BR122024003780A2 - POLYMORPHIC FORM OF N-{6-(2-HYDROXYPROPAN-2-YL)-2-[2-(METHYLSULFONYL)ETHYL]-2H-INDAZOL-5-YL}-6-(TRIFLUOROME-THYL)PYRIDINE-2-CARBOXAMIDE - Google Patents

Abstract

The present invention relates to crystalline forms of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine -2-carboxamide, processes for their preparation, pharmaceutical compositions that constitute them and their use in disease control.

Description

[001] The present invention relates to crystalline forms of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6- ( trifluoromethyl)pyridine-2-carboxamide, processes for their preparation, pharmaceutical compositions that constitute them, intermediate compounds and their use in disease control.

[002] N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H- indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide corresponds to compound of Formula (I):

[003] The compound of Formula (I) or its polymorphic B form of the compound of Formula (I) inhibits interleukin-1 receptor-associated kinase 4 (IRAK4).

[004] Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays an important role in activating the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammation-inhibiting substances. IRAK4 is expressed by several cells and mediates the signal transduction of Toll-like receptors (TLR), except TLR3, and interleukin (IL)-1ß family receptors consisting of IL-1R (receptor), IL-18R, IL-33R and IL-36R (Janeway and Medzhitov, Annu. Rev. Immunol., 2002; Dinarello, Annu. Rev. Immunol., 2009; Flannery and Bowie, Biochemical Pharmacology, 2010).

[005] Neither IRAK4 knockout mice nor human cells from patients lacking IRAK4 react to stimulation of TLRs (except TLR3) and the IL-1ß family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie , et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007;

[006] The junction of TLR ligands or IL-1 ß family ligands with the respective receptor leads to the recruitment and junction of MyD88 [Myeloid Differentiation Primary Response Gene (88)] to the receptor. As a result, MyD88 interacts with IRAK4, resulting in the formation of an active complex that interacts with or activates the kinases IRAKI or IRAK2 (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004; Precious et al., J Biol., 2009). As a result of this, the NF (nuclear factor)-kB signaling pathway and the MAPK (mitogen-activated protein kinase) signaling pathway are activated (Wang, Deng, et al., Nature, 2001). Activation of the NF-kB and MAPK signaling pathways leads to processes associated with different immune processes. For example, there is elevated expression of several inflammatory signaling molecules and enzymes such as cytokines, chemokines, and COX-2 (cyclooxygenase-2) and elevated mRNA stability of genes associated with inflammation, e.g., COX-2, IL- 6, IL-8 (Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004). Furthermore, these processes can be associated with the proliferation and differentiation of particular cell types, e.g., monocytes, macrophages, dendritic cells, T cells, and B cells (Wan, Chi, et al., Nat Immunol, 2006; McGettrick and J. O'Neill, British Journal of Haematology, 2007).

[007] The central role of IRAK4 in the pathology of several inflammatory disorders has already been shown by direct comparison of the wild-type (WT) mouse with genetically modified animals that have a kinase inactive form of IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have an improved clinical picture in the animal model of multiple sclerosis, atherosclerosis, myocardial infarction, and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009; Kim, Febbraio, et al., The Journal of Immunology, 2011; Furthermore, deletion of IRAK4 in the animal model was found to protect against virus-induced myocarditis by an elevated antiviral response with simultaneously reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013). It has also been shown that IRAK4 expression is correlated with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).

[008] Thus, like the essential function of IRAK4 in congenital immunity, there are also signs that IRAK4 influences the differentiation of what are called Th17 cells, components of adaptive immunity. In the absence of IRAK4 kinase activity, fewer T cells that produce IL-17 (Th17 T cells) are generated compared to the WT mouse. Therefore, IRAK4 inhibition is suitable for prophylaxis and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondyloarthritis, lupus erythematosus, psoriasis, vitiligo, chronic inflammatory bowel disease and viral diseases, e.g. HIV (immunodeficiency virus). human), hepatitis virus (Staschke, et al., The Journal of Immunology, 2009; Zambrano-Zaragoza, et al., International Journal of Inflammation, 2014).

[009] Due to the central role of IRAK4 in the MyD88-mediated signal cascade of TLRs (except TLR3) and the IL-1 receptor family, IRAK4 inhibition can be used for the prophylaxis and/or treatment of disorders mediated by mentioned receivers. TLRs and also components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, Sjogren's syndrome, and sepsis (Scanzello, Plaas, et al. Curr Opin Rheumatol, 2008; Roger, Froidevaux, et al, PNAS, 2009; Gambuzza, Licata, et al., Journal of Neuroimmunology, 2011; Akash, Shen et al. Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Pharmacology & Therapeutics, 2012; 2013; Sedimbi, Hagglof et al., Cell Mol Life Sci, 2013; Skin diseases such as psoriasis, atopic dermatitis, Kindler syndrome, allergic contact dermatitis, acne inversa, and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway (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; , J Invest Dermatol, 2012, Minkis, Aksentijevich, et al., Archives of Dermatology, 2012, Dispenza, Wolpert, et al., J Invest Dermatol, 2012, Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Veerdonk van, Seminars in Immunology, 2013, Selway, Kurczab, et al., BMC Dermatology, 2013, Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013, Wollina, Koch, et al. ; Foster, Baliwag, et al., The Journal of Immunology, 2014).

