N,N-dicyclohexylmethylamine were added at 25°C. The solution was stirred at 70°C for 3 h. 0.87 ml (5.95 mmol) of tert-butyl bromoacetate and 1.27 ml (5.95 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 70°C for an additional 24 h. The solid in the reaction mixture was filtered off and washed twice with tetrahydrofuran. The regioisomerically pure crystals were dried in a vacuum oven at 50°C for 3 h. This yielded 1.58 g (59% of theory) of product.

UPLC-MS (Method A1): R _t =1.36 min

MS (ESIpos): m/z = 451 (M+H) ⁺

¹ H NMR (400MHz, CHLOROFORM-d): δ = 1.50 (s, 9H), 4.04 (s, 3H), 5.04 (s, 2H), 7.06 (s, 1H) ),7.86(d,1H),7.92(s,1H),8.12(t,1H),8.50(d,1H),8.84(s,1H),10.72(s,1H).

Intermediates 8-16

tert-Butyl [5-({[6-(Trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

525 mg (3.80 mmol) of potassium carbonate were added to a solution of 582 mg (1.90 mmol) of N-(1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-4) and 309 μl (2.09 mmol) of tert-butyl bromoacetate in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 80°C for 24 h. Water was added, and the mixture was extracted three times with ethyl acetate. A solid precipitated from the ethyl acetate phase; it was filtered off with suction and washed with ethyl acetate. Drying under reduced pressure gave 72 mg (8% of theory) of the title compound. The ethyl acetate phase was concentrated, and the residue was purified by preparative HPLC. This gave a further 151 g (19% of theory) of the title compound.

¹ H-NMR (500MHz, DMSO-d6): δ = 1.45 (s, 9H), 5.27 (s, 2H), 7.56-7.61 (m, 1H), 7.6 1-7.64(m,1H),8.17(dd,1H),8.30-8.39(m),8.39-8.43(m,1H),10.38(s,1H).

Intermediates 8-17

Ethyl [6-isopropoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-1, 300 mg (1.08 mmol) of ethyl (5-amino-6-isopropoxy-2H-indazol-2-yl)acetate (Intermediate 7-5) was reacted with 227 mg (1.19 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid to give 487 mg (100% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.34 min

MS (ESIpos): m/z = 451 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.23 (t, 3H), 1.41 (d, 6H), 4.18 (q, 2H), 4.79–4.92 (m, 1H), 5.32 ( s,2H),7.18(s,1H),8.22(d,1H),8.33(s,1H),8.37–8.50(m,2H),8.75(s,1H),10.75(s,1H).

Intermediates 8-18

Ethyl (6-isopropoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate

Analogously to Intermediate 8-2, 0.3 g (1 mmol) of ethyl (5-amino-6-isopropoxy-2H-indazol-2-yl)acetate (Intermediate 7-5) was reacted with 137 mg (1.2 mmol) of 6-methylpyridine-2-carboxylic acid to give 380 mg (89% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.28 min

MS (ESIpos): m/z＝397 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.22 (t, 3H), 1.45 (d, 6H), 2.62 (s, 3H), 4.18 (q, 2H), 4.78–4.89 (m, 1H), 5. 31(s,2H),7.15(s,1H),7.52–7.60(m,1H),7.95–8.01(m,2H),8.29(s,1H),8.72(s,1H),10.99(s,1H).

Intermediates 8-19

tert-Butyl [6-(benzyloxy)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-15, 1.00 g (2.79 mmol) of N-[6-(benzyloxy)-1H-indazol-5-yl]-6-methylpyridine-2-carboxamide (Intermediate 14-5) was dissolved in 20 ml of tetrahydrofuran, and 1.64 ml (11.2 mmol) of tert-butyl bromoacetate and 2.39 ml (11.2 mmol) of N,N-dicyclohexylmethylamine were added at 25°C. After 3 h at 70°C, an additional 1.64 ml (11.2 mmol) of tert-butyl bromoacetate and 2.39 ml (11.2 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 70°C for an additional 24 h. The solid in the reaction mixture was filtered off and washed twice with tetrahydrofuran. The regioisomerically pure crystals were dried in a vacuum oven at 50°C for 3 h. This yielded 971 mg (74% of theory) of product.

UPLC-MS (Method A1): R _t =1.47 min

MS (ESIpos): m/z = 473 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 1.45 (s, 9H), 2.43 (s, 3H), 5.20 (s, 2H), 5.31 (s, 2H), 7.29 (s, 1H), 7.39-7.43 (m, 1H), 7 .45-7.53(m,3H),7.63-7.68(m,2H),7.93-7.97(m,1H),7.97-8.00(m,1H),8.29(d,1H),8.78(s,1H),10.87(s,1H).

Intermediate 8-20

3-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-methylpropanoic acid methyl ester

164 mg (1.19 mmol) of potassium carbonate and 83 μl (0.65 mmol) of methyl (2R)-3-bromo-2-methylpropanoate were added to 200 mg (0.60 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-2) in 5 ml of acetonitrile, and the mixture was stirred at 85° C. for 24 h. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. The crude product was dissolved in 2.0 ml of dimethyl sulfoxide and purified by preparative HPLC. The product fractions were lyophilized. This gave 25 mg (56% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.23 min

MS (ESIpos): m/z＝437 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ=1.08(d,3H),3.13(q,1H),3.55(s,3H),4.04(s,3H),4.48(dd,1H),4.62(dd ,1H),7.40(s,1H),8.02(s,1H),8.17-8.26(m,1H),8.40(t,1H),8.47(d,1H),8.71(s,1H),10.42(s,1H).

Intermediate 8-21

Benzyl [5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-6, 400 mg (1.29 mmol) of benzyl (5-amino-6-methoxy-2H-indazol-2-yl)acetate (Intermediate 7-6) was stirred with 245 mg (1.41 mmol) of 6-(difluoromethyl)pyridine-2-carboxylic acid (CAS No: 1256824-41-5), 197 mg (1.29 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 493 mg (2.57 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 537 μl (3.85 mmol) of triethylamine in 10 ml of tetrahydrofuran at 25°C for 24 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and concentrated. The crude product was dissolved in diethyl ether and a small amount of water and stirred for 30 minutes. The solid was filtered off with suction, washed three times with diethyl ether, and dried in a drying oven. This gave 401 mg (48% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.29 min

MS (ESIpos): m/z=467(M+H) ⁺ .

Intermediate 8-22

Benzyl [5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetate

Analogously to Intermediate 8-6, 300 mg (0.96 mmol) of (5-amino-6-methoxy-2H-indazol-2-yl)benzyl acetate (Intermediate 7-6), 295 mg (1.16 mmol) of 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylic acid potassium salt (Intermediate 19-11), 148 mg (0.96 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 277 mg (1.45 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 403 μl (2.89 mmol) of triethylamine were stirred in 10 ml of tetrahydrofuran at 25° C. for 24 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and concentrated. The crude product was dissolved in 4 ml of dimethyl sulfoxide and purified by preparative HPLC according to Method P5 (gradient: 30-70% B in 0-15 min; flow rate 150 ml/min). The product fractions were lyophilized. 209 mg (46% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.19 min

MS (ESIpos): m/z＝475 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ1.57(s,6H),4.00(s,3H),5.21(s,2H),5.41(s,2H),5.47(s,1H),7.13( s,1H),7.34-7.41(m,5H),7.94(dd,1H),7.99-8.12(m,2H),8.33(s,1H),8.69(s,1H),10.94(s,1H).

Intermediate 8-23

Benzyl (6-methoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate

In the presence of 8.01 ml (38.1 mmol) of N,N-dicyclohexylmethylamine, 7.57 g (19.0 mmol) of N-(6-methoxy-1H-indazol-5-yl)-6-methylpyridine-2-carboxamide (Intermediate 14-6) and 6.03 ml (38.1 mmol) of benzyl bromoacetate were stirred in 100 ml of tetrahydrofuran at 70°C for 2.5 hours and at 60°C for 17 hours. 3.02 ml (19.1 mmol) of benzyl bromoacetate and 4.01 ml (19.1 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 70°C for an additional 24 hours. The solid was filtered off with suction and washed with ethyl acetate. The filtrate was filtered again and washed twice with ethyl acetate, and the solid was dried. Water was added to the filtrate, and after phase separation, the aqueous phase was washed again with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter, and concentrated. Ethyl acetate was added to the crude product and the mixture was washed for 15 minutes. The solid was filtered off with suction, washed three times with ethyl acetate and dried in a drying cabinet. A total of 6.02 g (63% of theory) of the title compound was obtained.

LC-MS (Method A3): R _t =1.25 min

MS (ESIpos): m/z = 431 (M+H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 2.63 (s, 3H), 4.01 (s, 3H), 5.21 (s, 2H), 5.40 (s, 2H), 7.11 (s, 1H), 7 .34-7.40(m,5H),7.55(dd,1H),7.93-8.02(m,2H),8.30-8.33(m,1H),8.73(s,1H),10.72(s,1H).

Intermediate 8-24

tert-Butyl [6-methoxy-5-({[2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl]carbonyl}amino)-2H-indazol-2-yl]acetate

In the presence of 752 μl (3.55 mmol) of N,N-dicyclohexylmethylamine, 1.19 g (1.77 mmol) of N-(6-methoxy-1H-indazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxamide (Intermediate 14-7) was stirred with 524 μl (3.55 mmol) of tert-butyl bromoacetate in 10 ml of tetrahydrofuran at 70°C for 2.5 hours and at 60°C for 17 hours. 1.51 ml (9.5 mmol) of tert-butyl bromoacetate and 2.00 ml (9.5 mmol) of N,N-dicyclohexylmethylamine were then added, and the mixture was stirred at 70°C for an additional 6 hours. The solid was filtered off with suction and washed three times with ethyl acetate. Water was added to the filtrate, and after phase separation, the aqueous phase was washed again with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter, and concentrated. Ethyl acetate was added to the crude product, and the solid was filtered off with suction, washed three times with ethyl acetate and dried in a drying cabinet. This gave a total of 330 mg (41% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.23 min

MS (ESIpos): m/z = 457 (M+H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 1.44 (s, 9H), 1.72-1.86 (m, 2H), 1.91-2.02 (m, 2H), 3.17-3.27 (m, 1H), 3.48 (td, 2 H),3.92(dt,2H),3.97(s,3H),5.18(s,2H),7.10(s,1H),8.26(d,1H),8.57(s,1H),8.74(s,1H),9.41(s,1H).

Intermediate 8-25

tert-Butyl (5-{[(6-bromopyridin-2-yl)carbonyl]amino}-6-methoxy-2H-indazol-2-yl)acetate

In the presence of 5.18 ml (24.20 mmol) of N,N-dicyclohexylmethylamine, 4.20 g (12.10 mmol) of 6-bromo-N-(6-methoxy-1H-indazol-5-yl)pyridine-2-carboxamide (Intermediate 14-8) and 3.57 ml (24.20 mmol) of tert-butyl bromoacetate in 50 ml of tetrahydrofuran were stirred at 70°C for 2 h and at 60°C for 17 h. An additional 3.57 ml (24.20 mmol) of tert-butyl bromoacetate and 5.18 ml (24.20 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 70°C for a further 24 h. The reaction mixture was cooled in an ice bath, and the resulting solid was filtered off with suction, washed with water and diethyl ether, and dried under reduced pressure. This gave 3.67 g (66% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.33 min

MS (ESIpos): m/z = 461 (M + H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ = 1.44 (s, 9H) 4.00 (s, 3H) 5.20 (s, 2H) 7.14 (s, 1H) 7.90-8.10 (m, 2H) 8.20 (dd, 1H) 8.29 (s, 1H) 8.68 (s, 1H) 10.31 (s, 1H).

Intermediate 9-1

[6-Fluoro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

381 mg (0.93 mmol) of ethyl [6-fluoro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-1) were suspended in 9.2 ml of tetrahydrofuran and 0.45 ml of ethanol, and a solution of 222 mg (9.3 mmol) of lithium hydroxide in 2.3 ml of water was added. The mixture was stirred at 25° C. for 30 minutes and then acidified to pH 2 with 2N hydrochloric acid under ice cooling. 10 ml of water were added and the precipitate was filtered off with suction. This gave 332 mg (93% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.04 min

MS (ESIpos): m/z＝383 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 5.30 (s, 2H), 7.55 (d, 1H), 8.22 (m, 1H), 8.34-8.54 (m, 4H), 10.26 (m, 1H), 13.30 (s br, 1H).

Intermediate 9-2

(6-Fluoro-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetic acid

Analogously to Intermediate 9-1, 316 mg (0.89 mmol) of ethyl (6-fluoro-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate (Intermediate 8-2) was reacted with 212 mg (8.87 mmol) of lithium hydroxide in 2.2 ml of water, 8.8 ml of tetrahydrofuran, and 0.44 ml of ethanol. Workup gave 302 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t =0.99min

MS (ESIpos): m/z＝329 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6) δ = 2.62 (s, 3H), 5.28 (s, 2H), 7.44-7.63 (m, 2H), 7.90-8.06 (m, 2H), 8.45 (s, 1H), 8.56 (d, 1H), 10.38 (d, J = 1H).

Intermediate 9-3

[6-Fluoro-5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 364 mg (0.86 mmol) of ethyl [6-fluoro-5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-3) was reacted with 206 mg (8.6 mmol) of lithium hydroxide in 2.1 ml of water, 8.5 ml of tetrahydrofuran and 0.42 ml of ethanol. Workup gave 302 mg (89% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.87 min

MS (ESIpos): m/z＝395 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 3.93 (s, 3H), 5.30 (s, 2H), 7.55 (d, 1H), 7.92 (t, 2H), 8.0 3(t,1H),8.21(s,1H),8.39(d,1H),8.46(s,1H),8.52(s,1H),10.51(s,1H),13.26(s br,1H).

Intermediate 9-4

[6-Fluoro-5-({[5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 326 mg (0.74 mmol) of ethyl [6-fluoro-5-({[5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-4) was reacted with 177 mg (7.4 mmol) of lithium hydroxide in 1.8 ml of water, 7.3 ml of tetrahydrofuran and 0.36 ml of ethanol. Workup gave 305 mg (100% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.95 min

MS (ESIpos): m/z = 413 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 3.96 (s, 3H), 5.30 (s, 2H), 7.54 (d, 1H), 7.98 (m, 2H), 8.27 (m, 2H), 8.46 (s, 1H), 8.53 (s, 1H), 10.42 (s, 1H), 13.29 (s br,1H).

Intermediate 9-5

[6-Fluoro-5-({[6-(morpholin-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 436 mg (1.02 mmol) of ethyl [6-fluoro-5-({[6-(morpholin-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-5) was reacted with 244 mg (10.2 mmol) of lithium hydroxide in 2.5 ml of water, 10 ml of tetrahydrofuran and 0.5 ml of ethanol. Workup gave 295 mg (72% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.95 min

MS (ESIpos): m/z = 400 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 3.59 (m, 4H), 3.75 (m, 4H), 5.26 (s, 2H), 7.15 (d, 1H), 7.42–7.59 (m, 2H), 7.82 (t, 1H), 8.40–8.51 (m, 2H), 10.28 (m, 1H).

Intermediate 9-6

[6-(Benzyloxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 75 mg (0.15 mmol) of ethyl [6-(benzyloxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-6) was reacted with 18 mg (0.75 mmol) of lithium hydroxide in 271 μl of water and 2.5 ml of tetrahydrofuran. Workup gave 59 mg (83% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.26 min

MS (ESIpos): m/z = 471 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 7.31 (s, 1H), 7.33-7.47 (m, 3H), 7.54-7.63 (m, 2H), 8.12-8 .22(m,1H),8.31(s,1H),8.39(s,1H),8.46-8.51(m,1H),8.80(s,1H),10.47(s,1H).

Intermediate 9-7

[6-Isobutoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 200 mg (0.43 mmol) of ethyl [6-isobutoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-8) was reacted with 51 mg (2.15 mmol) of lithium hydroxide in 776 μl of water and 10 ml of tetrahydrofuran. Workup gave 64 mg (87% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.22 min

MS (ESIpos): m/z＝437 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=1.11(s,3H),1.13(s,3H),2.19(dt,1H),3.96(d,2H),5.21(s,2H),7.09( s,1H),8.22(dd,1H),8.31(s,1H),8.37-8.46(m,1H),8.46-8.52(m,1H),8.78(s,1H),10.58(s,1H).

Intermediate 9-8

[6-(Cyclopropylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 220 mg (0.48 mmol) of ethyl [6-(cyclopropylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-9) was reacted with 57 mg (2.38 mmol) of lithium hydroxide in 857 μl of water and 10 ml of tetrahydrofuran. Workup gave 181 mg (88% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.21 min

MS (ESIpos): m/z = 435 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ=0.42-0.48(m,2H),0.63-0.69(m,2H),1.29-1.41(m,1H),4.03(d,2H),5.20(s,2H ),7.07(s,1H),8.21(dd,1H),8.29(s,1H),8.37-8.44(m,1H),8.46-8.50(m,1H),8.76(s,1H),10.71(s,1H).

Intermediate 9-9

[6-(Pyridin-2-ylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 160 mg (0.32 mmol) of ethyl [6-(pyridin-2-ylmethoxy)-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-10) was reacted with 38 mg (1.60 mmol) of lithium hydroxide in 577 μl of water and 6.7 ml of tetrahydrofuran. Workup gave 129 mg (85% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.02min

MS (ESIpos): m/z = 472 (M + H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=5.02(s,2H),5.34(s,2H),7.30(s,1H),7.42(dd,1H),7.70(d,1H),7.80-7.92( m,1H),8.18(d,1H),8.27(s,1H),8.39(t,1H),8.44-8.53(m,1H),8.62(d,1H),8.80(s,1H),10.49(s,1H).

Intermediates 9-10

[5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 1.2 g (3.11 mmol) of ethyl [5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-11) (crude product) were first added to 10 ml of tetrahydrofuran, followed by 1.25 g (29.7 mmol) of lithium hydroxide monohydrate in 3 ml of water and 2 ml of ethanol. The mixture was stirred at 25° C. for 5 h. Water was added, followed by a pH of 4 with 10% citric acid. The mixture was extracted three times with ethyl acetate, and saturated sodium chloride solution was added to the aqueous phase. A solid precipitated from the aqueous phase; the solid was filtered off with suction, washed with water and ethyl acetate, and dried. 850 mg (54% of theory) of the title compound were obtained as a brown solid.

UPLC-MS (Method A1): R _t = 0.82 min

MS (ESIpos): m/z=37 (M+H)+.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 3.93 (s), 4.98 (s, 2H), 7.60 (s, 2H), 7.83-8.05 (m, 3H), 8.23-8.40 (m, 3H), 8.67 (s, 1H), 10.42 (s, 1H).

Intermediates 9-11

([6-Chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

1.45 g (3.19 mmol) of tert-butyl [6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-14) was dissolved in 15 ml of dichloromethane, and 2.46 ml (31.9 mmol) of trifluoroacetic acid were added at 25° C. The solution was stirred at 25° C. for 18 h. Water was added, and the resulting precipitate was filtered off with suction, washed three times with water and twice with diethyl ether, and the solid was dried under reduced pressure. This gave 1.28 g (98% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.11 min

MS (ESIpos): m/z = 399 (M+H) ⁺

¹ H-NMR (400MHz, DMSO-d6): δ = 5.31 (s, 2H), 7.93 (s, 1H), 8.22 (dd, 1H), 8.37-8.50 (m, 3H), 8.64 (s, 1H), 10.52 (s, 1H), 13.28 (br.s., 1H).

Intermediates 9-12

[6-Methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-11, 1.1 g (2.44 mmol) of tert-butyl [6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-15) was stirred with 3.76 ml (48.8 mmol) of trifluoroacetic acid in 20 ml of dichloromethane at 25° C. for 24 h. Workup gave 1.20 g (96% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.09 min

MS (ESIpos): m/z＝395 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 3.99 (s, 3H), 5.22 (s, 2H), 7.14 (s, 1H), 8.22 (dd, 1H), 8.31 (s, 1H), 8.42 (d, 1H), 8.46 (s, 1H), 8.71 (s, 1H), 10.51 (s, 1H).

Intermediates 9-13

[6-Ethoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 774 mg (1.77 mmol) of ethyl {[6-ethoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-12) were first added to 1 ml of ethanol and 25 ml of tetrahydrofuran, followed by a solution of 745 mg (17.74 mmol) of lithium hydroxide monohydrate in 5 ml of water, and the mixture was stirred for 3 days at 25° C. Workup gave 698 mg (94% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.13 min

MS (ESIpos): m/z = 409 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.49 (t, 3H), 4.20 (q, 2H), 5.17 (s, 2H), 7.09 (s, 1 H),8.21(dd,1H),8.28(s,1H),8.36-8.48(m,2H),8.71(s,1H),10.73(s,1H).

Intermediates 9-14

[5-({[6-(Trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

197 μl (2.57 mmol) of trifluoroacetic acid were added to a mixture of 216 mg (2.02 mmol) of tert-butyl [5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-16) in 3 ml of dichloromethane. The mixture was stirred at 25° C. for 3 days, and a further 197 μl (2.57 mmol) of trifluoroacetic acid were added, and the mixture was stirred at 25° C. Water was added to the reaction mixture. The mixture was stirred for 10 minutes, and then the solid was filtered off with suction, washed with water, and dried. This gave 142 mg (76% of theory) of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 5.25 (s, 2H), 7.52-7.62 (m, 2H), 8.14 (dd, 1H), 8.26-8.41 (m, 4H), 10.37 (s, 1H).

Intermediates 9-15

3-[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]propanoic acid

Analogously to Intermediate 9-1, 285 mg (0.70 mmol) of ethyl 3-[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]propanoate (Intermediate 8-13) was reacted with 168 mg (7.0 mmol) of lithium hydroxide. This gave 253 mg (95% of theory) of the title compound.

UPLC-MS (Method A1): R _t =0.99min

MS (ESIpos): m/z=379(M+H) ⁺ .

Intermediates 9-16

[6-Isopropoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-1, 490 mg (1.1 mmol) of ethyl [6-isopropoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-17) was reacted with 260 mg (11 mmol) of lithium hydroxide. This gave 367 mg (80% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.17 min

MS (ESIpos): m/z = 423 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.45 (d, 6H), 4.80–4.92 (m, 1H), 5.21 (s, 2H), 7.17 (s, 1H), 8. 19–8.25(m,1H),8.30(s,1H),8.36–8.49(m,2H),8.74(s,1H),10.75(s,1H),13.21(s,1H).

Intermediates 9-17

(6-Isopropoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetic acid

Analogously to Intermediate 9-1, 370 mg (0.93 mmol) of ethyl (6-isopropoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate (Intermediate 8-18) was reacted with 223 mg (9.33 mmol) of lithium hydroxide. This gave 280 mg (81% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.11 min

MS (ESIpos): m/z＝369 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.45 (d, 6H), 2.62 (s, 3H), 4.78–4.89 (m, 1H), 5.19 (s, 2H), 7.14 (s, 1H) ),7.52–7.60(m,1H),7.93-8.02(m,2H),8.27(s,1H),8.72(s,1H),10.99(s,1H),13.19(sbr,1H).

Intermediates 9-18

[6-(Benzyloxy)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-14, 100 mg (0.21 mmol) of tert-butyl [6-(benzyloxy)-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl]acetate (Intermediate 8-19) was dissolved in 6.7 ml of dichloromethane and stirred with 326 μl (4.23 mmol) of trifluoroacetic acid at 25° C. for 24 h. Workup gave 67 mg (76% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.20 min

MS (ESIpos): m/z = 417 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 2.43 (s, 3H), 5.22 (s, 2H), 5.31 (s, 2H), 7.29 (s, 1H), 7.42 (d, 1H), 7.44-7.54(m,3H),7.65(d,2H),7.91-8.02(m,2H),8.30(s,1H),8.78(s,1H),10.87(s,1H).

Intermediates 9-19

(6-Methoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetic acid

Analogously to Intermediate 9-1, 2.28 g (3.92 mmol, 74%) of benzyl (6-methoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetate (Intermediate 8-23) was dissolved in 20 ml of tetrahydrofuran and 3.0 ml of methanol, and a solution of 1.65 g (39.2 mmol) of lithium hydroxide monohydrate in 3.0 ml of water was added. The mixture was diluted with water and then acidified to pH 4 using 10% citric acid. The precipitated solid was filtered off, washed three times with water, three times with diethyl ether and dried under reduced pressure. 2.43 g of the title compound were obtained as a crude product.

UPLC-MS (Method A1): R _t = 1.00 min

MS (ESIpos): m/z=341(M+H) ⁺ .

Intermediates 9-20

[6-Methoxy-5-({[2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 9-11, 325 mg (0.71 mmol) of tert-butyl [6-methoxy-5-({[2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl]carbonyl}amino)-2H-indazol-2-yl]acetate (Intermediate 8-24) was dissolved in 5 ml of dichloromethane and stirred with 549 μl (7.12 mmol) of trifluoroacetic acid at 25° C. for 21 h. 275 μl (3.56 mmol) of trifluoroacetic acid were then added, and the mixture was stirred at 25° C. for a further 70 h. Water was added, the resulting precipitate was filtered off with suction, washed three times with water and three times with diethyl ether, and the solid was dried under reduced pressure. 313 mg of the title compound were obtained as a crude product.

UPLC-MS (Method A1): R _t = 0.91 min

MS (ESIpos): m/z = 401 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ=1.67-1.90(m,2H),1.98(d,2H),3.22(ddd,1H),3.40-3.54(m,2H),3 .87-4.01(m,6H),5.20(s,2H),7.10(s,1H),8.27(s,1H),8.56(s,1H),8.75(s,1H),9.42(s,1H).

Intermediate 9-21

(5-{[(6-bromopyridin-2-yl)carbonyl]amino}-6-methoxy-2H-indazol-2-yl)acetic acid

Analogously to Intermediate 9-11, 3.50 g (7.59 mmol) of tert-butyl (5-{[(6-bromopyridin-2-yl)carbonyl]amino}-6-methoxy-2H-indazol-2-yl)acetate (Intermediate 8-25) was dissolved in 100 ml of dichloromethane and stirred with 11.7 ml (15.54 mmol) of trifluoroacetic acid at 25° C. for 24 h. The reaction mixture was carefully added to saturated sodium bicarbonate solution with brief stirring, and the resulting precipitate was filtered off with suction and dried in a vacuum drying oven at 50° C. This gave 3.10 g of the title compound as a crude product.

UPLC-MS (Method A1): R _t =1.02min

MS (ESIpos): m/z＝405 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 4.00 (s, 3H) 5.21 (s, 2H) 7.13 (s, 1H) 7.95 (dd, 1H) 8.04 (t, 1H) 8.20 (dd, 1H) 8.28-8.31 (m, 1H) 8.68 (s, 1H) 10.30 (s, 1H).

Intermediate 9-22

3-[6-Methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-methylpropanoic acid

Analogously to Intermediate 4-1, 37 mg (0.09 mmol) of methyl 3-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-methylpropanoate (Intermediate 8-20) were dissolved in 2 ml of tetrahydrofuran and 0.1 ml of methanol. 36 mg (0.85 mmol) of lithium hydroxide monohydrate in 0.1 ml of water were then added, and the mixture was stirred at 25° C. for 23.5 h. The mixture was diluted with water, acidified to pH 4 with 10% strength citric acid, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, filtered through a hydrophobic filter, concentrated, and dried under reduced pressure. This gave 34 mg (94% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.13 min

MS (ESIpos): m/z = 423 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.04 (d, 3H), 3.00-3.13 (m, 2H), 3.98 (s, 3H), 4.37 (dd, 1H), 4.59 (dd, 1H), 7 .15(s,1H),8.22(dd,1H),8.29(s,1H),8.35-8.44(m,1H),8.44-8.49(m,1H),8.68(s,1H),10.49(s,1H).

Intermediate 9-23

3-[6-methoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]-2-propanoic acid

Analogously to Intermediate 4-1, 206 mg (0.43 mmol) of benzyl [5-({[6-(2-hydroxypropan-2-yl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetate (Intermediate 8-22) were suspended in 10 ml of tetrahydrofuran and 1.0 ml of methanol, 182 mg (4.33 mmol) of lithium hydroxide monohydrate in 1.5 ml of water were then added, and the mixture was stirred at 25° C. for 24 h. The mixture was diluted with water, acidified to pH 4 with 10% strength citric acid and concentrated. The precipitated solid was filtered off, washed once with water, three times with diethyl ether and dried under reduced pressure. This gave 155 mg (93% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.20 min

MS (ESIpos): m/z = 421 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.57 (s, 6H), 3.99 (s, 3H), 5.20 (s, 2H), 5.47 (s, 1H), 7.12 (s, 1H) ),7.93(dd,J=7.5,1.3Hz,1H),7.98-8.11(m,2H),8.28(s,1H),8.68(s,1H),10.93(s,1H).

Intermediate 9-24

[5-({[6-(Difluoromethyl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetic acid

Analogously to Intermediate 4-1, 613 mg of benzyl [5-({[6-(difluoromethyl)pyridin-2-yl]carbonyl}amino)-6-methoxy-2H-indazol-2-yl]acetate (Intermediate 8-21) was stirred with 469 mg of lithium hydroxide monohydrate in 3 ml of water, 15 ml of THF, and 1 ml of methanol at room temperature for 3 h. After similar workup, 378 mg of the title compound was obtained.

UPLC-MS (Method A1): R _t =0.98 min, mass measured (UV detector TIC) 376.00.

Intermediate 10 and Intermediate 11

tert-Butyl 6-bromo-5-[(tert-butoxycarbonyl)amino]-1H-indazole-1-carboxylate and tert-butyl 6-bromo-5-[(tert-butoxycarbonyl)amino]-2H-indazole-2-carboxylate

27.5 g (126.1 mmol) of di-tert-butyl dicarbonate was dissolved in 53.5 ml of tetrahydrofuran and cooled to 0°C. After adding 5.35 g (25.2 mmol) of 6-bromo-1H-indazol-5-amine (CAS No. 1360928-41-1) at 0°C, the mixture was stirred at 80°C for 24 h. The reaction mixture was concentrated, and dichloromethane was added. The reaction mixture was then washed with 0.5 M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate, and adsorbed onto HM-N (Biotage) during concentration. Isolute was applied to a Biotage SNAP column (340 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a flash purification system (mobile phase: hexane/ethyl acetate; gradient: isocratic 80:20 (9 CV)). 7.07 g (68% of theory) of a regioisomeric product mixture was obtained. (Ratio: 1-isomer/2-isomer: 85%/15%)

UPLC-MS (Method A2): R _t =1.48 min

MS(ESIneg):m/z=410(M( ^79Br )-H) ⁺

Intermediate 12-1

tert-Butyl 5-amino-6-chloro-1H-indazole-1-carboxylate

2.1 ml (11.8 mmol) of N,N-diisopropylethylamine and 2.34 g (10.7 mmol) of di-tert-butyl dicarbonate were added to 1.80 g (10.7 mmol) of 6-chloro-1H-indazol-5-amine (CAS No. 221681-75-0) in 18 ml of tetrahydrofuran, and the mixture was stirred at 25° C. for 18 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate and adsorbed onto Isolute during the concentration process. Isolute was applied to a Biotage SNAP column (100 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 50 ml/min; gradient: isocratic 100:0 (5 min), 100:0->75:25 (20 min), isocratic 75:25 (5 min), 75:25->50:50 (15 min), isocratic 50:50 (5 min), 50:50->0:100 (15 min)). The combined product fractions were concentrated and dried under reduced pressure. 1.23 g (43% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.16 min

MS (ESIpos): m/z＝268 (M+H) ⁺

Intermediate 12-2

tert-Butyl 5-amino-6-chloro-2H-indazole-2-carboxylate

7.5 g of 6-chloro-1H-indazol-5-amine (CAS No. 221681-75-0) were converted in analogy to the preparation of Intermediate 12-1. Purification by column chromatography on silica gel (hexane/ethyl acetate) gave 1.0 g of the title compound.

¹ H-NMR (500MHz, DMSO-d6): δ = 1.62 (s, 9H), 5.33 (s, 2H), 6.79 (s, 1H), 7.74 (s, 1H), 8.50 (d, 1H).

Intermediate 13

tert-Butyl 6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-1-carboxylate

Analogously to Intermediate 5-1, 1.23 g (4.59 mmol) of tert-butyl 5-amino-6-chloro-1H-indazole-1-carboxylate (Intermediate 12-1) was stirred in 20 ml of N,N-dimethylformamide with 1.14 g (5.97 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid at 25°C for 72 h. Water was added, the mixture was stirred for 15 min, and the solid was filtered off with suction, washed three times with water, and dried under reduced pressure. This yielded 2.02 g (98% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.57 min

MS (ESIpos): m/z = 441 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.65 (s, 9H), 8.19-8.27 (m, 2H), 8.37-8.53 (m, 3H), 8.75 (s, 1H), 10.59 (s, 1H).

Intermediate 14-1

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

Analogously to Intermediate 6-1, 6.7 ml (8.73 mmol) of trifluoroacetic acid were added to 3.85 g (8.73 mmol) of tert-butyl 6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-1-carboxylate (Intermediate 13) in 40 ml of dichloromethane, and the mixture was stirred for 18 h at 25° C. Workup gave 2.98 g (100% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.18 min

MS (ESIpos): m/z＝341(M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 7.83 (s, 1H), 8.14-8.27 (m, 2H), 8.36-8.49 (m, 2H), 8.60 (s, 1H), 10.50 (br.s., 1H), 13.25 (br.s., 1H).

Intermediate 14-2

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, dried over sodium sulfate, filtered, and the solution was concentrated. The residue was dissolved in dichloromethane, HM-N (Biotage) was added, and the residue was adsorbed onto Isolute during the concentration process. Isolute was applied to a Biotage SNAP column (340 g; KP-Sil) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; gradient 100:0->50:50 (9CV), isocratic 50:50 (4CV)). The combined product fractions were concentrated, and the beige solid was dried under reduced pressure. 3.75 g (47% of theory) of the title compound were obtained.

UPLC-MS (Method A1): 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 14-3

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

Analogously to Intermediate 5-1, 1.00 g (5.64 mmol) of 6-ethoxy-1H-indazol-5-amine and 1.29 g (6.77 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid were reacted in 50 ml of tetrahydrofuran at room temperature for 18 h. Workup and purification by column chromatography using a Biotage flash purification system (SNAP column (100 g; KP-Sil), mobile phase: hexane/ethyl acetate; gradient: isocratic 100:0 (1 CV), 100:0 -> 50:50 (10 CV), isocratic 50:50 (4.7 CV), 50:50 -> 3:97 (9.4 CV)) afforded 1.30 g (64% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.18 min

MS (ESIpos): m/z＝351(M+H) ⁺

¹ H-NMR (500MHz, DMSO-d6): δ=1.51(t,3H),4.24(q,2H),7.10(s,1H),8.00(s,1H),8.20( dd,1H),8.39-8.43(m,1H),8.46-8.48(m,1H),8.79(s,1H),10.67(s,1H),12.87(s,1H).

Intermediate 14-4

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

Analogously to Intermediate 5-1, 4.43 g (33.3 mmol) of 1H-indazol-5-amine (CAS No.: 19335-11-6) was reacted with 7.00 g (36.6 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid. After purification by column chromatography on silica gel (hexane/ethyl acetate), 7.8 g (73% of theory) of the title compound were obtained.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 7.51 (d, 1H), 7.68 (dd, 1H), 8.05 (s, 1H), 8.14 (dd, 1H), 8.25-8.41 (m, 3H), 10.42 (s, 1H), 13.04 (br.s., 1H).