[0010] Lung disorders such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension also show an association with several TLR-mediated signaling pathways. The pathogenesis of lung disorders can be mediated by infectious or non-infectious 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; ; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; , Martinez, et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013). TLRs and IL-1R family members are also involved in the pathogenesis of other inflammatory disorders such as Behçet's disease, gout, lupus erythematosus, adult Still's disease, and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. transplant rejection and also IRAK4 inhibition here is an appropriate therapy (Liu-Bryan, Scott, et al., Arthritis & Rheumatism, 2005; Christensen, Shupe, et al., Immunity, 2006; Cario, Inflammatory Bowel Diseases, 2010; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., Immunity, 2006; J Gastroenterol, 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Zhu, Jiang, et al., Autoimmunity, 2013; Yap and Lai, Nephrology, 2013). Due to the mechanism of action of the compound of Formula (I), they are also suitable for prophylactic and/or therapeutic use of TLR and IL-1R family-mediated disorders and atherosclerosis (Akoum, Lawson, et al., Human Reproduction, 2007 ; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; , et al., American Journal of Reproductive Immunology, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Khan, Kitajima, et al., Journal of Obstetrics and Gynecology Research, 2013 Santulli, Borghese, et al., Human Reproduction, 2013; Sedimbi, Hagglof, et al., Cell Mol Life Sci, 2013).

[0011] In addition to the disorders already mentioned, IRAK4-mediated TLR processes have been described in the pathogenesis of ophthalmological disorders such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis (Kaarniranta and Salminen, J Mol Med ( Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Experimental Ophthalmology, 2012; Guo, Gao, et al., Immunol Cell Biol, 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; ).

[0012] Due to the central role of IRAK4 in TLR-mediated processes, IRAK4 inhibition also enables the treatment and/or prevention of cardiovascular and neurological disorders, for example, myocardial reperfusion damage, myocardial infarction, hypertension (Oyama , Blais, et al., Circulation, 2004; Timmers, Sluijter, et al., Circulation Research, 2008; ., Clin Sci (Lond), 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013;) and also Alzheimer's disease, stroke, craniocerebral trauma and Parkinson's disease ( Brough, Tyrrell, et al., Trends in Pharmacological Sciences, 2011; American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson, et al., Disease Models & Mechanisms, 2013; Noelker, Morel, et al., Sci. Rep., 2013; Wang, Wang, et al., Stroke, 2013).

[0013] Due to the involvement of TLR signals and signals mediated by the IL-1 receptor family via IRAK4 in the case of itching and pain, for example, cancer pain, postoperative pain, inflammation-induced and chronic pain, it may Therapeutic effect is assumed in the aforementioned indications through the inhibition of IRAK4 (Wolf, Livshits, et al., Brain, Behavior, and Immunity, 2008; Kim, Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al., Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha, et al., European Journal of Pharmacology, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; and Ji, Pflugers Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; .

[0014] This also applies to some oncological disorders. Specific lymphomas, e.g. ABC-DLBCL (diffuse large B-cell lymphoma arising from activated B cells), mantle cell lymphoma and Waldenstrom's disease, and also chronic lymphatic leukemia, melanoma and hepatic cell carcinoma, are characterized by mutations in MyD88 or changes in MyD88 activity that can be treated by an IRAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; Furthermore, MyD88 has an important role in ras-dependent tumors, and IRAK4 inhibitors are also suitable for its treatment (Kfoury, A., K. L. Corf, et al., Journal of the National Cancer Institute, 2013).

[0015] Inflammatory disorders such as CAPS (cryopyrin-associated periodic syndromes) including FCAS (cold-associated familial autoinflammatory syndrome), MWS (Muckle Wells syndrome), NOMID (neonatal onset inflammatory multisystem disease) and CINCA syndrome (chronic infantile cutaneous and joint neurological); FMF (familial Mediterranean fever), SHID (hyper-IgD syndrome), TRAPS (tumor necrosis factor receptor 1-associated periodic syndrome), juvenile idiopathic arthritis, adult-onset Still's disease, Adamantiades-Behçet disease, rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca, and Sjogren's syndrome are treated by blocking the IL-1 signaling pathway; therefore, here also an IRAK4 inhibitor is suitable for the treatment of the mentioned diseases (Narayanan, Corrales, et 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; Rheumatology, 2012; Vijmasi, Chen, et al., Mol Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013). The IL-33R ligand, IL-33, is particularly involved in the pathogenesis of acute renal failure, thus, inhibition of IRAK4 for prophylaxis and/or treatment is an appropriate therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011). Components of the IL-1 receptor family are associated with myocardial infarction, different pulmonary disorders such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), thus the prophylactic and/or Therapy should be expected in the aforementioned indications through IRAK4 inhibition (Kang, Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al. , The Journal of Immunology, 2009; Abbate, Kontos, et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; , et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li, et al., Clinical & Experimental Immunology, 2012; et al., The Journal of Clinical Investigation, 2013; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J Interferon Cytokine Res, 2013; Martínez-González, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Immunology, 2014).