Intermediate 14-5

N-[6-(Benzyloxy)-1H-indazol-5-yl]-6-methylpyridine-2-carboxamide

Analogously to Intermediate 14-2, 1.00 g (4.18 mmol) of 6-(benzyloxy)-1H-indazol-5-amine (Intermediate 1-3) and 688 mg (5.02 mmol) of 6-methylpyridine-2-carboxylic acid were dissolved in 50 ml of tetrahydrofuran and stirred at 25° C. for 24 h with 640 mg (4.18 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.60 g (8.36 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1.75 ml (12.54 mmol) of triethylamine. After concentrating the solution, water was added to the resulting precipitate, which was filtered off with suction, washed with water and diethyl ether, and dried under reduced pressure. This gave 1.13 g (76% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.26 min

MS (ESIpos): m/z＝359 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 2.43 (s, 3H), 5.34 (s, 2H), 7.29 (s, 1H), 7.35-7.57 (m ,4H),7.65(d,2H),7.86-8.07(m,3H),8.84(s,1H),10.82(s,1H),12.95(s,1H).

Intermediate 14-6

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

Analogously to Intermediate 14-2, 5.00 g (30.64 mmol) of 6-methoxy-1H-indazol-5-amine (CAS No. 749223-61-8) and 4.62 g (33.70 mmol) of 6-methylpyridine-2-carboxylic acid were dissolved in 100 ml of tetrahydrofuran and stirred at 25° C. for 20 h with 4.69 g (30.64 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 11.74 g (61.28 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 21.35 ml (153.2 mmol) of triethylamine. Water was added, and the reaction mixture was concentrated. The resulting precipitate was filtered off with suction, washed three times with water, three times with diethyl ether, and dried in a drying oven. This yielded 7.89 g (65% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.49 min

MS (ESIpos): m/z＝283 (M+H) ⁺

Intermediate 14-7

N-(6-methoxy-1H-indazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxamide

Analogously to Intermediate 14-2, 782 mg (4.80 mmol) of 6-methoxy-1H-indazol-5-amine (CAS No. 749223-61-8) and 1.04 g (5.27 mmol) of 2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylic acid (CAS No. 955401-82-8) were dissolved in 15 ml of tetrahydrofuran and stirred at 25°C for 26 h with 734 mg (4.80 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.84 g (9.59 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 3.34 ml (24.0 mmol) of triethylamine. Water was added, and the reaction mixture was concentrated. The resulting precipitate was filtered off with suction, washed three times with water and three times with diethyl ether, and dried in a drying oven. This gave 1.19 g (37% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.94 min

MS (ESIpos): m/z=343(M+H) ⁺ .

Intermediate 14-8

6-Bromo-N-(6-methoxy-1H-indazol-5-yl)pyridine-2-carboxamide

2.0 g (12.26 mmol) of 6-methoxy-1H-indazol-5-amine (CAS No. 749223-61-8) was dissolved in 50 ml of tetrahydrofuran. 4.72 g (14.71 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 2.56 ml (14.71 mmol) of N,N-diisopropylethylamine were added, and the mixture was stirred at 25°C for 30 minutes. 2.56 ml (14.71 mmol) of 6-bromopyridine-2-carboxylic acid (CAS No. 21190-87-4) was added, and the mixture was stirred at 25°C for an additional 24 hours. The reaction mixture was concentrated, and the residue was added to 400 ml of water. The resulting precipitate was filtered off with suction, washed twice with water and twice with diethyl ether, and dried in a vacuum drying oven at 50°C for 4 hours. This gave 4.18 g (98% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.93 min

MS (ESIpos): m/z＝347 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 4.02 (s, 3H) 7.13 (s, 1H) 7.89-8.10 (m, 3H) 8.20 (dd, 1H) 8.71 (s, 1H) 10.22 (s, 1H) 12.90 (br.s., 1H).

Intermediate 14-9

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

4.5 g (23.53 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 1-6) was dissolved in 45 ml of tetrahydrofuran, 9.07 g (28.24 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 4.92 ml (28.24 mmol) of N,N-diisopropylethylamine were added, and the mixture was stirred at 25°C for 30 minutes. 4.95 ml (25.89 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid (CAS No. 21190-87-4) was added, and the mixture was stirred at 25°C for a further 24 hours. The reaction mixture was filtered off with suction through a membrane filter, washed with tetrahydrofuran and water, and dried in a vacuum drying oven at 50°C for 24 hours. The filtrate was concentrated with acetonitrile, and the resulting precipitate was filtered off with suction, washed, and dried. This gave 8.60 g (84% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.21 min

MS (ESIpos): m/z＝365 (M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 3.97 (s, 3H), 8.13-8.27 (m, 2H), 8.30 (s, 1H), 8.3 3-8.45(m,1H),8.45-8.51(m,1H),9.15(s,1H),12.57(s,1H),13.44(s,1H).

Intermediate 14-10

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

500 mg (2.62 mmol) of methyl 5-amino-1H-indazole-6-carboxylate (Intermediate 1-6) was dissolved in 5 ml of tetrahydrofuran, 1.01 g (3.14 mmol) of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 547 μl (3.14 mmol) of N,N-diisopropylethylamine were added, and the mixture was stirred at 25°C for 30 minutes. 395 mg (2.88 mmol) of 6-methylpyridine-2-carboxylic acid (CAS No. 21190-87-4) was added, and the mixture was stirred at 25°C for a further 8 hours. The reaction mixture was added to water and stirred vigorously for 10 minutes. The precipitate was filtered off with suction through a nylon filter. The precipitate was washed twice with water and twice with diethyl ether. The solid was dried in a vacuum drying oven at 50°C for 3 hours. This gave 790 mg (92% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.05 min

MS (ESIpos): m/z＝311(M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 2.65 (s, 3H), 4.00 (s, 3H), 7.55 (dd, 1H), 7.91-7.99 (m, 1H), 7.99-8.04(m,1H),8.23(s,1H),8.29(s,1H),9.18(s,1H),12.65(s,1H),13.41(s,1H).

Intermediate 14-11

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

6.9 ml (5 equivalents) of a 3M solution of methylmagnesium bromide in diethyl ether were carefully added to an ice-cold solution of 1.50 g (4.12 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Intermediate 14-9) in 20 ml of THF. The mixture was stirred for 1 h under ice-bath cooling and then at room temperature for 19.5 h. 2 equivalents of methylmagnesium bromide solution were added, and the mixture was stirred for a further 24 h at room temperature. Saturated aqueous ammonium chloride solution was added, the mixture was stirred and extracted three times with ethyl acetate. The combined organic phases were washed with sodium chloride solution, filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate gradient). 763 mg (45% of theory) of the title compound were obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]＝1.63(s,6H),5.99(s,1H),7.49(s,1H),8.06(s,1H),8.14-8.19( m,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.32(s,1H),12.97(s,1H).

Intermediate 16-1

6-Bromo-N-isobutylpyridin-2-amine

In a pressure reactor, 1.0 g of 2,6-dibromopyridine and 340 mg of 2-methylpropan-1-amine were stirred with 1.43 ml of 2,2,6,6-tetramethylpiperidine at 190°C for 16 hours. The mixture was poured into saturated sodium bicarbonate solution, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel. 920 mg of the title compound was obtained.

¹ H-NMR (300MHz, CHLOROFORM-d): δ=[ppm]=1.00(d,6H),1.81–1.98(m,1H),3.05(t,2H),4.76(br.s.,1H),6.29(d,1H),6.72(d,1H),7.22-7.35(m,2H).

Intermediate 17-1

6-(1-Hydroxyethyl)pyridine-2-carboxylic acid methyl ester

2.00g 1-(6-bromopyridin-2-yl)ethanol (Telfer, Shane G.; Kuroda, Reiko, Chemistry A European Journal, 2005, 11, 57-68) was suspended in 20ml methanol and 30ml dimethyl sulfoxide. 265mg 1,3-bis(diphenylphosphino)propane, 140mg palladium (II) acetate and 3.2 triethylamine were added, the mixture was flushed three times with carbon monoxide and stirred in a carbon monoxide atmosphere (stirred at 12bar for 0.5h, then stirred at 16bar overnight). Water was added, the mixture was extracted with ethyl acetate, and the extract was concentrated. 1.7g of 6-(1-hydroxyethyl)pyridine-2-carboxylic acid (crude product) was obtained as an oil.

¹ H-NMR (400MHz, CHLOROFORM-d): δ = 1.57 (d, 3H), 4.02 (s, 3H), 5.03 (q, 1H), 7.56 (d, 1H), 7.88 (t, 1H), 8.05 (d, 1H).

Intermediate 17-2

6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxylic acid methyl ester

Under a carbon monoxide atmosphere, 1.04 g (4.06 mmol) of 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanol (CAS 1093880-21-7) was reacted in a manner analogous to Intermediate 17-1. After similar workup, the crude product was purified by preparative HPLC to yield 696 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 3.89 (s, 3H), 5.15-5.28 (m, 1H), 7.18-7.25 (m, 1H), 7.86 (dd, 1H), 8.05-8.14 (m, 2H).

Intermediate 17-3

6-(2-Hydroxypropan-2-yl)pyridine-2-carboxylic acid methyl ester

Under a carbon monoxide atmosphere, 1.00 g of 2-(6-bromopyridin-2-yl)propan-2-ol was reacted in a manner similar to Intermediate 17-1. After similar workup, the crude product was purified by preparative HPLC to give 540 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.44 (s, 6H), 3.86 (s, 3H), 5.34 (s, 1H), 7.86-7.99 (m, 3H).

Intermediate 17-4

6-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylic acid methyl ester

A mixture of 250mg 6-fluoropyridine-2-carboxylic acid methyl esters, 361mg 3-aminoazetidine-1-carboxylic acid tert-butyl esters (1.3 equivalents) and 0.84ml N-ethyl-N-isopropylpropane-2-amine in 3.0ml 1-methylpyrrolidin-2-one is stirred at 80 DEG C. 0.5 equivalents of 3-aminoazetidine-1-carboxylic acid tert-butyl esters are added, and the mixture is stirred at 100 DEG C overnight. 0.5 equivalents of 3-aminoazetidine-1-carboxylic acid tert-butyl esters are added, and the mixture is stirred at room temperature for 3 days. Water is added, the mixture is extracted with ethyl acetate, the organic phase is concentrated, and the residue is purified by preparative HPLC. 230mg title compound is obtained.

UPLC-MS (Method A1): R _t =1.07 min (UV detector TIC), mass measured 307.15.

Intermediate 17-5

6-({[1-(tert-Butoxycarbonyl)azetidin-2-yl]methyl}amino)pyridine-2-carboxylic acid methyl ester

A mixture of 500 mg of methyl 6-fluoropyridine-2-carboxylate, 720 mg of tert-butyl 2-(aminomethyl)azetidine-1-carboxylate, and 2.2 ml of N-ethyl-N-isopropylpropan-2-amine in 7.5 ml of 1-methylpyrrolidin-2-one was stirred at 100° C. for 30 min, at 120° C. for 4 h, and at 140° C. for 3 h. The mixture was concentrated, and the product was purified by preparative HPLC (column: Reprospher C18-DE 5 μm 125 x 30 mm, solvent system: A = water + 0.1% by volume formic acid (99%), B = acetonitrile, gradient 0-5.5 min 40-80% B). 230 mg of the title compound was obtained as a crude product. Mass measured (UV detector TIC) 321.17.

Intermediate 17-6

6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridine-2-carboxylic acid methyl ester

Analogously to Intermediate 17-4, 300 mg of methyl 6-fluoropyridine-2-carboxylate was reacted with 334 mg of (2R,6S)-2,6-dimethylmorpholine at 80°C overnight. 0.5 equivalents of (2R,6S)-2,6-dimethylmorpholine were then added, and the mixture was stirred at 100°C for 7 h. Aqueous workup afforded 875 mg of crude product, which still contained 1-methylpyrrolidin-2-one. UPLC-MS (Method A1): R _t = 1.05 min (UV detector TIC), mass measured 250.00.

Intermediate 17-7

6-(Isobutylamino)pyridine-2-carboxylic acid methyl ester

Under a carbon monoxide atmosphere, 900 mg of 6-bromo-N-isopropylpyridin-2-amine (Intermediate 16-1) was reacted in a manner similar to Intermediate 17-1. The crude product was purified by column chromatography on silica gel to give 796 mg of the title compound.

¹ H-NMR (300MHz, CHLOROFORM-d): d[ppm]＝1.02(d,3H),1.83–1.98(m,1H),3.08 (t,2H),3.97(s,3H),4.97(br.s.,1H),6.58(d,1H),7.42(d,1H),7.58(t,1H).

Intermediate 19-1

Potassium 6-(1-hydroxyethyl)pyridine-2-carboxylate

First, 541 mg of methyl 6-(1-hydroxyethyl)pyridine-2-carboxylate (Intermediate 17-1, crude product) was added to 5 ml of methanol, 120 mg of potassium hydroxide was added, and the mixture was stirred at 50° C. overnight. More potassium hydroxide was added, and the mixture was stirred at 50° C. for 5 h. The mixture was concentrated to give 625 mg of potassium 6-(1-hydroxyethyl)pyridine-2-carboxylate as a crude product.

Intermediate 19-2

6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid

First, 500 mg (2.31 mmol) of methyl 6-bromopyridine-2-carboxylate, 578 mg (1.2 equivalents) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, and 192 mg of lithium chloride were added to 5 ml of toluene and 3 ml of ethanol. 162 mg of bis(triphenylphosphine)palladium(II) chloride and 3.5 ml of 2M aqueous sodium carbonate solution were added, and the mixture was heated in a microwave at 120°C. The mixture was acidified to pH 5 with 10% strength citric acid solution and extracted three times with ethyl acetate. The extracts were washed with sodium chloride solution, filtered, and concentrated. The residue was purified by preparative HPLC (column XBridge C18 5 μm 100 x 30 mm). This gave 70 mg (15% of theory) of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 3.89 (s, 3H), 7.79-7.94 (m, 3H), 8.09 (s, 1H), 8.39 (s, 1H), (12.9br.s, 1H).

Intermediate 19-3

6-(1-Methyl-1H-pyrazol-5-yl)pyridine-2-carboxylic acid

Analogously to the synthesis of intermediate 19-2, 500 mg (2.31 mmol) of methyl 6-bromopyridine-2-carboxylate was reacted with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a microwave at 120° C. for 90 min. Purification by preparative HPLC according to Method P1 gave 34 mg (15% of theory) of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 4.22 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H), 7.96-8.10 (m, 3H), 13.29 (br.s., 1H).

Intermediate 19-4

6-(1H-pyrazol-4-yl)pyridine-2-carboxylic acid

Analogously to the synthesis of intermediate 19-2, 1 g (2.31 mmol) of 6-bromopyridine-2-carboxylic acid and 1.15 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted in a microwave at 120 ° C for 90 min. Ethyl acetate and water were added, the mixture was filtered, the organic phase was separated and extracted twice with ethyl acetate. The ethyl acetate phase was discarded. A 10% citric acid solution was added to the aqueous phase until pH 4 was reached, the mixture was extracted three times with ethyl acetate, and the ethyl acetate phase was concentrated. A residue was obtained, which was purified by preparative HPLC (column XBridge C18). 110 mg (12% of theoretical value) of the title compound were obtained.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 7.77-7.98 (m, 3H), 8.31 (s, 2H), 13.03 (br.s., 2H).

Intermediate 19-5

5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid

500 mg of methyl 6-bromo-5-fluoropyridine-2-carboxylate were reacted analogously with 533 mg (1.2 equivalents) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a microwave at 120° C. for 90 min. This gave 380 mg (80% of theory) of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.72 min

MS (ESIpos): m/z = 222 (M+H ⁾

Intermediate 19-6

6-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid

Analogously to the synthesis of Intermediate 19-2, 500 mg (2.31 mmol) of methyl 6-bromopyridine-2-carboxylate was reacted with 617 mg of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a microwave oven at 120° C. for 90 min. Purification by HPLC gave 66 mg (13% of theory) of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 2.47 (s), 3.80 (s, 3H), 7.71-7.81 (m, 2H), 7.88-7.94 (m, 1H), 8.27 (s, 1H), 12.95 (br.s., 1H).

Intermediate 19-7

6-(3-Methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid

Analogously to the synthesis of intermediate 19-2, 216 mg of methyl 6-bromopyridine-2-carboxylate was reacted with 250 mg of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a microwave oven at 120° C. for 90 min. After purification by HPLC, 68 mg (33% of theory) of the title compound were obtained as a mixture with methyl 6-(3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylate.

UPLC-MS (Method A1): R _t = 0.50 min

MS (ESIpos): m/z = 204 (M+H) ⁺

Intermediate 19-8

6-[3-(Methylsulfonyl)phenyl]pyridine-2-carboxylic acid

First, 500 mg (2.31 mmol) of methyl 6-bromopyridine-2-carboxylate and 694 mg (1.5 equivalents) of [3-(methylsulfonyl)phenyl]boronic acid were added to 10 ml of DMSO. 267 mg of tetrakis(triphenylphosphine)palladium(0), 736 mg of sodium carbonate, and 2 ml of water were added, and the mixture was heated in a microwave at 110°C for 2 h. The mixture was diluted with water and acidified to pH 4 with 10% citric acid solution. Ethyl acetate was added, the mixture was filtered, the phases of the filtrate were separated, the aqueous phase was extracted with ethyl acetate, the extract was washed with sodium chloride solution, and concentrated. 2.5 ml of methanol and 917 mg of lithium hydroxide monohydrate were added to 10 ml of water, and the mixture was stirred at room temperature for 5 h. The mixture was diluted with water, acidified to pH 4 with 10% citric acid solution, and extracted with ethyl acetate. The extract was washed with sodium chloride solution and concentrated. 776 mg of the title compound was obtained as a crude product.

UPLC-MS (Method A1): R _t = 0.75 min

MS (ESIpos): m/z＝278 (M+H ⁾

Intermediate 19-9

6-[3-(Trifluoromethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic acid

In analogy to the preparation of Intermediate 19-8, 250 mg of methyl 6-bromopyridine-2-carboxylate was reacted with 394 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole to give 442 mg of the title compound as a crude product.

UPLC-MS (Method A1): R _t = 0.82 min

MS (ESIpos): m/z＝258 (M+H) ⁺

Intermediate 19-10

Potassium 6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxylate

165 mg of potassium hydroxide was added to 693 mg of methyl 6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxylate (Intermediate 17-2) in 5.0 ml of methanol, and the mixture was stirred for 20 h at 50° C. Concentration gave 787 mg of a solid, which was further processed without any further purification.

Intermediate 19-11

Potassium 6-(2-hydroxypropan-3-yl)pyridine-2-carboxylate

Analogously to Intermediate 19-10, 535 mg of methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate (Intermediate 17-3) was reacted with 0.28 g of potassium hydroxide in 6.0 ml of methanol at 50° C. After concentration, 876 mg of the title compound was obtained as a crude product.

Intermediate 19-12

6-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylic acid

0.31g lithium hydroxide monohydrate dissolved in 1.0ml water and 0.5ml ethanol is added to a mixture of 230mg 6-{[1-(tert-butoxycarbonyl)azetidin-3-yl]amino}pyridine-2-carboxylic acid methyl esters (intermediate 17-4) in 4.0ml THF, and the mixture is stirred at room temperature overnight. The mixture is diluted with water, acidified to pH 6 with citric acid solution, and extracted with ethyl acetate, and the extract is washed with saturated sodium chloride solution, filtered through a hydrophobic filter and concentrated. 202mg of oil is obtained, which can be used without further purification.

Intermediate 19-13

Potassium 6-({[1-(tert-butoxycarbonyl)azetidin-2-yl]methyl}amino)pyridine-2-carboxylate

24 mg of potassium hydroxide was added to 230 mg of methyl 6-({[1-(tert-butoxycarbonyl)azetidin-2-yl]methyl}amino)pyridine-2-carboxylate (Intermediate 17-5) in 3.0 ml of ethanol, and the mixture was stirred overnight at 50° C. The mixture was concentrated to give 265 mg of a crude product, which was used further without purification.

Intermediate 19-14

6-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]pyridine-2-carboxylic acid

First, 875mg of 6-[(2R, 6S)-2,6-dimethylmorpholine-4-yl]pyridine-2-carboxylic acid methyl ester (intermediate 17-6) was added to 5ml of THF and 1ml of methanol, 698mg of lithium hydroxide monohydrate was added to 2.5ml of water, and the mixture was stirred at room temperature overnight. Toluene was added twice, and after each addition, the mixture was also concentrated. Methanol was added, the mixture was stirred, the solid was filtered out and washed with ether, the filtrate was concentrated and purified by preparative HPLC (method P1). 224mg of the title compound was obtained.

UPLC-MS (Method A1): R _t =0.66 min (UV detector TIC), mass measured 236.1.

Intermediate 19-15

Potassium 6-(isopropylamino)pyridine-2-carboxylate

454 mg of lithium hydroxide was added to a solution of 790 mg of methyl 6-(isopropylamino)pyridine-2-carboxylate (Intermediate 17-7) in 3.4 ml of water, 32 ml of THF and 3.2 ml of methanol, and the mixture was stirred at room temperature overnight. After concentration, 1.15 g of a solid was obtained, which was used without further purification.

UPLC-MS (Method A1): R _t =0.58 min (UV detector TIC), mass measured 194.00.

Intermediate 20-1

6-Bromo-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

Analogously to Intermediate 8-6, 1.00 g (2.47 mmol) of (5-{[(6-bromopyridin-2-yl)carbonyl]amino}-6-methoxy-2H-indazol-2-yl)acetic acid (Intermediate 9-21), 258 μl (2.96 mmol) of morpholine, 378 mg (2.47 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 946 mg (4.94 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1.03 ml (7.40 mmol) of triethylamine were stirred in 35 ml of tetrahydrofuran at 25° C. for 24 h. The reaction mixture was concentrated, water was added, and the resulting precipitate was filtered off with suction, washed with water and diethyl ether, and concentrated under reduced pressure. This gave 586 mg (50% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.07 min

MS (ESIpos): m/z = 474 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 3.47 (d, 2H), 3.58 (br.s., 4H), 3.64 (d, 2H), 4.00 (s, 3H), 5.4 0(s,2H),7.93-7.99(m,1H),8.05(t,1H),8.14-8.29(m,2H),8.68(s,1H),10.31(s,1H).

Intermediate 21-1

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

1.30 g (3.57 mmol) of [5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid (Intermediate 9-14) was dissolved in 50 ml of tetrahydrofuran and 5.4 ml of N,N-dimethylformamide, and the mixture was stirred at 25°C for 30 minutes. 997 mg (5.35 mmol) of tert-butyl piperazine-1-carboxylate, 546 mg (3.57 mmol) of 1-hydroxy-1H-benzotriazole hydrate, and 1.37 g (7.14 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were then added, and the mixture was stirred at 25°C for a further 24 hours. The reaction mixture was added to water. The resulting solid was filtered off with suction and washed twice with water. The solid was dissolved in dichloromethane, the solution was dried over sodium sulfate, filtered, and concentrated. The yellow solid was dried under reduced pressure. This gives 1.78 g (94% of theory) of tert-butyl 4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylate.

UPLC-MS (Method A1): R _t =1.21 min

MS (ESIpos): m/z＝533 (M+H) ⁺

Intermediate 22-1

N-{2-[2-Oxo-2-(piperazin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

1.93 ml (25.08 mmol) of trifluoroacetic acid were added to 1.78 g (3.34 mmol) of tert-butyl 4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylate (Intermediate 21-1) in 11 ml of dichloromethane, and the mixture was stirred at 25° C. for 24 h. The mixture was then poured into saturated sodium bicarbonate solution. The resulting suspension was filtered, and the filter cake was washed with 30 ml of water and 10 ml of diethyl ether. Drying under reduced pressure gave 1.41 g (97% of theory) of N-{2-[2-oxo-2-(piperazin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide as a crude product.

UPLC-MS (Method A1): R _t = 0.80 min

MS (ESIpos): m/z = 433 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ=2.66(br.s.,2H),2.73(br.s.,2H),3.39(br.s.,2H),3.47(br.s.,2H),5 .44(s,2H),7.47-7.68(m,2H),8.17(d,J=7.1Hz,1H),8.30(s,2H),8.33-8.43(m,2H),10.37(s,1H).

Intermediate 23-1

tert-Butyl 5-{[(benzyloxy)carbonyl]amino}-6-chloro-2H-indazole-2-carboxylate

1.50ml N-ethyl-N-isopropylpropane-2-amine and 1.11ml benzyl chloroformate are added to 2.09g 5-amino-6-chloro-2H-indazole-2-carboxylic acid tert-butyl ester (intermediate 12-2) in 15ml THF, and the mixture is stirred at room temperature overnight. 1.50ml N-ethyl-N-isopropylpropane-2-amine and 1.11ml benzyl chloroformate are added again, and the mixture is stirred at room temperature for 3 days. 1.50ml N-ethyl-N-isopropylpropane-2-amine and 1.11ml benzyl chloroformate are added again, and the mixture is stirred at room temperature overnight. Water is added, the mixture is extracted with ethyl acetate, and the extract is washed with sodium chloride solution and concentrated. 4.61mg crude product is obtained, which is further processed but does not need to be further purified.

UPLC-MS (Method A1): R _t =1.40 min (UV-TIC), mass measured 401.00.

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

Example

General Step 1a

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5.0 equivalents of triethylamine, and 1.5 equivalents of the mentioned carboxylic acid were stirred in tetrahydrofuran at 25°C for 24 hours. Water and ethyl acetate were added to the reaction mixture. The resulting precipitate was filtered, washed with water and diethyl ether, and dried.

General Step 1b

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine, and 1.5 equivalents of the mentioned carboxylic acid were stirred in N,N-dimethylformamide at 25° C. for 24 hours to obtain a suspension. The resulting precipitate was filtered, washed twice with N,N-dimethylformamide and diethyl ether, and dried.

General Step 1c

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5.0 equivalents of triethylamine, and 1.3 equivalents of the mentioned carboxylic acid were stirred in tetrahydrofuran at 25° C. for 24 h. Water was added, and the reaction mixture was repeatedly extracted with ethyl acetate. The combined organic phases were concentrated, and the residue was purified by preparative HPLC according to Method P1.

General Step 1d

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine and 1.2 equivalents of the mentioned carboxylic acid were stirred in 1 ml of N,N-dimethylformamide for 24 h at 25° C. The reaction mixture was diluted with a further 1.5 ml of N,N-dimethylformamide and purified by preparative HPLC according to Method P1.

General Step 1e

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.0 equivalents of triethylamine, and 1.2 equivalents of the mentioned carboxylic acid were stirred in 1.0 ml of tetrahydrofuran at 25° C. for 24 hours. The reaction mixture was poured into 25 ml of water. The resulting precipitate was filtered off, washed twice with diethyl ether, and dried in a drying cabinet.

Table 1: Examples 1-18

Exemplary compounds were prepared by General Experimental Procedures 1a-1e from appropriate intermediates and carboxylic acids.

*Prepared according to the described procedure, yields in % are shown in brackets.

[a]: The reaction was carried out in a mixture of tetrahydrofuran/N,N-dimethylformamide (5:1) using 3 equivalents of triethylamine.

[b]: 1.3 equivalents of pyridinecarboxylic acid were used.

[c]: 1.5 equivalents of pyridinecarboxylic acid were used. The product was in the aqueous phase.

[d]: Preparative HPLC was performed according to method P1.

[e]: The product precipitated directly from the reaction mixture was filtered off, washed repeatedly with water and dried in a drying cabinet.

**2-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]amino}-1,3-thiazole-4-carboxylic acid was prepared from 3-bromo-2-oxopropionic acid and tert-butyl 3-aminoazetidine-1-carboxylate similarly to Bioorganic and Medicinal Chemistry Letters, 1996, 6, 12, 1409–1414 and Chemical and Pharmaceutical Bulletin, 2005, 53, 4, 437–440.

Example 19

2-(azetidin-3-ylamino)-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-1,3-thiazole-4-carboxamide

21 mg (0.03 mmol) of tert-butyl 3-{[4-({2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamoyl)-1,3-thiazol-2-yl]amino}azetidine-1-carboxylate (Example 18) was dissolved in 1 ml of dichloromethane and 25 μl (0.03 mmol) of trifluoroacetic acid were added. The reaction mixture was stirred at 25 ° C for 24 h. The mixture was then diluted with more dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture was subsequently filtered through a hydrophobic filter and concentrated. The residue was dried under reduced pressure. 7 mg (31% of theory) of the title compound were obtained.

UPLC-MS (Method A2): R _t = 0.86 min

MS (ESIpos): m/z＝539 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 2.21 (s, 3H), 2.29 (br.s., 2H), 2.38 (br.s., 2H), 3.42-3.49 (m, 4H), 3.54 (br.s .,2H),3.69-3-73(m,1H),5.50(s,2H),7.49(s,1H),7.72(s,1H),8.42(s,1H),8.64(s,1H),9.58(s,1H).

Example 20

N-{6-cyano-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

First, 50 mg (0.10 mmol) of N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 15), 5 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0), and 12 mg (0.10 mmol) of zinc cyanide were placed in a microwave container and suspended in 1 ml of N,N-dimethylformamide. The reaction mixture was stirred in a microwave at 150°C for 15 minutes. Since the reaction was still incomplete, an additional 5 mg (0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) and 5.5 mg (0.05 mmol) of zinc cyanide were added, and the mixture was stirred in a microwave at 150°C for an additional 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The solution was then filtered through a hydrophobic filter and concentrated. The crude product was dissolved in 2.5 ml of N,N-dimethylformamide and purified by preparative HPLC according to Method P1. The product fractions were lyophilized. This gave 25 mg (56% of theory) of the title compound.

LC-MS (Method A3): R _t =1.07 min

MS (ESIpos): m/z = 472 (M + H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ=2.22(s,3H),2.27-2.33(m,2H),2.36-2.42(m,2H),3.44-3.50(m,2H),3.52-3.5 8(m,2H),5.59(s,2H),8.21-8.26(m,2H),8.37-8.43(m,2H),8.43-8.47(m,1H),8.51(d,1H),10.66(s,1H).

Example 21

6'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

75 mg (0.16 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide (Example 231) was dissolved in a degassed mixture of 1.73 ml of dioxane and 0.25 ml of water. 45 mg (0.33 mmol) of (6-methylpyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, and 52 mg (0.49 mmol) of sodium carbonate were added. The reaction mixture was stirred in a microwave at 105°C for 90 minutes. The reaction mixture was then filtered, and saturated ammonium chloride solution and dichloromethane were added to the filtrate. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The crude product was dissolved in 2.5 ml of N,N-dimethylformamide and purified by preparative HPLC according to Method P1. The product fractions were lyophilized. This gave 40 mg (52% of theory) of the title compound.

LC-MS (Method A3): R _t =0.46 min

MS (ESIpos): m/z = 470 (M + H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=2.22(s,3H),2.31(br.s.,2H),2.39(br.s.,2H),2.57(s,3H),3.48(br.s.,2H),3.55(d,2H),5.47( s,2H)7.44(d,1H),7.62(s,2H),8.08-8.20(m,2H),8.26-8.32(m,2H),8.34(s,1H),8.68(dd,1H),9.43(d,1H),10.54(s,1H).

Example 22

5'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

Analogously to Example 21, 75 mg (0.16 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide were stirred with 45 mg (0.33 mmol) of (5-methylpyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 52 mg (0.49 mmol) of sodium carbonate in a degassed mixture of 1.73 ml of dioxane and 0.25 ml of water in a microwave at 105° C. for 90 minutes. Workup and preparative HPLC according to Method P1 gave 41 mg (53% of theory) of the title compound.

LC-MS (Method A3): R _t =0.51 min

MS (ESIpos): m/z = 470 (M + H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=2.23(s,3H),2.32(br.s.,2H),2.41(br.s.,2H),2.45(s,3H),3.48(br.s.,2H),3.56(br.s.,2 H),5.47(s,2H),7.62(s,2H),8.11-8.23(m,2H),8.27-8.37(m,3H),8.55(s,1H),8.60(s,1H),9.38(d,1H),10.55(s,1H).

Example 23

4'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

Analogously to Example 21, 75 mg (0.16 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide were stirred with 45 mg (0.33 mmol) of (4-methylpyridin-3-yl)boronic acid, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 52 mg (0.49 mmol) of sodium carbonate in a degassed mixture of 1.73 ml of dioxane and 0.25 ml of water in a microwave at 105° C. for 90 minutes. Workup and preparative HPLC according to Method P1 gave 16 mg (21% of theory) of the title compound.

LC-MS (Method A3): R _t =0.45 min

MS (ESIpos): m/z = 470 (M + H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ = 2.21 (s, 3H), 2.30 (br.s., 2H), 2.38 (br.s., 2H), 3.47 (br.s., 2H), 3.54 (d, 2H), 5.45 (s, 2H), 7.42(d,1H),7.57(d,2H),7.91(t,1H),8.19(d,2H),8.28(s,1H),8.34(s,1H),8.54(d,1H),8.78(s,1H),10.41(s,1H).

Example 24

6'-Methoxy-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

Analogously to Example 21, 50 mg (0.11 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide were stirred with 33 mg (0.22 mmol) of (6-methoxypyridin-3-yl)boronic acid, 9 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and 35 mg (0.33 mmol) of sodium carbonate in a degassed mixture of 1.15 ml of dioxane and 0.17 ml of water in a microwave at 105° C. for 90 minutes. Workup and preparative HPLC according to Method P1 gave 28 mg (52% of theory) of the title compound.

LC-MS (Method A3): R _t =0.74 min

MS (ESIpos): m/z = 486 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 2.21 (s, 3H), 2.30 (t, 2H), 2.38 (t, 2H), 3.45-3 .52(m,2H),3.52-3.60(m,2H),3.96(s,3H),5.46(s,2H),6.96-7.01(m,1H ),7.58-7.66(m,2H),8.07-8.11(m,1H),8.11-8.16(m,1H),8.24(dd,1H), 8.30(s,1H),8.32-8.34(m,1H),8.74(dd,1H),9.22(d,1H),10.52(s,1H).

Example 25

6'-acetamido-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

Analogously to Example 21, 50 mg (0.11 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide was stirred with 57 mg (0.22 mmol) of N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide, 9 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride and 35 mg (0.33 mmol) of sodium carbonate in a degassed mixture of 1.15 ml of dioxane and 0.17 ml of water in a microwave at 105° C. Workup and preparative HPLC according to Method P1 gave 21 mg (37% of theory) of the title compound.

LC-MS (Method A3): R _t =0.59 min

MS (ESIpos): m/z = 513 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 2.15 (s, 3H), 2.21 (s, 3H), 2.27-2.34 (m, 2H), 2.3 5-2.41(m,2H),3.44-3.51(m,2H),3.52-3.58(m,2H),5.46(s,2H),7.58-7. 68(m,2H),8.09-8.12(m,1H),8.12-8.17(m,1H),8.23-8.29(m,2H),8.30(s ,1H),8.34(s,1H),8.79(dd,1H),9.32(dd,1H),10.53(s,1H),10.69(s,1H).

Example 26

N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6'-nitro-2,3'-bipyridine-6-carboxamide

Analogously to Example 21, 75 mg (0.16 mmol) of 6-bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide were stirred with 82 mg (0.33 mmol) of 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 13 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 52 mg (0.49 mmol) of sodium carbonate in a degassed mixture of 1.73 ml of dioxane and 0.25 ml of water in a microwave at 105° C. Workup and preparative HPLC according to Method P1 gave 26 mg (32% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.78 min

MS (ESIpos): m/z＝501(M+H) ⁺

¹ H NMR (300MHz, DMSO-d6): δ=2.22(s,3H),2.31(br.s.,2H),2.39(br.s.,2H),3.48(br.s.,2H),3.56(br.s.,2H) ),5.47(s,2H),7.63(s,2H),8.22-8.38(m,4H),8.45-8.55(m,2H),9.22(dd,1H),9.72(d,1H),10.63(s,1H).