[0016] The prior art discloses several IRAK4 inhibitors (see, for example, the Annual Reports in Medicinal Chemistry (2014), 49, 117 - 133).

[0017] US8293923 and US20130274241 disclose IRAK4 inhibitors as having a substituted 3-indazole structure. There is no description of substituted 2-indazoles.

[0018] WO2013/106254 and WO2011/153588 disclose disubstituted 2,3-indazole derivatives.

[0019] WO2007/091107 describes substituted 2-indazole derivatives for the treatment of Duchenne muscular dystrophy. The disclosed compounds do not have a 6-hydroxyalkyl substitution.

[0020] WO2015/091426 describes indazoles, their alkyl group substituted in position 2 by a carboxamide structure.

[0021] WO2015/104662 discloses indazole compounds of Formula (I)

[0022] particularly inhibitors of IRAK4, and pharmaceutically acceptable salts or stereoisomers thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in diseases or disorders mediated by the kinase enzyme, particularly IRAK4.

[0023] Document WO2016/083433, published after the priority date of the present application, describes new substituted indazoles of the following formula:

[0024] methods for their production, use alone or in combinations to treat and/or prevent diseases and their use to produce pharmaceuticals to treat and/or prevent diseases, in particular to treat and/or prevent endometriosis and pain associated with endometriosis and others symptoms associated with endometriosis, such as dysmenorrhea, dyspareunia, dysuria and dyschezia, lymphomas, rheumatoid arthritis, spondyloarthritis (in particular psoriatic spondyloarthritis and Bekhterev's disease), systemic lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disease, resistance insulin, tumor diseases and psoriasis.

[0025] Therefore, there is a need to obtain crystalline forms of the compound of Formula (I) with ideal physicochemical properties that can be used advantageously in pharmaceutical processing and pharmaceutical compositions.

[0026] The new IRAK4 inhibitors are especially suitable for the treatment and prevention of proliferative and inflammatory disorders characterized by an overreactive immune system. Particular mention should be made here of inflammatory skin disorders, cardiovascular disorders, pulmonary disorders, ophthalmological disorders, gynecological disorders, especially endometriosis and cancer.

[0027] A process would be disclosed that would allow the production of indazole (I) on a technical scale with a special focus on the following requirements: • Expansion/scalability of the manufacturing process • High regioselectivity in the N2 alkylation reaction • Rejection of separation steps and chromatographic purification • Final processing via crystallization • Final adjustment of polymorphic modification using Class 3 solvents (according to FDA guidelines)

[0028] Considerably, a process can be disclosed that meets all the requirements mentioned above.

[0029] Surprisingly, the following crystalline forms of the compound of Formula (I) were identified, which are the polymorphic form A, the polymorphic form B and a pseudopolymorphic form which is a crystalline 1,7-Hydrate. In this context, modifications, polymorphic forms and polymorphs have the same meanings. Furthermore, there is the amorphous form. Together, the polymorphic forms, the pseudopolymorphic form and the amorphous form are different solid forms of the compound of Formula (I).

[0030] The compound of Formula (I) in its polymorphic form B was described in the priority application EP16167652.3, filed on April 29, 2016, of this patent application as polymorphic form A of the compound of Formula (I). According to the rules described in Joel Bernstein, Polymorphism in molecular crystals, Clarendon Press 2002, page 8-9, the designation and naming of polymorphs is commonly carried out according to the order of their melting points , starting with the one that has the highest melting point called as polymorphic form A. As it becomes evident during laboratory tests in recent months, that the polymorphic form A of the compound of Formula (I) as described in the priority application EP16167652. 3 is that with the lower melting point compared to the other polymorphic form, we have therefore corrected the naming of this compound as described in EP16167652.3, presented on April 29, 2016, as form A for the polymorphic form B of the compound of Formula ( I).

[0031] The polymorphic form B of the compound of Formula (I) is the thermodynamically stable form. Surprisingly, the polymorphic form B of the compound of Formula (I) exhibits beneficial properties over the other solid forms of the compound of Formula (I), which are, for example, but not limited to stability (e.g., thermodynamic stability, mechanical stability, chemical stability and/or storage stability), compatibility with other ingredients, purity, hygroscopicity, solubility (thermodynamic and/or kinetic), crystallization properties, habitus, bioavailability, adverse effects, pharmacokinetic behavior, efficacy, beneficial properties during chemical synthesis or isolation which may be, for example, improved filtration capacity) and/or beneficial properties during the manufacture of a pharmaceutical composition.

[0032] Therefore, polymorphic form B is suitable and preferred over other solid forms of the compound of Formula (I) for use in the pharmaceutical field, in particular suitable for the manufacture of pharmaceutical compositions, for example manufacture of tablets containing the form polymorphic B of the compound of Formula (I).

[0033] In particular, the polyformic form B of the compound of Formula (I) ensures that an unwanted conversion to another form of the compound of Formula (I) and an associated change in properties, as described above, are avoided. This increases the safety and quality of preparations comprising the compound of Formula (I) and the risk to the patient is reduced.