Example 27

6'-amino-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide

Dissolve 20 mg (0.04 mmol) of N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6'-nitro-2,3'-bipyridine-6-carboxamide in 2.5 ml of methanol, add 4 mg (0.004 mmol, 10%) of palladium/carbon, and hydrogenate the mixture under a 1 bar hydrogen atmosphere for 4 h. The reaction mixture is filtered through Celite, the filter cake is repeatedly washed with methanol, and the filtrate is concentrated and dried under reduced pressure. This yields 8 mg (43% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 0.81 min

MS (ESIpos): m/z = 471 (M + H) ⁺

¹ H NMR (400MHz, METHANOL-d4): δ = 2.34 (s, 3H), 2.43-2.49 (m, 2H), 2.53 (br.s., 2H), 3.66 (br.s., 4H), 5.46 (s, 2H), 6.73 (d, 1H), 7 .51-7.58(m,1H),7.60-7.67(m,1H),7.94-8.04(m,2H),8.07(d,1H),8.21(s,1H),8.34(br.s.,2H),8.55(s,1H),8.77(s,1H).

General Step 2a

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, and 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 3 ml of tetrahydrofuran and 0.33 ml of dimethylformamide at 25° C. for 30 minutes. 1.5 equivalents of an amine were then added, and the mixture was stirred at 25° C. for 30 minutes. The mixture was poured into 50 ml of water, filtered with suction, washed with water, and dried.

General Step 2b

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 3.0 equivalents of triethylamine were stirred in 1.5 ml of N,N-dimethylformamide at 25° C. for 30 min. 1.2 equivalents of the amine were then added. The reaction mixture was diluted with an additional 1.0 ml of N,N-dimethylformamide and purified by preparative HPLC according to Method P1.

General Step 2c

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine, and 1.2 equivalents of the amine were stirred in tetrahydrofuran at 25°C for 18 hours. Water was added to the reaction mixture. The solid was filtered, washed with water and diethyl ether, and dried.

General Step 2d

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine, and 1.5 equivalents of an amine were stirred in tetrahydrofuran at 25° C. for 18 h. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phases were concentrated, and the crude product was purified by preparative HPLC according to Method P4.

General Step 2e

At 25°C, 1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine and 1.3 equivalents of the amine were stirred in tetrahydrofuran for 18 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phases were concentrated and 1 ml of dimethyl sulfoxide was added. The solid was filtered off with suction, washed three times with dimethyl sulfoxide (0.5 ml each time), washed three times with diethyl ether and dried. The filtrate was concentrated and purified by preparative HPLC according to Method P2. The resulting product fractions were combined with the solid.

General Step 2f

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.0 equivalents of triethylamine, and 1.2 equivalents of the amine were stirred in tetrahydrofuran at 25°C for 18 hours. The resulting precipitate was filtered off and washed with tetrahydrofuran. The solid was triturated with methyl tert-butyl ether and ethyl acetate, then dissolved in dichloromethane and water added. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution was concentrated, and the resulting solid was dried.

General Step 2g

1.0 equivalent of the corresponding intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine, and 1.3 equivalents of the amine were stirred in tetrahydrofuran at 50°C for 18 hours. Water and ethyl acetate were added to the reaction mixture. The solid was filtered, washed with water and diethyl ether, and dried.

Table 2: Examples 28-71

Exemplary compounds were prepared by General Procedures 2a-2g from appropriate intermediates and amines.

*Prepared according to the described method, the yield in % is shown in brackets.

[a]: Piperazine was used in the form of its hydrochloride. In addition to piperazine, 1.6 equivalents of triethylamine were added to the reaction mixture.

[b]: The product was purified by preparative HPLC according to Method P1.

[c]: Gradient for preparative HPLC: isocratic ethanol/methanol/diethylamine 50:50:0.1;

Flow rate: 35ml/min

[d]: Gradient for preparative HPLC: isocratic hexane/ethanol/diethylamine 70:30:0.1;

Flow rate: 40ml/min

[e]: Gradient for preparative HPLC: isocratic hexane/ethanol/diethylamine 70:30:0.1; flow rate: 31 ml/min

[f]: Use N,N-dimethylformamide instead of dimethyl sulfoxide.

[g]: HPLC was performed according to method P1.

[h]: 1.5 equivalents of piperazine were used.

[i]: The product was triturated with N,N-dimethylformamide and dimethyl sulfoxide.

Example 72

N-{2-[2-(4-Benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Analogously to Intermediate 8-1, 103 mg (0.27 mmol) of 2-(5-amino-3-methyl-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone (Intermediate 6-15, crude product) was reacted with 78 mg (0.41 mmol) of 6-(trifluoromethyl)pyridine-2-carboxylic acid. After 24 h at 25° C., water was added. The solid was filtered off, washed with water and diethyl ether, and dried under reduced pressure. This gave 43 mg (29% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.12 min

MS (ESIpos): m/z = 551 (M+H) +.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 3.34-3.73 (m, 8H), 5.48 (br.s., 2H), 7.42-7.58 (m, 7H), 8.14-8.23 (m, 2H), 8.32-8.43 (m, 2H), 10.35 (s, 1H).

Example 73

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

Analogously to Intermediate 8-1, 80 mg (0.21 mmol) of 3-[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]propanoic acid (Intermediate 9-15) was stirred in 0.3 ml of N,N-dimethylformamide and 2.9 ml of tetrahydrofuran with 32 mg (0.21 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 81 mg (0.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride for 30 minutes. 60 mg (0.32 mmol) of phenyl(piperazin-1-yl)methanone was added. The reaction mixture was stirred at 25° C. for 2.5 h and added dropwise to 50 ml of water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The crude product was stirred in 2 ml of dimethyl sulfoxide for 30 min, filtered and washed with 30 ml of water. The solid was purified by preparative HPLC according to Method P1. This gave 5 mg (4% of theory) of the title compound.

UPLC-MS (Method A1): R _t = 1.10 min

MS (ESIpos): m/z＝551(M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 3.10 (br.s., 2H), 3.50 (br.s., 6H), 4.65 (t, 2H), 7.36-7.42 (m, 2H), 7. 42-7.47(m,3H),7.53-7.63(m,2H),8.17(dd,1H),8.28(s,1H),8.32-8.42(m,3H),10.35(s,1H).

The exemplary compounds in Tables 3-17 were synthesized by amide synthesis similar to Experimental Procedures 1a-1g and 2a-2g or by the methods shown in the tables and analyzed by analytical LC-MS (Method A4).

Table 3: Examples 74-77

Exemplary compounds were prepared from 2-(5-amino-2H-indazol-2-yl)-1-[4-(cyclopropylcarbonyl)piperazin-1-yl]ethanone (Intermediate 6-10) and the starting materials shown in the table.

Table 4: Examples 78-83

Exemplary compounds were prepared from 2-(5-amino-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone and the starting materials shown in the table.

Table 5: Examples 84-85

Exemplary compounds were prepared from 2-(5-amino-2H-indazol-2-yl)-1-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethanone (Intermediate 6-13) and the starting materials shown in the table.

Table 6: Example 86

Exemplary compounds were prepared from 4-[(5-amino-2H-indazol-2-yl)acetyl]-1-ethylpiperazin-2-one and the starting materials shown in the table.

Table 7: Examples 87-121

Exemplary compounds were prepared from 2-(5-amino-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone (Intermediate 6-11) and the starting materials shown in the table.

Table 8: Examples 122-200

Exemplary compounds were prepared from [5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid (Intermediate 9-14) and the starting materials shown in the table.

Table 9: Examples 201-205

Exemplary compounds were prepared from [5-({[6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid (Intermediate 9-10) and the starting materials shown in the table.

Table 10: Examples 206-208

Exemplary compounds were prepared from the intermediates shown in the table.

Table 11: Examples 209-210

Exemplary compounds (Examples) were prepared from 2-(5-amino-6-methoxy-2H-indazol-2-yl)-1-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]ethanone (Intermediate 6-5).

Table 12: Examples 211-213

Exemplary compounds were prepared from 2-(5-amino-2H-indazol-2-yl)-1-(4-benzoylpiperazin-1-yl)ethanone (Intermediate 6-11).

Table 13: Examples 214-216

Table 14: Examples 217-222

Exemplary compounds were prepared from [6-isopropoxy-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid (Intermediate 9-16) or (6-isopropoxy-5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2H-indazol-2-yl)acetic acid (Intermediate 9-17) and the starting materials shown in the table according to general procedure 2a.

Table 15: Examples 223-226

Exemplary compounds were prepared from N-{2-[2-oxo-2-(piperazin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 22-1) and the starting materials shown in the table via an amide synthesis method similar to the above examples.

Table 16: Examples 227-244

Exemplary compounds were prepared from the intermediates and starting materials shown in the table.

Table 17: Examples 245-247

Table 18: Examples 248-260

Exemplary compounds were prepared by General Procedures 2a-2g from appropriate intermediates and amines.

Example 261

N-{6-(3-hydroxy-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

Step A:

N-{6-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

100 mg (0.22 mmol) of N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Example 287) was dissolved in 2.0 ml of N,N-dimethylformamide and 46 mg (0.33 mmol) of potassium carbonate was added with stirring. The suspension was stirred at 25° C. for 10 minutes, and then 94 mg (0.33 mmol) of (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane was added. The reaction mixture was stirred in a microwave at 100° C. for 1 hour. The reaction mixture was then filtered and purified by preparative HPLC. 34 mg (24% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.70 min

MS (ESIpos): m/z＝650 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ=-0.17--0.09(m,6H),0.75(s,9H),1.07(s,6H),3.42-3.51(m,2H),3.54-3.64(m,2H),3.54-3.64(m,4H),3. 64-3.71(m,2H),3.88(s,2H),5.40(s,2H),7.05(s,1H),8.17-8.27(m,2H),8.42(t,1H),8.49-8.56(m,1H),8.79(s,1H),10.42(s,1H).

Step B:

Dissolve 40 mg (0.06 mmol) of N-{6-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide in 2.5 ml of tetrahydrofuran. Add 185 μl (0.18 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran, and stir the mixture at 25°C for 2 hours. Add 5 ml of water, and concentrate the reaction mixture. The resulting precipitate is filtered, washed with water and diethyl ether, and dried under reduced pressure. This gave 26 mg (48% of theory) of N-{6-(3-hydroxy-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide.

UPLC-MS (Method A1): R _t =1.09 min

MS (ESIpos): m/z＝536 (M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ = 1.06 (s, 6H), 3.42 (d, Hz, 2H), 3.45-3.51 (m, 2H), 3.54-3.63 (m, 4H), 3.63-3.68 (m, 2H), 3.90 (s, 2H),4.63-4.69(m,1H),5.40(s,2H),7.05(s,1H),8.17-8.25(m,2H),8.41(t,1H),8.51(d,1H),8.81(s,1H),10.44(s,1H).

Example 262

6-ethyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

50 mg (0.11 mmol) of 6-bromo-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide (Intermediate 15-2) was suspended in 750 μl of dry dioxane, 86 μl (0.09 mmol) of a 1.1 M solution of diethylzinc in toluene and 4 mg (0.01 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex were added, and the mixture was stirred at 40°C for 24 h. Another 86 μl (0.09 mmol) of a 1.1 M solution of diethylzinc in toluene and 4 mg (0.01 mmol) of 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex were added, and the mixture was stirred at 60°C for another 24 h. A further 86 μl (0.09 mmol) of a 1.1 M solution of diethylzinc in toluene and 4 mg (0.01 mmol) of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex were added, and the mixture was stirred at 60°C for a further 24 h. The reaction mixture was filtered and the filtrate concentrated. The crude product was dissolved in 2.5 ml of dimethyl sulfoxide and purified by preparative HPLC according to Method P1. The product fractions were lyophilized. This gave 5.8 mg (11% of theory) of the title compound.

UPLC-MS (Method A1): R _t =1.11 min

MS (ESIpos): m/z = 424 (M+H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 1.37 (t, 3H), 2.92 (q, 2H), 3.42-3.50 (m, 2H), 3.58 (br.s., 4H), 3.62-3.69 (m, 2H), 4 .00(s,3H),5.39(s,2H),7.10(s,1H),7.57(dd,2H),7.97-8.02(m,2H),8.21(s,1H),8.71(s,1H),10.88(s,1H).

Example 263

6-Isobutyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide

50 mg (0.11 mmol) of 6-bromo-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide (intermediate 15-2) were dissolved in 1.5 ml of tetrahydrofuran, 316 μl (0.16 mmol) of a 0.5 M solution of 2-methylpropylzinc bromide in tetrahydrofuran and 3 mg (0.01 mmol) of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at 25° C. for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The crude product was dissolved in 2.5 ml of dimethyl sulfoxide and purified by preparative HPLC according to method P1. The product fractions were lyophilized. 2.8 mg (6% of theory) of the title compound were obtained.

UPLC-MS (Method A1): R _t =1.27 min

MS (ESIpos): m/z = 452 (M + H) ⁺

¹ H-NMR (300MHz, DMSO-d6): δ = 0.99 (d, 6H) 2.15-2.29 (m, 1H) 2.77 (d, 2H) 3.47 (d, 2H) 3.53-3.69 (m, 6H) 3. 99(s,3H)5.39(s,2H)7.09(s,1H)7.53(dd,1H)7.94-8.03(m,2H)8.21(s,1H)8.71(s,1H)10.85(s,1H).

Example 264

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

100 mg (0.60 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (intermediate 14-9) was dissolved in 1 ml of tetrahydrofuran, 228 mg (1.10 mmol) of 2-bromo-1-(morpholin-4-yl)ethanone and 235 μl (1.10 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 75° C. for 24 h. The reaction mixture was filtered using a membrane filter, and the filtrate was diluted with 1 ml of dimethyl sulfoxide and purified by preparative HPLC. The product fractions were lyophilized. This gave 15 mg (11% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 1.10 min

MS (ESIpos): m/z = 492 (M+H) ⁺

^1H NMR (400MHz, CHLOROFORM-d): δ = 3.45-3.50 (m, 2H), 3.54-3.64 (m, 4H), 3.64-3.70 (m, 2H), 3.97 (s, 3H),5.59(s,2H),8.21(dd,1H),8.36-8.43(m,1H),8.44-8.49(m,3H),9.08(s,1H),12.52(s,1H).

Example 265

5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazole-6-carboxylic acid methyl ester

50 mg (0.16 mmol) (intermediate 14-10) was dissolved in 2.5 ml of tetrahydrofuran, 134 mg (0.64 mmol) of 2-bromo-1-(morpholin-4-yl)ethanone and 138 μl (0.64 mmol) of N,N-dicyclohexylmethylamine were added, and the mixture was stirred at 80 ° C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane, washed three times with 1M hydrochloric acid solution, washed three times with saturated sodium chloride solution, filtered through a hydrophobic filter, and adsorbed onto HM-N (Biotage) during the concentration process. Isolute was applied to a column (40 g; Puriflash) pre-equilibrated with hexane, and chromatography was performed using a rapid purification system (Biotage) (mobile phase: hexane/ethyl acetate; flow rate: 25 ml/min; gradient: 90:10->25:75). The combined product fractions were concentrated and dried. This gave 20 mg (28% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 1.05 min

MS (ESIpos): m/z = 438 (M+H) ⁺

¹ H NMR (400MHz, CHLOROFORM-d): δ = 2.65 (s, 3H), 3.48 (d, 2H), 3.59 (dd, 4H), 3.67 (d, 2H), 3.99 (s, 3 H),5.58(s,2H),7.55(dd,1H),7.81-8.04(m,2H),8.38-8.47(m,2H),9.09(s,1H),12.57(s,1H).

Table 19: Examples 266-286

Exemplary compounds were prepared by General Experimental Procedures 1a-1e from appropriate intermediates and carboxylic acids.

*Intermediate 6-16 reacts with potassium 6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxylate to afford N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxamide as a racemic mixture. This mixture was separated into the pure enantiomers by preparative chiral HPLC using the following conditions:

System: Agilent: Prep 1200, 2xPrep pumps, DLA, MWD, Gilson:

Liquid Handler 215

Column: Chiralpak IC 5μm 250x30mm

Solvent: ethanol/methanol 50:50 (v/v)

Flow rate: 35ml/min

Temperature: Room temperature

Solution: 401 mg/8 ml dichloromethane/MeOH

Injection volume: 10×0.8ml

Detection: UV 280nm

Fraction R _t (min) Purity (%) Quantity (mg) Peak identity

Corresponding Example 8.0-8.7 98.8 70 Peak 2-2.88min

273

Corresponding Example 10.1-11.1 99.1 59 Peak 4-3.81min

272

Work-up: the fractions were concentrated by evaporation, mixed with tBuOH, frozen at -65°C and then freeze-dried.

Example 287

N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

2.43 g (4.50 mmol) of N-{6-(benzyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (Beispiel 280) were suspended in 470 ml of tetrahydrofuran, the flask was evacuated and then flushed with nitrogen (this step was repeated twice more). 958 mg (0.9 mmol, 10%) of palladium on carbon and 95 ml (370.6 mmol) of 25% strength ammonium formate solution were added, and the mixture was stirred vigorously at 25° C. for 40 minutes. The reaction mixture was filtered through Celite and concentrated. The resulting precipitate was filtered off with suction, washed repeatedly with water, and dried under reduced pressure in a drying cabinet at 50° C. This gave 2.01 g (90% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.64 min

MS (ESIpos): m/z＝450(M+H) ⁺

¹ H NMR (400MHz, DMSO-d6): δ=3.40-3.50(m,2H),3.52-3.61(m,4H),3.61-3.67(m,2H),5.36(s,2H),6 .91(s,1H),8.16-8.23(m,2H),8.40(t,1H),8.47(d,1H),8.69(s,1H),10.55(s,1H),10.65(s,1H).

General Step 3a

1.0 equivalents of N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)picolinamide were stirred with 1.5 equivalents of the appropriate halide and 3.0 equivalents of potassium carbonate in N,N-dimethylformamide in a microwave at 100° C. for 1 h. Water was added to the reaction mixture, and the resulting precipitate was filtered, washed with water and diethyl ether, and dried.

General Step 3b

1.0 equivalents of N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)picolinamide were stirred with 1.5 equivalents of the appropriate halide and 3.0 equivalents of potassium carbonate in N,N-dimethylformamide in a microwave for 1 h at 100° C. The reaction mixture was filtered, dimethyl sulfoxide was added, and the product was purified by preparative HPLC according to Method P1.

General Step 3c

1.0 equivalents of N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)picolinamide were stirred with 3.0 equivalents of the appropriate halide, 5.0 equivalents of potassium carbonate, and 0.1 equivalents of potassium iodide in N,N-dimethylformamide in a microwave at 150° C. for 1 h. The reaction mixture was filtered, dimethyl sulfoxide was added, and the product was purified by preparative HPLC according to Method P5 (Gradient: 0-15 min 10-50% B).

Table 20: Examples 304-328

Exemplary compounds were prepared from N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide and the halides listed in the table according to general procedures 3a, 3b or 3c.

*Prepared according to the method, the yield in % is shown in brackets

[a]: After 60 min, another 1 equivalent of halide was added and the mixture was stirred in the microwave at 120° C. for another 60 min.

[b]: The crude product was purified by preparative HPLC.

[c]: The crude product was purified by preparative HPLC according to method P5 (gradient: 0-15 min 30-70% B).

[d]: The reaction mixture was added to water, the precipitate was filtered off with suction and washed with diethyl ether. The crude product was purified by preparative HPLC according to Method P5 (Gradient: 0-15 min 15-55% B). [e]: The crude product was purified by preparative HPLC according to Method P5 (Gradient: 0-15 min 15-55% B).

[f] The alkylated intermediate was deprotected using the following procedure (the second yield in % shown in the table refers to the deprotection yield). One equivalent of the silyl-protected intermediate was dissolved in tetrahydrofuran, 3 equivalents of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added, and the mixture was stirred at 25°C for 24 hours. Water was added to the reaction mixture, and the resulting precipitate was filtered, washed with water, and dried under reduced pressure in a drying oven at 50°C.

[g]: An additional 0.1 equivalents of potassium iodide was added to the reaction mixture.

[h]: The crude product was purified by preparative HPLC (column: XBridge C18 5 μm 100×30 mm).

Example 308

2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propanoic acid

Analogously to Intermediate 4-1, 50 mg (0.09 mmol) of ethyl 2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propanoate (Example 306) was dissolved in 0.5 ml of tetrahydrofuran, 11 mg (0.45 mmol) of lithium hydroxide monohydrate in 164 μl of water were added, and the mixture was stirred at 25° C. for 24 h. The reaction mixture was filtered, dimethyl sulfoxide was added, and the product was purified by preparative HPLC (column: XBridge C18 5 μm 100×30 mm). This gave 7 mg (15% of theory) of the title compound.

UPLC-MS (Method A2): R _t = 0.67 min

MS (ESIpos): m/z＝522 (M+H) ⁺

^1H NMR (400MHz, DMSO-d6): δ = 1.64 (d, 3H), 3.46 (br.s., 2H), 3.58 (br.s., 4H), 3.64 (d, 2H), 4.99 (d, 1H), 5.38 (s,2H),6.97(s,1H),8.15-8.25(m,2H),8.35-8.45(m,1H),8.45-8.51(m,1H),8.73(s,1H),10.82(s,1H).

Example 309

N-{6-(2-hydroxypropan-2-yl)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

536 mg (4 equivalents) of 2-bromo-1-(morpholin-4-yl)ethanone were added to a mixture of 250 mg (0.69 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 14-11) and 0.59 ml of N,N-dicyclohexylmethylamine in 1.5 ml of THF, and the mixture was stirred at 70° C. overnight. Water was added, the mixture was extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, filtered through a hydrophobic filter, and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane/methanol). This gave 46 mg (14% of theory) of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]＝1.62(s,6H),3.46(d,3H),3.42-3.69(m),5.45(s,2H),5.95(s,1H),7.54(s ,1H),8.15(dd,1H),8.25(s,1H),8.36(t,1H),8.45(d,1H),8.73(s,1H),12.35(s,1H).

UPLC-MS (Method A2): Rt=0.99 min (UV-TIC), mass measured 491.00.

Example 31 0

N-{6-chloro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide

First, 98 mg (0.32 mmol) of 2-(5-amino-6-chloro-2H-indazol-2-yl)-1-(4-methylpiperazin-1-yl)ethanone (Intermediate 6-21) and 82 mg of 6-(difluoromethyl)pyridine-2-carboxylic acid were added to 3.0 ml of THF. 49 mg of 1-hydroxy-1H-benzotriazole hydrate, 121 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 0.13 ml of triethylamine were added, and the mixture was stirred at room temperature for 19.5 hours. The mixture was diluted with water, and the precipitated solid was filtered off, washed twice with water, three times with ether, and dried under reduced pressure. This gave 129 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ[ppm]＝2.21(s,3H),2.25–2.42(m,4H),3.42-3.59(m,4H),5.50(s,2H),7.14( t,1H),7.91(s,1H),8.02(dd,1H),8.29-8.44(m,3H),8.64(s,1H),10.60(s,1H).

UPLC-MS (Method A2): R _t =1.06 min (UV-TIC), mass measured 462.00.

Example 311

N-{6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide

Analogously to the preparation of Example 310, 137 mg of 2-(5-amino-6-chloro-2H-indazol-2-yl)-1-(morpholin-4-yl)ethanone (Intermediate 6-22) was reacted with 70 mg of 6-(difluoromethyl)pyridine-2-carboxylic acid at room temperature for 68 h. Water was added, and the solid was filtered off with suction, washed with acetone, water, and diethyl ether, and dried under reduced pressure. This yielded 91 mg of the title compound.

UPLC-MS (Method A1): Rt = 1.06 min (UV-TIC), mass measured 449.00.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ[ppm]=3.42-3.68(m,8H),5.50(s,2H),7.90(s,1H),8.01(dd,1H),8.29-8.36(m,2H),8.41(d,1H),8.64(s,1H),10.59(s,1H).

Physiological efficacy evaluation

The in vitro activity of the compounds of the invention can be shown in the following assays:

Irak4 kinase assay

The Irak4 inhibitory activity of the inventive substances of the present invention was measured in the Irak4 TR-FRET assay (TR-FRET=time-resolved fluorescence resonance energy transfer) described in the subsequent paragraphs.

A recombinant fusion protein derived from N-terminal GST (glutathione-S-transferase) and human Irak4 was used as the enzyme, expressed in baculovirus-infected insect cells (Hi5, BTI-TN-5B1-4, a cell line purchased from Invitrogen, catalog number B855-02) and purified by 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. For the assay, 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)) was 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 μM) 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 approximately 0.2 nM. The reaction was terminated by adding 5 μl of a solution of TR-FRET detection reagent [0.1 μM streptavidin-XL665 (Cisbio Bioassays; France, catalog number 610SAXLG) and 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 AD0071, or 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 the phosphorylated substrate was subsequently 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 the phosphorylated substrate. The data were normalized (enzyme reaction without test substance = 0% inhibition, with all other assay components without enzyme = 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. A 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 21: _IC50 values of exemplary compounds in the IRAK4 kinase assay.

TNF-α secretion in THP-1 cells

Using this test, substances can be tested for their ability 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 fetal calf serum (FCS) 10% (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 cell culture medium (RPMI 1460 medium containing L-Glutamax, supplemented with FCS 10%).

In each case, the cell suspension of 2-2.5 μ l per well (corresponding to 4000 cells) was assigned to a 384-well test plate (Greiner, catalog number (Cat. No.) 784076), wherein in each case, 40-50 nl of the substance was dissolved in 100% DMSO. In this article, in each case, 10 different concentrations of each substance were used in the range of 20 μ M to 0.073 nM. The cells were incubated at room temperature for 15 min. 2-2.5 μ l 0.1 μ g/ml LPS (Sigma, Escherichia coli 055:B5, catalog number (Cat. No.) L5418) (final concentration 0.05 μ g/ml) dissolved in the cell culture medium was then assigned to each well. As a neutral control, cells were processed with 0.05 μ g/ml LPS and 1% DMSO, and as an inhibition control, only 1% DMSO was used once.

The plate was centrifuged at 80 g for 30 s and incubated for 17 h at 37° C., 5% CO ₂ , 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 a detection solution consisting of an anti-TNF-α-XL665 conjugate and an 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 h or overnight at 4° C. 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 inhibition control in percent. The _IC50 values are calculated using a 4-parameter fit.

Table 22: _IC50 values of exemplary compounds on TNF-α secretion in THP-1 cells.

*: Highest _IC50 value achievable due to assay limitations

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

The compounds of the present invention were tested for their efficacy on cytokine production induced in human PBMCs. 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 platelet-containing plasma 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 (RPMI1640, 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 culture medium. PBMCs were seeded into 96-well plates at a cell density of 2.5×10 ⁵ cells/well. The compound of the present invention was serially diluted with a constant volume of 100% DMSO and applied to the assay at 8 different concentrations ranging from 10 μM to 3 nM, so that the final DMSO concentration was 0.4% DMSO. Before actual stimulation, the cells were pre-incubated therein for 30 min. In order to induce cytokine secretion, the cells were stimulated with 0.1 μg/ml LPS (Sigma, catalog number L4516) 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 HumanProInflammatory 9-Plex Tissue Culture Kit (MSD, catalog number K15007B) according to the manufacturer's instructions. By way of example, exemplary compound 1 was active at 1 to 10 μM, and exemplary compounds 47, 64, and 71 were active at ≤ 1 μM.

In vitro tumor-associated NF-kB reporter gene activity

The efficacy of the compounds of the present invention on the NF-kB signaling pathway was tested in human DLBCL (diffuse large B-cell lymphoma) cell lines. TMD-8, HBL-1, U2932, HT, and WSU-DLCL2 were stably transduced with a lentiviral NF-kB reporter gene construct (Cignal Lenti NFκB Reporter (luc) Kit: CLS-013L, Qiagen) to generate TMD-8-NF-kB-luc, HBL-1-NF-kB-luc, U2932-NF-kB-luc, HT-NF-kB-luc, and WSU-DLCL2-NF-kB-luc reporter gene cell lines. 10,000 cells were transferred to 384-well plates (Perkin Elmer, white) in 30 μl/well of growth medium (RPMI (Biochrom, catalog no. FG 1215), 20% FCS (Biochrom, catalog no. S 0615)) or RPMI 1640 medium supplemented with 10% FCS and incubated overnight at 37°C. After 24 h, the cells were treated with the test substances and incubated at 37°C for 6 h and 24 h. The test substances were added to the cells in 7-fold dilutions, either alone or as a combination of two different concentrations of the test substances (ratios of substance 1 and substance 2: 1:0, 0.85:0.15; 0.7:0.3; 0.5:0.5; 0.3:0.7; 0.15:0.85; 0:1) using an HP D300 digital dispenser. As a control, the cells were treated with vehicle (DMSO). After 6h and 24h, cells were processed with One-Glo solution (Promega, catalog number (Cat. No.) E6110) in 30 μl/well and incubated for 10min at room temperature, and luminescence was measured using VICTOR V (Perkin Elmer) to measure the NF-KB reporter gene activity at the end of the treatment. For each test substance, the efficacy for the NF-KB reporter gene activity and the _IC50 value obtained therefrom were measured in percentage. _IC50 values were calculated using 4-parameter fitting.

By way of example, exemplary compound 289 was active at 1 to 10 μM against the cell lines TMD-8-NF-κB-luc, HBL-1-NF-κB-luc, U2932-NF-κB-luc, and WSU-DLCL2-NF-κB-luc.

In vitro tumor-associated interleukin-6 and interleukin-10 secretion

The compounds of the present invention were tested for their efficacy in secreting interleukin-6 and interleukin-10 in human TMD-8DLBCL cells. 15,000 cells/well were seeded in 100 μl of fresh growth medium (RPMI (Biochrom, catalog number FG 1215), 20% FCS (Biochrom, catalog number S 0615)) in a 96-well plate (Perkin Elmer). The test substance diluted 7 times was added to the cells using an HPD300 digital dispenser and incubated for 24 hours. After the incubation time, the supernatant was collected and the interleukin concentration was determined according to the manufacturer's instructions using Human IL-6/IL-10 Elisa Kit (Life Technologies, catalog number KHC0062, KHC0101). For each test substance, the efficacy for interleukin secretion was measured in percentage.

By way of example, exemplary compound 289 is mentioned to be active on the secretion of interleukin-6 and interleukin-10 at 1 to 10 μM.

The suitability of the compounds of the present invention for the treatment of inflammatory disorders, tumor disorders and ophthalmological disorders such as wet AMD (age-related macular degeneration) can be shown in the following animal models:

In vivo model of TLR-mediated inflammation

The in vivo efficacy of the compounds of the present invention in an in vivo TLR-mediated inflammation model was detected. Since an LPS-mediated inflammation model was used, this mechanistic model particularly illustrates the potential efficacy of the compounds of the present invention for TLR4-mediated diseases. In this article, female Balb/c mice (approximately 8 weeks old; Charles River Laboratories, Germany) were grouped with 5 animals per group. The control group was treated with a carrier (material carrier) in which the substance can be dissolved and a carrier in which LPS can be dissolved. The group treated with the substance and the positive control group were given 0.2 mg LPS/kg body weight (Sigma, catalog number L4391) (lipopolysaccharide from E. coli 0111:B4) via intraperitoneal (i.p.) administration. In addition, the positive control group was treated with the above-mentioned material carrier. 8 hours before inducing inflammation by administering LPS, the substance was orally administered. In order to detect the efficacy of the compounds of the present invention for inflammation, a final blood sample was taken from the animals 1.5 hours later. The concentrations of certain cytokines in plasma were determined using the Mouse Pro Inflammatory 7-Plex Tissue Culture Kit (MSD, catalog number K15012B) according to the manufacturer's instructions. Figure 1 shows the amount of TNF-α in plasma, which was reduced in a dose-dependent manner by administration of exemplary compound 64 compared to the LPS-induced concentration.

In vivo model of IL-1β-mediated inflammation

In order to evaluate the potential efficacy of the compounds of the present invention in IL-1β-mediated diseases, female Balb/c mice (about 8 weeks old; Charles River Laboratory, Germany) were given IL-1β intraperitoneally, and the efficacy of the compounds of the present invention for IL-1β-mediated cytokine secretion was detected. In each case, the group size was 5 animals. The control group was treated with a carrier that can be used to dissolve the substance and IL-1β. In each case, 90 μg IL-1β/kg body weight (R&D, catalog number 401-ML/CF) was administered intraperitoneally for the group treated with the substance and the positive control group. 4 hours before IL-1β was administered, the carrier in the substance or positive control group was administered. 2 hours after IL-1β was administered, the determination of TNF-α in plasma was performed after final blood collection using Mouse ProInflammatory 7-Plex Tissue Culture Kit (MSD, catalog number K15012B) according to the manufacturer's instructions. Administration of IL-1β resulted in elevated plasma concentrations of TNF-α, which were inhibited by treatment with exemplary compound 64. This is shown in FIG2 .

Oxygen-induced retinopathy (OIR) model in vivo

Oxygen-induced retinopathy has been shown to be a useful animal model for studying pathological retinal angiogenesis. This model is based on the observation that hyperoxia during the early postnatal development of the retina can lead to stagnation or delay of normal retinal blood vessel growth. After 7 days of hyperoxia, when the animals are returned to normoxic room air, this is equivalent to a state of relative hypoxia. The ischemic condition induced in this way leads to abnormal neovascularization, which has many similarities with the pathophysiological neovascularization of eye diseases such as wet AMD (age-related macular degeneration). In addition, the neovascularization induced is highly reproducible, quantifiable, and is an important parameter for detecting disease mechanisms and feasibility treatments for various forms of retinal diseases. This is why this model is suitable for testing the efficacy of the compounds of the present invention against this pathological process.

To this end, 7-day-old murine animals, such as young C57Bl/6 animals, are exposed to a hyperoxic environment (70% oxygen) for 5 days. From day 12 to day 17, the mice are placed in normoxic conditions (normoxia means room air containing 21% oxygen). During this period, the animals are divided into a substance-treated group and a vehicle group and treated according to the group. The animals are sacrificed on day 17, and the eyes are then removed and fixed in 4% formalin. After washing in phosphate-buffered saline, the retinas are removed, prepared, and stained with an isolectin B4 antibody (Tual-Chalot, Allinson et al., J. Vis. Exp., 2013). Quantification of neovascularization is performed using a Zeiss ApoTome.

In vivo model of laser-induced choroidal neovascularization

This study investigated the efficacy of test substances in reducing extravasation/edema formation and/or choroidal neovascularization in a rat model of laser-induced choroidal neovascularization. In this animal model, laser-mediated photocoagulation leads to disruption of Bruch's membrane with accompanying vascular damage and inflammation-related neovascularization. These two processes correspond to the pathological mechanisms of macular degeneration (Grossniklaus, Kang, Berglin, Prog Retin Eye Res., 2010).