[0034] The compound of Formula (I) in polymorphic form B can be isolated by crystallization from solution using acetonitrile, tetrahydrofuran or acetone by evaporation at room temperature or evaporation under cooling conditions (refrigerator or freezer).

[0035] Representations of the present invention are not only each single crystalline form of the compound of Formula (I) which are the polymorphic form A, the polymorphic form B and the 1,7-Hydrate of the compound of Formula (I), but also mixtures which comprise two or three crystalline forms of the aforementioned.

[0036] A pharmaceutical composition according to the present invention comprises a crystalline form of the compound of Formula (I) selected from the group consisting of its polymorphic form A, its polymorphic form B, its 1,7-Hydrate and mixture thereof and others pharmaceutically acceptable excipients.

[0037] A pharmaceutical composition according to the present invention preferably comprises only one of the crystalline forms selected from the group comprising the polymorphic form A, the polymorphic form B and the 1,7-hydrate of the compound of the Formula ( I) mainly and no otherwise significant fraction of the compound of Formula (I). More preferably the pharmaceutical composition contains more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, of the polymorphic form B of the compound of Formula (I) related to the total amount of all compounds of all forms of the compound of Formula (I) present in the composition.

[0038] Preference is given to a pharmaceutical composition comprising the compound of Formula (I) in polymorphic form B mainly and without significant fractions of another solid form of the compound of Formula (I), for example, in another polymorphic or pseudopolymorphic form of compound of Formula (I). The pharmaceutical composition preferably contains more than 80 percent by weight, preferably more than 90 percent by weight, more preferably more than 95 percent by weight of the B polymorphic form of the compound of Formula (I) related to the total amount of all forms of the compound of Formula (I) present in the composition.

[0039] Further preference is given to a pharmaceutical composition comprising the compound of Formula (I) in polymorphic form A mainly and without significant fractions of another solid form of the compound of Formula (I), for example, in another pseudopolymorphic form of the compound of Formula (I). The pharmaceutical composition preferably contains more than 80 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, of the compound of Formula (I) in polymorphic form A related to the total amount of all forms of the compound of Formula (I) present in the composition.

[0040] Further preference is given to a pharmaceutical composition comprising 1,7-hydrate of the compound of Formula (I) in the anhydrate form mainly and without significant fractions of another solid form of the compound of Formula (I), e.g. another polymorphic form of the compound of Formula (I). The pharmaceutical composition preferably contains more than 85 percent by weight, more preferably more than 90 percent by weight, more preferably more than 95 percent by weight, of the compound of Formula (I) as 1,7-hydrate related to the amount total of all forms of the compound of Formula (I) present in the composition. The different forms of the compound of Formula (I) can be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), solid state NMR, IR-, Raman-, NIR-, FIR- and 13C spectroscopy.

[0041] The different forms of the compound of Formula (I) were characterized by X-ray powder diffraction, DSC and TGA thermogram:

[0042] FIGURE 1: X-ray powder diffractogram of polymorphic form B of compound (I)

[0043] FIGURE 2: X-ray powder diffractogram of polymorphic form A of compound (I)

[0044] FIGURE 3: X-ray powder diffraction diagram of 1,7-hydrate of compound (I)

[0045] FIGURE 4: DSC and TGA thermogram of the polymorphic form B of compound (I)

[0046] FIGURE 5: DSC and TGA thermogram of the polymorphic form A of compound (I)

[0047] FIGURE 6: DSC and TGA thermogram of the 1,7-hydrate of compound (I)

[0048] The polymorphic form B of the compound of Formula (I) can be characterized unambiguously by an X-ray powder diffractogram (at 25°C and with Cu-K alpha 1 as the radiation source) which presents at least the following reflections: 9.7, 10.1, 15.4, preferably at least the following reflections: 9.7, 10.1, 15.4, 16.1, 20.2, most preferably at least the following reflections: 9 .7, 10.1, 15.4, 16.1, 20.2, 22.3, more preferably at least the following reflections: 9.7, 10.1, 15.4, 16.1, 20.2 , 22.3, 25.2, each quoted as 2 Theta value ± 0.2°. The compound of Formula (I) in polymorphic form B can also be characterized unambiguously by the X-ray diffractogram (at 25°C and with Cu-K alpha 1 as the radiation source) as shown in Figure 1.

[0049] The polymorphic form A of the compound of Formula (I) can be characterized unambiguously by an X-ray powder diffractogram (at 25°C and with Cu-K alpha 1 as the radiation source) which presents at least the following reflections: 9.2; 9.8; 19.3; preferably at least the following reflections: 9.2, 9.8, 19.3, 20.4, 20.7, more preferably at least the following reflections: 9.2, 9.2, 9.8, 19.3 , 20.4, 20.7, 21.6 more preferably at least the following reflections: 9.2, 9.8, 19.3, 20.4, 20.7, 21.6, 21.7, 23, 1, 23.2, each quoted as 2Theta value ± 0.2°. The compound of Formula (I) in polymorphic form A can also be characterized unambiguously by the X-ray diffractogram (at 25°C and with Cu-K 1 as the radiation source) as shown in Figure 2.

[0050] The 1,7-hydrate of the compound of Formula (I) can be characterized unambiguously by an X-ray powder diffractogram (at 25°C and with Cu-K alpha 1 as the radiation source) which presents at least the following reflections: 10.6; 11.8; 14.5; preferably at least the following reflections: 10.6, 11.8, 14.5, 14.9, 15.1, more preferably at least the following reflections: 10.6, 11.8, 14.5, 14.9 , 15.1, 17.6, 18.7, more preferably at least the following reflections: 10.6, 11.8, 14.5, 14.9, 15.1, 17.6, 18.7, 19 .8, each quoted as 2 Theta value ± 0.2°. The 1,7-hydrate of the compound of Formula (I) can also be characterized unambiguously by the X-ray diffractogram (at 25°C and with Cu-K alpha 1 as the radiation source) as shown in Figure 3. Preparation process :

[0051] The preparation of compound (I) through a surprisingly highly selective alkylation in N2 is described below:

[0052] Preparations of substituted N2-indazoles have been previously described in the literature. However, these procedures have considerable disadvantages, making them unsuitable for technical scale-up. It is possible to selectively prepare N2-substituted indazoles through complex sequences of synthetic steps, which do not involve any direct alkylation step. However, these sequences are long and tedious and involve considerable losses resulting in a low total yield. Therefore, synthetic routes that allow direct preparation of N2-substituted indazoles from 1H-indazole precursors via direct and selective N2 alkylation are the most interesting. In an attempt to directly alkylate the 1H-indazole precursor of general Formula (II), a mixture consisting of the N1-(III) and N2-alkylated regioisomers (III) is generally obtained.

[0053] Indazole and its derivatives, a typical class of aromatic N-heterocycles, have aroused significant interest in synthetic and medicinal chemistry due to their different biological activities. Furthermore, different heterocyclic structures could be accessed from indazole-derived N-heterocyclic carbons. Among indazoles, N1/N2-substituted indazoles are widely used as anticancer, anti-inflammatory, anti-HIV and antimicrobial drugs. In general, the synthesis of N2-substituted indazoles involves cyclization procedures using different starting materials. Unfortunately, general methodologies remain scarce in the literature. Only moderate yields were obtained.

[0054] Regarding the current state of technology, several publications are known and will be discussed in the following section. None of the published procedures characterize the reaction conditions that lead to a direct N2-selective alkylation with the use of methyl vinyl sulfone as the alkylating agent. There is no conversion observed or the selectivity and yield are low. The problem with prior art procedures is the use of relatively simple alkylating agents that do not have labile functional groups. These agents are mainly linked to 1H-indazole by nucleophilic substitution of their halides, tosylates, triflates or mesylates. When more functionalized parts are used, the yield and selectivity decrease drastically. In the following section, the reasons why these prior art procedures are not applicable to the challenge at hand are presented: 1. WO 2011/043479: Reactions are carried out in THF at reflux (see scheme 2). This does not work for the case in question (methyl vinyl sulfone). The preparation of the corresponding triflate from e.g. alcohol is not possible as its decomposition occurs instantaneously. Furthermore, only a simple substrate without side chain functionality was used. 2. SR Baddam, NU Kumar, AP Reddy, R. Bandichhor, Tetrahedron Lett.2013, 54, 1661: Only simple indazoles without functional groups were used in the reaction. Only methyl trichloroacetimidate was used as the alkylating agent. Attempts to transfer acid-catalyzed conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. This procedure cannot be easily scaled up. 3. Q. Tian, Z. Cheng, HH Yajima, SJ Savage, KL Green, T. Humphries, ME Reynolds, S. Babu, F. Gosselin, D. Askin, Org. Process Res. Dev.2013, 17, 97 : The preparation of a THP-ether with preference for N2 of indazole is presented. This reaction occurs via a different mechanism and does not represent a general method since the THP-ether product cannot be easily converted. Furthermore, selective methods for protection of indazoles using p-methoxybenzyl derivatives under acidic conditions are presented. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 4. DJ Slade, NF Pelz, W. Bodnar, JW Lampe, PS Watson, J. Org. Chem. 2009, 74, 6331: THP-ether and PMB protection using acidic conditions (PPTS: pyridinium para-toluenesulfonate), see scheme 2; Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 5. M. Cheung, A. Boloor, JA Stafford, J. Org. Chem. 2003, 68, 4093: Highly reactive and highly carcinogenic Meerwein salts were used as alkylating agents (see scheme 2). This method comprises only simple non-functionalized ethyl and methyl Meerwein salts. The reaction proceeds in polar ethyl acetate at room temperature. These conditions could not be transferred to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone.