To determine the efficacy of the compounds of the invention, Brown Norway rats (Charles River Laboratories) were divided into appropriate groups (substance and vehicle) and anesthetized, and 0.5% tropicamide was instilled into the eyes to dilate the pupils. After the animals were anesthetized (15 mg/kg xylazine and 80 mg/kg ketamine), choroidal neovascularization was triggered by burning 6 holes (lesion size: 50 μm-75 μm; laser intensity: 150 mW; duration: 100 ms) in the retina of each eye of each animal using a 532 nm argon laser. From day 1 or day 7 up to and including day 23, the animals were treated with the substances of the invention or the corresponding vehicle. Angiography was performed on day 21. For this purpose, the animals were anesthetized in all cases, the pupils were dilated, and a 10% sodium fluorescein solution was injected subcutaneously. Angiograms were recorded up to 10 minutes after injection and evaluated by three blinded examiners using a scoring system (0 = no staining = no tissue damage, 1 = slight staining = slight tissue damage, 2 = moderate staining = moderate tissue damage, 3 = maximum staining = maximum tissue damage). The animals were sacrificed on day 23, after which the eyes were removed and placed in a 4% paraformaldehyde solution at room temperature for one hour. After washing once, the retina was carefully peeled off, the sclera-choroid complex was stained with FITC isolectin B4 antibody, and then placed flat on a microscope slide. The specimens obtained in this way were evaluated using a fluorescence microscope (Apotom, Zeiss) at an excitation wavelength of 488 nm. The volume or area of choroidal neovascularization was calculated by morphometric analysis using Axiovision 4.6 software.

Working Examples of Pharmaceutical Compositions

The compounds of the present invention can be converted into the following pharmaceutical preparations:

tablet:

composition:

100 mg of the compound of Example 64, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight: 212 mg. Diameter: 8 mm, radius of curvature: 12 mm.

preparation:

A mixture of the compound of the invention, lactose, and starch is granulated with a 5% (w/w) aqueous solution of PVP. The granules are dried and then mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (tablet specifications are described above). A guideline value for compression is a compression force of 15 kN.

Solution for oral administration:

composition

500 mg of the compound of Example 64, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention.

preparation

The compound of the present invention is suspended in the mixture of polyethylene glycol and polysorbate under stirring and the stirring operation is continued until the compound of the present invention is completely dissolved.

composition:

1 mg of the compound of Example 64, 15 g of polyethylene glycol 400 and 250 g of water for injection purposes.

preparation:

The compound of the invention is dissolved in water together with polyethylene glycol 400 by stirring. The solution is sterilized by filtration (pore size 0.22 μm) and dispensed into heat-sterilized infusion bottles under aseptic conditions. The infusion bottles are sealed with infusion stoppers and crimped caps.

Claims (15)