[0055] Scheme 1: N-alkylation of 1H-indazoles

[0056] Scheme 2: N-alkylation methods of indazoles known in the prior art 6. M.-H. Lin, H.-J. Liu, W.-C. Lin, C.-K. Kuo, T.-H. Chuang, Org. Biomol. Chem. 2015, 13, 11376: The procedure is selective for N2, however, it cannot be scaled up with Ga and Al metal being used in stoichiometric amounts. Under the conditions of the reactions described, Broensted acids are formed, which react with the corresponding metals to produce hydrogen gas. Only relatively simple substrates are used as alkylating agents (without sulfone groups). When more functionalized substrates were used, a significant reduction in yield was observed. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 7. G. Luo, L. Chen, G. Dubowchick, J. Org. Chem. 2006, 71, 5392: 2-(Trimethylsilyl)ethoxymethyl (SEM-Cl) in THF was used for N2 substitution of indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. The corresponding products described in this publication are ethers and are not related to our target molecule. The use of highly carcinogenic 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) as well as benzyloxymethyl chloride (BOM-Cl) does not represent a scalable option for obtaining the target compound. 8. A. E. Shumeiko, A. A. Afon'kin, N. G. Pazumova, M. L. Kostrikin, Russ. J. Org. Chem. 2006, 42, 294: Only very simple substrates were used in this method. No significant selectivity is reported. A slight preference for N1 alkylation was observed in indazole. 9. G. A. Jaffari, A. J. Nunn, J. Chem. Soc. Perkin 1 1973, 2371: Very simple substrates and only methylating agents were used. A more complex substrate, such as a combination of formaldehyde and protonated methanol, resulted in only product (ether) substituted in N1. 10. V. G. Tsypin et al., Russ. J. Org. Chem. 2002, 38, 90: The reaction proceeds in sulfuric acid and chloroform. Only conversions of simple indazoles with adamantyl alcohol as the sole alkylating agent are described. These conditions could not be transferred to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone. 11. S. K. Jains et al. RSC Advances2012, 2, 8929: This publication presents an example of N-benzylation of indazoles with low selectivity for the N1 substitution. This KF/alumina catalyzed method cannot be efficiently used for the synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 12. L. Gavara et al. Tetrahedron2011, 67, 1633: Only relatively simple substrates were used. The described acidic THP-ether formation and benzylation in refluxing THF are not applicable to our substrate. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 13. M. Chakrabarty et al. Tetrahedron2008, 64, 6711: Alkylation of N2 was observed, but the alkylated N1 product was preferentially obtained. The described conditions of use of aqueous sodium hydroxide and phase transfer catalyst in THF are not applicable to 2-substituted indazoles. Attempts to transfer these conditions to our system (methyl vinyl sulfone) have failed. 14. M. T. Reddy et al. Der Pharma Chemica 2014, 6, 411: The reaction proceeds in the corresponding alkylating agent as solvent. Only the use of highly reactive ethyl bromoacetate as an alkylating agent is reported. There are no data on selectivity. These conditions are not applicable to a selective synthesis of N2-substituted indazole. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 15. S. N. Haydar et al. J. Med. Chem. 2010, 53, 2521: Only simple non-functionalized alkyl groups (methyl, isopropyl, isobutyl) are described. Cesium carbonate was used as a base, and the reaction resulted in a mixture of N1 and N2 alkylated products. These conditions are not applicable to compounds such as 2-indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 16. Zh. V. Chirkova et al. Russ. J. Org. Chem. 2012, 48, 1557: In this method, relatively simple substrates are converted with potassium carbonate as a base into DMF. Mixtures of alkylated products N1 and N2 are obtained. The conditions are not applicable to a selective synthesis of N2-substituted indazole. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 17. C. Marminon et al. Tetrahedron2007, 63, 735: The ortho-substituent R at position 7 in indazole directs alkylation to N2 by protecting N1 from electrophilic attack. The conditions, sodium hydride as base in THF, are not applicable to a selective synthesis of N2-substituted indazoles as they preferentially result in alkylation at N1 in the absence of a substituent at the 7-position of the indazole. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 18. D. A. Nicewicz et al. Angew. Chem. Int. -d. 2014, 53, 6198: Only simple substrates were used. This method describes a photochemical reaction that cannot be easily scaled up and is not applicable to a general selective synthesis of N-substituted indazoles. Very specific styrene derivatives are used under radical reaction conditions. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 19. A. Togni et al. Angew. Chem. Int. Ed. 2011, 50, 1059: This publication describes only one special type of substituent (hypervalent iodine as a trifluoromethylation reagent in combination with acetonitrile). This special case is not applicable to a general selective synthesis of N2-substituted indazoles. 20. L. Salerno et al. European J. Med. Chem. 2012, 49, 118: This publication describes the conversion of indazoles to molten bromoketone. The reaction conditions cannot be transferred to the selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 21. K. W. Hunt, D. A. Moreno, N. Suiter, C. T. Clark, G. Kim, Org. Lett.2009, 11, 5054: This publication essentially describes an N1 selective alkylation method with addition of different bases. Simple substrates were used. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 22. J. Yang et al. Synthesis2016, 48, 48, 1139: This publication describes an N1-selective base-catalyzed aza-Michael reaction. No substitution in N2 was observed. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 23. P.R. Kym et al. J. Med. Chem. 2006, 49, 2339: Essentially N1 alkylations are described. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 24. A. J. Souers et al. J. Med. Chem. 2005, 48, 1318: This publication also describes the use of potassium carbonate as a base. This method proceeds mainly with preference for N1 substitution and is therefore not applicable to a selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed. 25. P. Bethanamudi et al. --Journal of Chemistry2012, 9, 1676: The use of ionic liquids together with potassium carbonate as a base results in N1 and N2 alkylated indazole mixtures in low yields. Selectivity shows a tendency towards substitution in N1. The use of ionic liquid cannot be transferred to our system. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed.

[0057] S. Palit et al. Synthesis2015, 3371: The reaction described here is essentially non-selective with a slight substitution preference at N1 of indazole. Only single alkyl groups were used. Sodium hydride and strongly similar bases were used. Attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain into the N2 position of an indazole core structure via reaction with methyl vinyl sulfone have failed.

[0058] It was shown that the compound of Formula (I) can be synthesized in a manner analogous to methods previously published in the literature through direct alkylation using 2-bromoethyl methyl sulfone. However, a mixture of N1 and N2 alkylated products was obtained with a preference for the N1 regioisomer (N1:N2 = ca. 2:1). The desired N2-alkylated indazole of Formula (I) can also be obtained in low yield as described in WO2016/083433, published after the priority date of the present application, with the following reaction procedure:

[0059] 160 mg (0.44 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H- indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5- 1) were suspended with 182 mg of potassium carbonate and 36 mg of potassium iodide in 1.0 mL of DMF and the mixture was stirred at room temperature for 15 min. Then, 123 mg of 2-bromoethyl methyl sulfone was added, and the mixture was stirred at room temperature overnight. Water was added, the mixture was extracted twice with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride solution, filtered through a hydrophobic filter and concentrated. Purification of the residue by preparatory HPLC yielded 20 mg (97.7% yield) of the title compound.

[0060] Preparatory and consumptive HPLC proved to be indispensable for an efficient separation of the N1-/N2 regioisomers. The objective of this new process of the invention is to avoid HPLC separation by obtaining better selectivity in the reaction in favor of N2 substitution followed by a new recrystallization procedure of the invention.

[0061] The present invention provides a process for preparing compounds of general Formula (III) from compounds of general Formula (II)

[0062] in which

[0063] R1 2-(methylsulfonyl)ethyl;

[0064] R4 is difluoromethyl, trifluoromethyl or methyl; It is

[0065] R5 is hydrogen or fluorine; preferably with R4 = Trifluoromethyl and R5=H

[0066] unexpectedly, it was found that methyl vinyl sulfone (lX) can replace the corresponding alkyl halide in the reaction. The use of vinyl sulfones for N2 alkylation of indazoles is surprisingly unprecedented and therefore highly inventive. After reacting compounds of general Formula (li) with methyl vinyl sulfone in toluene, optionally with addition of an organic base, such as N,N-diisopropylethylamine or triethylamine, the desired N2 isomer according to Formulas (ill) and ( l ) is obtained with high selectivity. The selectivity in the reaction mixture was between 8:1 to 10:1 in favor of the N2-alkylated product (lll) as well as (l). The undesirable substituted N1-byproduct mainly remained in the main liquid after processing the reaction mixture (mostly <2% after crystallization).

[0067] The reaction works without the use of an additional base. The compound of general Formula (II) or (V) placed in a reaction vessel. 1 - 2 equivalents of methyl vinyl sulfone are added and the reaction mixture is heated to reflux in toluene (ca. 110°C internal temperature). The reaction can be carried out using 5 to 30 volumes of toluene in relation to the amount of starting material (II) or (V). Preferably, the reaction is carried out with 8 to 15 volumes and best with 10 volumes of toluene. The reaction time is 12 to 100 h. It is preferably carried out between 48 and 72 hours. In some cases, it has proven advantageous to add the methyl vinyl sulfone in portions to the reaction mixture, e.g., starting with 1 equivalent and then adding 0.3 equivalents after 24 and a further 0.3 equivalents after 48 h.

[0068] Optionally, the reaction works with catalytic amounts of an organic auxiliary base, e.g., N,N-diisopropylethylamine. The compound of general Formula (II) or (V) is placed in a reaction vessel together with the solvent (toluene or xylene) and catalytic amounts of an organic base.

[0069] An auxiliary organic base, e.g. N,N-diisopropylethylamine, N,N-dicyclohexylamine or triethylamine can be added in amounts between 0.01 and 1 equivalent. The reaction proceeds with 0.01 to 0.1 equivalents of base.

[0070] It is worth noting and certainly surprising that using chlorine or ethylbenzene as a solvent at the same reaction temperature or xylene as a solvent at a higher reaction temperature, alkene (IV) was obtained in higher quantities via elimination of water. Surprisingly, this elimination was only observed in very small amounts when using toluene as the solvent. Therefore, toluene must be considered as a solvent of the invention with unique and completely unforeseen properties in relation to this specific reaction. The formation of (IV) was also found to depend on the quality of (V). When (V) was used with a higher than usual water content (1% by weight instead of <0.5% by weight), a more significant amount of (IV) was obtained in the reaction. It is worth noting that the formation of the elimination product (VI) can be efficiently suppressed by removing excess water from (V) via azeotropic distillation with toluene and by adding catalytic amounts of an organic base, in particular N,N- diisopropylethylamine.