1. Compounds of general formula (I), and their diastereomers, enantiomers, and salts, in: ^R0 represents hydrogen or _C1 - _C4 -alkyl, wherein the _C1 - _C4 -alkyl group may optionally be monosubstituted or polysubstituted by the same or different groups selected from hydroxyl and halogens; ^R1 represents hydrogen, halogen, cyano, C(=O)OH, C(=O) ^ORa , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , C(=O) ^Rd , hydroxyl, or _C1 - _C6 -alkyl, wherein the _C1 - _C6 -alkyl group is optionally mono- or poly-substituted by the same or different groups selected from the following: Hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, _NH2 , ^NHRa , N( ^Ra ) ^Rb , _C1 - _C6 -alkoxy optionally mono- or poly-substituted with the same or different halogen groups, _C3 - _C8 -cycloalkoxy optionally mono- or poly-substituted with the same or different halogen groups, heterocyclic alkyl optionally mono- or poly-substituted with the same or different ^Rc groups, Or it may represent _C1 - _C6 -alkoxy, wherein the _C1 - _C6 -alkoxy group may optionally be mono- or poly-substituted by the same or different groups selected from the following: Hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, _NH2 , ^NHRa , N( ^Ra ) ^Rb , _C3 - _C8 -cycloalkyl optionally mono- or poly-substituted with the same or different halogen groups, _C1 - _C6 -alkoxy optionally mono- or poly-substituted with the same or different halogen groups, _C3 - _C8 -cycloalkoxy optionally mono- or poly-substituted with the same or different halogen groups, heterocyclic alkyl optionally mono- or poly-substituted with the same or different ^Rc groups, aryl optionally mono- or poly-substituted with the same or different ^Rc groups, or 5- or 6-membered heteroaryl optionally mono- or poly-substituted with the same or different ^Rc groups. Or it may represent a _C3 - _C8 -cycloalkoxy or heterocycloalkoxy group that may be optionally mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, and _C1 - _C6 -alkyl. Or it may represent an aryloxy group or a 5- or 6-membered heteroaryloxy group, wherein the aryloxy group and the 5- or 6-membered heteroaryloxy group may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORα , _C1 - _C6 -alkyl and _C1 - _C6 -alkoxy. Or it may represent a _C3 - _C8 -cycloalkyl or heterocycloalkyl group that may be optionally mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, and _C1 - _C6 -alkyl. Or it may represent _C2 - _C6 -alkenyl or _C2 - _C6 -ynyl. Or it may represent aryl, 5- to 10-membered heteroaryl, aryl- _C1 - _C4 -alkyl or 5- or 6-membered heteroaryl- _C1 - _C4 -alkyl, wherein the aryl and heteroaryl may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, C(=O)OH, C(=O) ^ORα , _C1 - _C6 -alkyl, _C3 - _C8 -cycloalkyl and _C1 - _C6 -alkoxy; ^Ra represents _C1 - _C6 -alkyl, _C3 - _C10 -cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. The alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, _C1 - _C3 -alkyl, _C1 - _C3 -alkoxy, heterocycloalkyl, -C(=O) _OC1 - _C6 -alkyl, and S(=O) ₂ - _C1 - _C6 -alkyl; ^Rb represents _C1 - _C6 -alkyl or _C3 - _C10 -cycloalkyl; Alternatively, ^Ra and ^Rb together with nitrogen atoms form a 5- or 6-membered heterocycle, which may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, and _C1 - _C6 -alkyl; ^Rc represents hydroxyl, halogen, cyano, _C1 - _C3 -alkyl, or _C1 - _C3 -alkoxy; ^Rd represents hydrogen, _C1 - _C6 -alkyl, or _C3 - _C10 -cycloalkyl; ^R2 represents hydrogen, _C1 - _C6 -alkyl, or _C3 - _C6 -cycloalkyl; R ¹³ represents hydrogen or _C1 - _C6 -alkyl; W represents a 5-membered heteroaryl group containing one to three heteroatoms selected from N, O, and S, and may optionally be monosubstituted by ^R3 and may optionally be monosubstituted or polysubstituted by the same or different groups ^R4 , or W represents pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl, which may optionally be monosubstituted by R ³ and may optionally be monosubstituted or polysubstituted by the same or different groups R ⁴ ; ^R3 represents hydrogen, halogen, cyano, C(=O) ^Ra , _NH2 , ^NHRa , N( ^Ra ) ^Rb , N(H)C(=O) ^Ra , or _C1 - _C6 -alkyl, where _C1 - _C6 -alkyl groups may optionally be mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, _NH2 , ^NHRa , N( ^Ra ) ^Rb , _C1 - _C6 -alkoxy, _C3 - _C8 -cycloalkoxy. The _C1 - _C6 -alkoxy and _C3 - _C8 -cycloalkoxy groups may optionally be mono- or poly-substituted with the same or different halogen groups; Alternatively, the _C1 - _C6 -alkyl group may be mono- or poly-substituted with the same or different groups selected from _C3 - _C6 -cycloalkyl and heterocyclic alkyl groups. The _C3 - _C6 cycloalkyl and heterocycloalkyl groups may optionally be monosubstituted, disubstituted, or trisubstituted by the same or different groups selected from the following: halogen, cyano, _C1 - _C3 -alkyl, and _C1 - _C3 -alkoxy. Alternatively, the _C1 - _C6 -alkyl group may be mono- or poly-substituted with the same or different groups selected from the group consisting of aryl and 5- or 6-membered heteroaryl groups. The aryl and 5- or 6-membered heteroaryl groups may optionally be monosubstituted, disubstituted, or trisubstituted by the same or different groups selected from the following groups: halogen, cyano, _C1 - _C3 -alkyl, and _C1 - _C3 -alkoxy. or ^R3 represents _C1 - _C6 -alkoxy, where The _C1 - _C6 -alkoxy group may optionally be mono- or poly-substituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C3 - _C8 -cycloalkyl, _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkoxy. Or it may represent _C3 - _C6 -cycloalkyl, heterocycloalkyl _{, or C5-C11 -} spirocycloalkyl, wherein the cycloalkyl, heterocycloalkyl, and spirocycloalkyl may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , _C1 - _C6 -alkyl, and _C1 - _C4 -alkoxy; It may represent aryl or 5 to 10-membered heteroaryl, among which The aryl and heteroaryl groups may optionally be mono- or poly-substituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, _NO2 , _NH2 , ^NHRa , N( ^Ra ) ^Rb , N(H)C(=O) ^Ra , _C3 - _C8 -cycloalkyl, _C1 - _C3 -alkoxy, and _C1 - _C3 -alkyl, wherein _C1 - _C3 -alkyl groups may optionally be mono- or poly-substituted with the same or different halogen groups; ^R4 represents a halogen; a hydroxyl group; a cyano group or a _C1 - _C6 -alkyl group, wherein the _C1 - _C6 -alkyl group may optionally be mono- or poly-substituted with the same or different groups selected from the halogen; a _C1 - _C6 -alkoxy group, wherein the _C1 - _C6 -alkoxy group may optionally be mono- or poly-substituted with the same or different groups selected from the halogen; a _C2 - _C6 -alkenyl group; a _C2 - _C6 -alkynyl group; a _C3 - _C10 -cycloalkyl group; a 3- to 10-membered heterocyclic alkyl group; and an aryl group, wherein the aryl group may optionally be mono- or poly-substituted with the same or different groups R. or ^R4 represents an aryl or heteroaryl group that may be optionally mono- or poly-substituted by the same or different groups R. or R ⁴ represents C(=O)R ^a , C(=O)NH ₂ , C(=O)N(H)R ^a , C(=O)N(R ^a )R ^b , C(=O)OR ^a , NH ₂ , NHR ^a , N(R ^a )R ^b , N(H)C(=O)R ^a , N(R ^a )C(=O)R ^a , N(H)C(=O)NH ₂ ^{. ​ ​ ​} _​ ^{​ ​ ​ ​ ​ ​ ​ ​} _​ ^{. ​ ​} _​ ^{​ ​} _​ ^{​ ​ ​ ​} _​ ^{​ ​ ​} , SH, SR ^a , S(=O)R ^a , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(=O) ₂ NHR ^a , S(=O) ₂ N(R ^a )R ^b or S(=O)(=NR ^a )R ^b ; R represents halogen, cyano, _C1 - _C6 -alkyl, _C2 - _C6 -alkenyl, _C2 - _C6 -ynyl, C3- _C10 -cycloalkyl, 3- to ₁₀ -membered heterocyclic alkyl, aryl, heteroaryl, C(=O) ^Ra , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , C(=O) ^ORa , _NH2 , ^NHRa , N( ^Ra ) ^Rb , N(H)C(=O) ^Ra , N( ^Ra )C(=O) ^Ra , N(H)C(=O) _NH2 , N(H)C(=O) ^NHRa , N(H)C(=O)N( ^Ra ) ^Rb , N( ^Ra )C(=O) _NH2 , N(Ra ⁾ )C(=O)NHR ^a ,N(R ^a )C(=O)N(R ^a )R ^b ,N(H)C(=O)OR ^a ,N(R ^a )C(=O)OR ^a ,NO ₂ ,N(H)S(=O)R ^a ,N(R ^a )S(=O)R ^a ,N(H)S(=O) ₂ R ^a ,N(R ^a )S(=O) ₂ R ^a , N=S(=O)(R ^a )R ^b , OH, C ₁ -C ₆ -alkoxy, OC(=O)R ^a , OC(=O)NH ₂ , OC(=O)NHR ^a , OC(=O)N(R ^a )R ^b , SH, SR ^a , S(=O)R ^a , S(=O) ₂ R ^a , S(=O) ₂ NH ₂ , S(＝O) ₂ NHR ^a , S(=O) ₂ N(R ^a )R ^b or S(=O)(=NR ^a )R ^b ; n represents 0 or 1; Y represents a group selected from the following: The asterisk (*) represents a point where a group is attached to the rest of the molecule; R ⁵ represents hydrogen, _C1 - _C6 -alkyl, or _C3 - _C10 -cycloalkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy and _C3 - _C8 -cycloalkyl; ^R6 represents hydrogen or _C1 - _C6 -alkyl, where _C1 - _C6 -alkyl groups may optionally be mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C3- _{C10 -} cycloalkyl, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, and _C3 - _C8 -cycloalkoxy. Or it may represent _C3 - _C10 -cycloalkyl, wherein The _C3 - _C10 cycloalkyl group may optionally be mono- or poly-substituted with the same or different groups selected from the following groups: hydroxyl, halogen, cyano, and _C1 - _C6 alkyl, wherein _C1 - _C6 -alkyl groups may optionally be substituted with hydroxyl groups. Or represents a heterocyclic alkyl group, wherein Heterocyclic alkyl groups may optionally be mono- or poly-substituted by the same or different groups selected from: halogen, cyano, _C1 - _C3 -alkyl, and _C1 - _C3 -alkoxy. It may represent aryl, 5-membered, or 6-membered heteroaryl, among which The aryl and 5- or 6-membered heteroaryl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following groups: halogen, cyano, _C1 - _C3 -alkyl, _C1 - _C3 -alkoxy, S(=O) _2NH2 , S(=O) _2NHRa ^and S(=O) _{2N (} ^Ra ) ^Rb ; R ^7a represents hydrogen, halogen, N( ^Ra ) ^Rb , _C1 - _C6 -alkyl or _C3 - _C10 -cycloalkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; R ^7b represents hydrogen, halogen, or _C1 - _C6 -alkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; Alternatively, ^R7a and ^R7b together with carbon atoms form a _C3 - _C6 -cycloalkyl group, which may optionally be mono- or poly-substituted by the same or different groups selected from: hydroxyl, halogen, cyano, and _{C1 - C6 -} alkyl. Or R ^7a and R ^7b together represent an oxo group; R ^7c represents hydrogen, halogen, N( ^Ra ) ^Rb , _C1 - _C6 -alkyl or _C3 - _C10 -cycloalkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; R ^7d represents hydrogen, halogen, or _C1 - _C6 -alkyl, where _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; Alternatively, ^R7c and ^R7d together with carbon atoms form a _C3 - _C6 -cycloalkyl group, which may optionally be mono- or poly-substituted by the same or different groups selected from: hydroxyl, halogen, cyano, and _{C1 - C6 -} alkyl. Or R ^7c and R ^7d together represent an oxo group; R ^8a represents hydrogen, halogen, N( ^Ra ) ^Rb , _C1 - _C6 -alkyl or _C3 - _C10 -cycloalkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; R ^8b represents hydrogen, halogen, or _C1 - _C6 -alkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; Alternatively, ^R8a and ^R8b together with carbon atoms form a _C3 - _C6 -cycloalkyl group, which may optionally be mono- or poly-substituted by the same or different groups selected from: hydroxyl, halogen, cyano, and _{C1 - C6 -} alkyl. R ^8c represents hydrogen, halogen, N( ^Ra ) ^Rb , _C1 - _C6 -alkyl or _C3 - _C10 -cycloalkyl, wherein _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; R ^8d represents hydrogen, halogen, or _C1 - _C6 -alkyl, where _C1 - _C6 -alkyl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy, _C3 - _C8 -cycloalkyl and heterocyclic alkyl; Alternatively, ^R8c and ^R8d together with carbon atoms form a _C3 - _C6 -cycloalkyl group, which may optionally be mono- or poly-substituted by the same or different groups selected from: hydroxyl, halogen, cyano, and _{C1 - C6 -} alkyl. Or R ^8c and R ^8d together represent an oxo group; o represents 0, 1, or 2. p represents 0, 1, or 2. q represents 0, 1, or 2. r represents 0, 1, or 2. s represents 0, 1, or 2. Where o, p, q, r, and s do not all represent 0; Z represents a group selected ^from C(=O), ^CR9R10 , ^NR11 , O, S, S(=O) and S(=O) ₂ ; R ⁹ represents hydrogen or _C1 - _C6 -alkyl. R ¹⁰ represents hydrogen, halogen, cyano, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , C(=O) _NH2 , C(=O)N( ^H )Ra, C(=O)N( ^Ra ) ^Rb , N(H)C(=O) ^Ra , N( ^Rb )C(=O) ^Ra , S(=O) _2Ra , hydroxyl, N( ^{Ra ) Rb} , and _C1 - _C6 -alkyl, wherein... _C1 - _C6 -alkyl groups may optionally be mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C1 - _C4 -alkoxy and _C3 - _C8 -cycloalkoxy. Or it may represent _C1 - _C6 -alkoxy, where The _C1 - _C6 -alkoxy group may optionally be mono- or poly-substituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORa , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C3 - _C8 -cycloalkyl, _C1 - _C4 -alkoxy, C3- _{C8 -} cycloalkoxy, heterocyclic alkyl, aryl, or 5- or 6-membered heteroaryl, wherein The aryl group and the 5- or 6-membered heteroaryl group may optionally be mono- or poly-substituted by the same or different groups selected from the following groups: halogen, cyano, _C1 - _C3 -alkyl, and _C1 - _C3 -alkoxy. Or it may represent an aryloxy group or a 5-membered or 6-membered heteroaryloxy group, in which The aryloxy group and the 5- or 6-membered heteroaryloxy group may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O)OH, C(=O) ^ORα , _C1 - _C3 -alkyl and _C1 - _C3 -alkoxy. Or it may represent _C3 - _C8 -cycloalkyl, _C3 - _C8 -cycloalkyl- _C1 - _C4 -alkyl, heterocycloalkyl, or heterocycloalkyl- _C1 - _C4 -alkyl, which may optionally be mono- or poly-substituted by the same or different groups selected from: hydroxyl, halogen, cyano, C(=O) ^Ra , C(=O)OH, C(=O) ^ORa , _C1 - _C6 -alkyl, and _C1 - _C6 -alkoxy, wherein _C1 - _C6 -alkoxy groups may optionally be mono- or poly-substituted with the same or different halogen or oxo groups; Or it may represent _C2 - _C6 -alkenyl or _C2 - _C6 -ynyl. Or it may represent aryl, 5- to 10-membered heteroaryl, aryl- _C1 - _C4 -alkyl, or 5- or 6-membered heteroaryl- _C1 - _C4 -alkyl, wherein Aryl and heteroaryl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, C(=O)OH, C(=O) ^ORa , ^NHRa , N( ^Ra ) ^Rb , _C1 - _C3 -alkyl, _C3 - _C8 -cycloalkyl and _C1 - _C3 -alkoxy; Or ^R9 and ^R10 together with carbon atoms form _C3 - _C8 -cycloalkyl or 4- to 6-membered heterocycles, wherein _C3 - _C8 -cycloalkyl groups or 4- to 6-membered heterocycles may optionally be mono- or poly-substituted by the same or different groups selected from the following groups: hydroxyl, halogen, cyano, _C1 - _C6 -alkyl, C(=O) ^Ra and oxo groups; ^R11 represents hydrogen, C(=O) ^Ra , C(=O) ^ORa , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , S(=O) _2Ra , S(=O) ^2N ( ^Ra ) ^Rb , or _{C1 -C6 -} alkyl, wherein _C1 - _C6 -alkyl groups may optionally be mono- or poly-substituted with the same or different groups selected from the following: hydroxyl, halogen, cyano, C(=O) ^Ra , C(=O) ^ORa , C(=O) _NH2 , C(=O)N(H) ^Ra , C(=O)N( ^Ra ) ^Rb , S(=O) ₂ - _C1 - _C6 -alkyl, N( ^Ra ) ^Rb , _C3 - _C8 -cycloalkyl, _C1 - _C4 -alkoxy, and _C3 - _C8 -cycloalkoxy, wherein _C3 - _C8 -cycloalkyl, _C1 - _C4 -alkoxy, and _C3 - _C8 -cycloalkoxy groups may optionally be mono- or poly-substituted with the same or different groups selected from hydroxyl and halogens; Or it may represent _C3 - _C8 -cycloalkyl, heterocycloalkyl, or heterocycloalkyl- _C1 - _C4 -alkyl, which may optionally be mono- or poly-substituted with the same or different groups selected from: hydroxyl, halogen, cyano, _C1 - _C6 -alkyl, _C1 - _C6 -alkoxy, wherein the alkyl and alkoxy groups may optionally be mono- or poly-substituted with the same or different groups selected from halogen and oxo groups. Or it may represent _C2 - _C6 -alkenyl or _C2 - _C6 -ynyl. Or it may represent aryl, 5- to 10-membered heteroaryl, aryl- _C1 - _C4 -alkyl, or 5- or 6-membered heteroaryl- _C1 - _C4 -alkyl, wherein Aryl and heteroaryl groups may optionally be monosubstituted or polysubstituted by the same or different groups selected from the following: halogen, hydroxyl, cyano, C(=O)OH, C(=O) ^ORα , _C1 - _C3 -alkyl, _C3 - _C8 -cycloalkyl and _C1 - _C3 -alkoxy. 2. The compound according to claim 1, wherein ^R1 represents hydrogen; halogen; hydroxyl; cyano; _C1 - _C6 -alkyl; _C1 - _C5 -alkyl substituted with hydroxyl; _C1 - _C6 -alkoxy; C1- _C6 -alkoxy substituted with _C3 -C8-cycloalkyl; _C1 - _C6 -alkoxy substituted with up to three fluorine atoms; _{C1 - C6} -alkoxy substituted with aryl, wherein the aryl group is optionally monosubstituted or polysubstituted with the same or different groups selected from ^Rc ; or represents _a 5- or 6-membered heteroaryl group, which is optionally monosubstituted or polysubstituted with the same or different groups selected from ^Rc . 3. The compound according to claim 1, wherein W represents a group selected from formulas (III) to (IX): in R ¹² represents hydrogen, halogen, _C1 - _C6 -alkyl optionally mono- or poly-substituted with the same or different halogen groups, _C3 - _C6 -cycloalkyl optionally mono- or poly-substituted with the same or different halogen groups, aryl optionally mono- or poly-substituted with the same or different groups selected from ^Rc , or 5- or 6-membered heteroaryl optionally mono- or poly-substituted with the same or different groups selected from ^Rc ; or represents NHR ^a ; m represents 0, 1, 2, or 3, and ^R3 and ^R4 have the meanings given above, and * represents a point where a group is attached to the rest of the molecule. 4. The compound according to claim 1, wherein W represents a group of general formula (X). Furthermore, ^R3 and ^R4 have the meanings given in claim 1. 5. The compound according to claim 1, wherein Y is a group of general formula (II), wherein ^R7a , ^R7b , ^R7c , ^R7d , ^R8a , ^R8b , ^R8c and ^R8d are as defined in claim 1: ^6. The compound according to claim 1, wherein Y is a group ^NR5R6 , wherein ^R5 and ^R6 are as defined in claim 1. 7. The compound of claim 1, wherein W represents a group of general formula (IX). in m represents 0, and ^R2 , ^R0 , and ^R13 all represent hydrogen, and ^R3 represents trifluoromethyl, ethyl, methyl, cyclopropyl, 2,2,2-trifluoro-1-hydroxyethyl, or 1-hydroxyethyl; Y represents 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, or morpholino-4-yl, n represents 0, and ^R1 represents cyclopropylmethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, chlorine, ethoxy, methoxy, 2-hydroxypropyl-2-yl, or 3-hydroxypentyl-3-yl. 8. The compound according to claim 7, wherein R ¹ represents cyclopropylmethoxy, methoxy, or ethoxy-2-hydroxypropyl-2-yl. 9. The compound according to claim 7, wherein ^R3 is a trifluoromethyl or cyclopropyl group. 10. The compound according to claim 1, specifically comprising: N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6-Ethyl-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide 5-Fluoro-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide N-(2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-6-methyl-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-cyclopropylpyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-(1-hydroxyethyl)pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}pyridine-2-carboxamide 3-{[4-({2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}carbamoyl)-1,3-thiazolyl]amino}azacyclobutane-1-carboxylic acid tert-butyl ester N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-{6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-cyclopropyl-1,3-oxazol-4-carboxamide 3-{[4-({6-bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}carbamoyl)-1,3-thiazolyl]amino}azacyclobutane-1-carboxylic acid tert-butyl ester 2-(azacyclobutane-3-ylamino)-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-1,3-thiazolyl-4-carboxamide N-{6-cyano-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide 5'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide 4'-Methyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide 6'-Methoxy-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide 6'-Acetamido-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6'-nitro-2,3'-bipyridine-6-carboxamide 6'-Amino-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,3'-bipyridine-6-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-{6-fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{6-fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-fluoro-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-fluoro-2H-indazol-5-yl)-6-(morpholin-4-yl)pyridine-2-carboxamide N-{6-fluoro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide N-{6-(benzyloxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-isobutoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-isobutoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-isobutoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-isobutoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(cyclopropylmethoxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(cyclopropylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(cyclopropylmethoxy)-2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(cyclopropylmethoxy)-2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridin-2-carboxamide N-[2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-(pyridin-2-ylmethoxy)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridin-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-chloro-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 4-{[6-chloro-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylic acid ethyl ester N-(6-chloro-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-[4-(3-hydroxy-2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-[3-(dimethylamino)azacyclobutane-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-oxo-2-[3-(piperidin-1-yl)azacyclobutan-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-[4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-(4-hydroxy-1,4'-bipiperidin-1'-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(dimethylamino)piperidin-1-yl]-2-oxoethyl}-6-ethoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-ethoxy-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-ethoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-ethoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-ethoxy-2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-ethoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-3-methyl-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[3-(4-benzoylpiperazin-1-yl)-3-oxopropyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-2-(pyridin-3-yl)-1,3-thiazolyl-4-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-2-(pyridin-4-yl)-1,3-thiazolyl-4-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide 6-(azacyclobutane-3-ylamino)-N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(pyridin-3-yl)-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-4-yl)pyridine-2-carboxamide 6-(1,3-Dimethyl-1H-pyrazol-4-yl)-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide 6-Ethyl-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-{2-oxo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-ethyl-3-oxopirarin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(pyridin-4-yl)-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-chloropyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-methyl-1,3-oxazol-5-carboxamide 6-Amino-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazole-5-yl}pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-methyl-1,3-oxazol-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methoxypyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-cyclopropyl-1,3-oxazol-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(4H-1,2,4-triazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-phenyl-2H-1,2,3-triazol-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-5-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(trifluoromethyl)-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-1-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1-ethyl-1H-pyrazole-3-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(4-chloro-1H-pyrazol-1-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-4-(trifluoromethyl)-1,3-thiazolyl-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2,4'-bipyridine-6-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-5-fluoro-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1H-1,2,4-triazol-1-yl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-ethoxypyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(cyclopropylmethoxy)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-ethylpyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(4-methoxyphenyl)-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-bromo-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(4-fluorophenyl)-1,3-thiazolyl-4-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-fluoropyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-bromopyridine-2-carboxamide N-(2-{2-[4-(4-fluorobenzoyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyridin-2-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(methoxyacetyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-cyclopentyl-3-oxopirarin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-oxo-2-(3-oxo-4-phenylpiperazin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2,2-dimethylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-oxo-2-(pyridazin-4-ylamino)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxy-2-methylpropionyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyridin-3-ylcarbonyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-isonicotinylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-(methylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyrazin-2-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(1-hydroxyethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(6-acetyl-2,6-diazaspiro[3.3]hept-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-oxo-2-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(6-methyl-2,6-diazaspiro[3.5]non-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(7-oxa-2-azaspiro[3.5]non-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(1,4'-bipiperidin-1'-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[2-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[3-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-carbamoylpiperidin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[3-(dimethylamino)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[3-(morpholin-4-ylmethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(cyclopropylcarbonyl)amino]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(3-ethyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[3-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{[3-(dimethylaminosulfonyl)phenyl]amino}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(1,2-oxazol-4-ylamino)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(methylsulfonyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-oxo-2-{4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}ethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(phenylsulfonyl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[(3-aminosulfonylphenyl)amino]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[isonicotinyl(methyl)amino]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-(isopropylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(1,1-dioxotetrahydrothiophene-3-yl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(methoxyacetyl)(methyl)amino]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxylic acid ethyl ester N-(2-{2-[4-(cyclohexylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-(cyclopropylamino)-2-oxoethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[2-(2-hydroxyethyl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(1H-pyrrolo-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(3-hydroxypropyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide 4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxamide N-(2-{2-oxo-2-[4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(1,1-dioxothiomorpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-isopropylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(2-thienylcarbonyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-cyclopropyl-2-oxoethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N,N-Diethyl-4-{[5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetyl}piperazine-1-carboxamide N-{2-[2-oxo-2-(thiomorpholino-4-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(2-furanylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(3-thienylmethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4'-methyl-1,4'-bipiperidin-1'-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-cyclopentylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(dimethylaminosulfonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyridin-4-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(methylsulfonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide Formic acid N-[2-(2-{4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1:1) N-(2-{2-[4-(diethylaminosulfonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(pyridin-3-yl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-oxo-2-[4-(piperidin-1-ylsulfonyl)piperazin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylmethyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide 6-(1-Methyl-1H-pyrazol-4-yl)-N-(2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide N-{2-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-(2-{2-[4-(dimethylamino)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyridine-2-carboxamide N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-ethoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[(cyclopropylmethyl)(methyl)amino]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide 6-Cyclopropyl-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide 6-(1-Hydroxyethyl)-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide 6-(azacyclobutane-3-ylamino)-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-[(azacyclobutane-2-ylmethyl)amino]-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(3-hydroxyazacyclobutane-1-yl)pyridine-2-carboxamide 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide N-[2-(2-{4-methyl-4-[(4-methylpiperazin-1-yl)carbonyl]piperidin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-oxo-2-[(3R)-piperidin-3-ylamino]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-isopropoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-(2-{2-[4-(cyclopropylcarbonyl)piperazin-1-yl]-2-oxoethyl}-6-isopropoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-isopropoxy-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-isopropoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-isopropoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-isopropoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-(2-{2-[4-(cyclobutylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-(2-{2-[4-(cyclopentylcarbonyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[3-(methylsulfonyl)benzoyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide N-[2-(2-{4-[2-methoxy-5-(methylsulfonyl)benzoyl]piperazin-1-yl}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 6-Bromo-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)pyridine-2-carboxamide 2-(4-methoxyphenyl)-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-1,3-thiazolyl-4-carboxamide 2-(4-Fluorophenyl)-N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-1,3-thiazolyl-4-carboxamide N-(6-methyl-2-{2-oxo-2-[4-(pyrrolidin-1-yl)piperidin-1-yl]ethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide 6-Bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-Bromo-N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-6-(trifluoromethoxy)-2H-indazol-5-yl}-6-(4H-1,2,4-triazol-4-yl)pyridine-2-carboxamide 2-Bromo-N-{6-Bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1,3-thiazolyl-4-carboxamide N-{6-hydroxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-(benzyloxy)-2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-2H-indazol-5-yl]-6-methylpyridine-2-carboxamide 6-Bromo-N-{6-Bromo-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{6-(benzyloxy)-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide 2-(azacyclobutane-3-ylamino)-N-{2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-1,3-thiazolyl-4-carboxamide 6-Acetamido-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-(dimethylamino)-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide 6-(dimethylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-Acetamido-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide 6-(dimethylamino)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-[3-(methylsulfonyl)phenyl]pyridine-2-carboxamide N-{2-[1-(4-benzoylpiperazin-1-yl)-1-oxopropyl-2-yl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-[6-chloro-2-(2-{[trans-4-(2-hydroxypropyl-2-yl)cyclohexyl]amino}-2-oxoethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide 6-(2-hydroxypropyl-2-yl)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{6-chloro-2-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-(2-oxa-7-azaspiro[3.5]non-7-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-(6-chloro-2-{2-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]-2-oxoethyl}-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-methoxy-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6-(difluoromethyl)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{2-[2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-methylpyridine-2-carboxamide N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-carboxamide N-{2-[2-(1,1-dioxo-1-thia-6-azaspiro[3.3]hept-6-yl)-2-oxoethyl]-6-methoxy-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-methoxy-2-[2-(2-oxa-6-azaspiro[3.3]hept-6-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(3-hydroxy-2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6-Ethyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-Isobutyl-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazole-6-carboxylic acid methyl ester 5-{[(6-methylpyridin-2-yl)carbonyl]amino}-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazole-6-carboxylic acid methyl ester N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(pyrrolid-1-yl)pyridine-2-carboxamide N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(morpholin-4-yl)pyridine-2-carboxamide 6-(cyclopropylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-(Butylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(propylamino)pyridine-2-carboxamide 6-(isobutylamino)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide R-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxamide S-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carboxamide 6-(1-Hydroxyethyl)-N-{6-methoxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-(cyclopropylamino)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(propylamino)pyridine-2-carboxamide 6-(isobutylamino)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide 6-(1-hydroxyethyl)-N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}pyridine-2-carboxamide N-{6-methoxy-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-4-methyl-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(benzyloxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide 6-(cyclopropylamino)-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide 6-(Butylamino)-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-[(2-methoxyethyl)amino]pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(propylamino)pyridine-2-carboxamide N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-(isobutylamino)pyridine-2-carboxamide 5-Fluoro-N-(2-{2-[4-(2-hydroxypropyl-2-yl)piperidin-1-yl]-2-oxoethyl}-6-methoxy-2H-indazol-5-yl)-6-methylpyridine-2-carboxamide N-{6-hydroxy-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(3-cyanopropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-(2,2,2-trifluoroethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(cyclohexylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(2,2-dimethylpropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-(tetrahydrofuran-2-ylmethoxy)-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(cyclopentoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(cyanomethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide ({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)acetic acid N-{6-(cyclobutylmethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-[2-(pyrrolidin-1-yl)ethoxy]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-[2-(morpholin-4-yl)ethoxy]-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{2-[2-(morpholin-4-yl)-2-oxoethyl]-6-[2-(piperidin-1-yl)ethoxy]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(3-hydroxypropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(2-hydroxypropoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(2-hydroxyethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-(2-methoxyethoxy)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide ({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)ethyl acetate) 4-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)methyl butyrate Ethyl 2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propionate ethyl 3-methyl-2-({2-[2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)butyrate 2-({2-[2-(morpholin-4-yl)-2-oxoethyl]-5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-6-yl}oxy)propionic acid N-{6-(2-hydroxypropyl-2-yl)-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide N-{6-chloro-2-[2-(morpholin-4-yl)-2-oxoethyl]-2H-indazol-5-yl}-6-(difluoromethyl)pyridine-2-carboxamide. 11. The use of a compound of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for the treatment and/or prevention of the following diseases: tumors, skin diseases, gynecological diseases, cardiovascular diseases, lung diseases, eye diseases, neurological diseases, metabolic diseases, inflammatory diseases, autoimmune diseases, and pain. 12. A compound of formula (I) as defined in any one of claims 1 to 10, used to prepare a medicament for treating and/or preventing the following diseases: lymphoma, macular degeneration, endometriosis, psoriasis, lupus erythematosus, multiple sclerosis, COPD, and rheumatoid arthritis. 13. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 10, combined with an inert, non-toxic, pharmaceutically acceptable excipient. 14. A method for preparing compounds of general formula (III) from compounds of general formula (II) by means of a Grignard reaction with methylmagnesium bromide or ethylmagnesium bromide. ^R14 is a methyl group or an ethyl group. 15. Compounds of general formula (III) ^R14 is a methyl group or an ethyl group.