[0071] Isolation procedure: After completion of the reaction, toluene can be partially distilled from the reaction mixture. Subsequently, a second solvent, such as methyl tert-butyl ether (MTBE) or diisopropyl ether (preferably methyl tert-butyl ether) can be added to the reaction mixture. After addition of the respective solvent, the product precipitates almost quantitatively from the mixture. In some cases, it has proven useful to seed the mixture with small amounts of crystals to obtain reproducible crystallization. After cooling and prolonged stirring of the resulting suspension, the product is isolated by filtration, washed with solvent and dried at 50 to 60°C under vacuum typically resulting in 59 to 67% yield. The purity of the crude product is typically 95 to 97% (area) with less than 2% (area) N1 regioisomer.

[0072] It must be emphasized that the reaction of a substituted vinyl sulfone for a highly selective targeted preparation of N2-functionalized indazoles is new, without precedence in the literature and therefore, a highly scientifically significant invention for the preparation of these substitution standards.

[0073] The preparation of GMP material, which will also be used in clinical trials, requires an additional purification step. Furthermore, since the active pharmaceutical ingredient will be used for the production of a pharmaceutical composition such as a tablet, a procedure is required that reproducibly provides the identical crystal habit. Surprisingly, this can be accomplished using ethanol or isopropanol as the solvent for recrystallization. Ethanol is the preferred solvent. Therefore, the compound is first dissolved in acetone and subsequently passed through a particulate filter (GMP filtration). A solvent change from acetone to ethanol is accomplished via distillation. Distillation is continued until a final volume of 6 to 7 volumes of ethanol relative to the input material is reached. Distillation is canceled when the boiling point of the ethanol has been reached (ca. 77-78°C) ensuring that all acetone has been removed by distillation. The mixture is cooled, stirred, and the crystallized product is isolated by filtration and dried under vacuum at an elevated temperature. The crystallization yield is typically >90%. The product that is obtained from this crystallization procedure has the desired polymorphism properties required for the preparation of a pharmaceutical composition, such as a tablet. The product exhibits very high purity as well as very high content. The most important analytical data for typical batches are presented in Table 1:

[0074] Table 1: Analytical data of batch examples, as shown in Table 7

[0075] The polymorph obtained through the crystallization procedure described above exhibits good stability during storage. It can also be easily micronized without losing its crystalline properties.

[0076] The preparation of compounds according to general Formula (II) as well as (V) is described in document WO 2015/091426. This new inventive process focuses on the compound shown by Formula (V):

[0077] In the published patent application WO 2015/091426, the compound according to Formula (V) is prepared by reacting the methyl ester compound according to Formula (VI):

[0078] using a solution of methylmagnesium bromide in diethyl ether. After processing, the crude product is subjected to a column chromatographic purification supply compound according to Formula (V) in 45% yield.

[0079] Document WO2016/083433, published after the priority date of the present application, also describes a synthetic route for the preparation of the compound according to Formula (V), starting from the compound according to Formula (VI) by a Grignard reaction using alkylmagnesium halides, for example, methylmagnesium chloride or methylmagnesium bromide in THF or in diethyl ether or in mixtures of THF and diethyl ether.

[0080] This procedure is not suitable for producing the compound of Formula (V) on a technical scale due to the following drawbacks: • The use of diethyl ether should be avoided due to its low ignition point and its highly explosive potential. • Relatively expensive methylmagnesium bromide was used instead of the more common methylmagnesium chloride, which is easier to obtain. • Chromatographic separations should be avoided on a technical scale, as they generally require a solid uneconomical consumption of organic solvents. • No crystallization procedure has been described. In accordance with common practice in research laboratories, the compound of Formula (V) was evaporated until dry. This operation is not viable on a technical scale. • The yield is unsatisfactory: for technical purposes, a yield of at least 75% must be achieved.

[0081] Surprisingly, it was found that the compound of Formula (V) could be prepared in a significantly higher yield when methylmagnesium chloride and lithium chloride (2:1) in THF were used. The reactions proceeded with fewer side products which, using the method described in WO 2015/091426 and WO2016/083433, had to be removed by means of fatiguing column chromatography. It was found that the reaction proceeded better with THF as the solvent. 6 to 10 equiv. of methylmagnesium chloride (about 3 M in THF) and 3 to 5 equivalents of lithium chloride are stirred and maintained at -10 to 0°C. In 1 to 3 h, preferably 2 h, the compound according to Formula (VI) is added to the mixture as a solution in THF. The reaction mixture is stirred for 5 to 30 min in the indicated temperature range (-10 °C to 0 °C) and subsequently finished by pouring into water. The resulting mixture is stirred vigorously. The pH of the mixture is then adjusted to approx. 4 by adding a mineral or organic acid (preferably citric acid) and ethyl acetate. The phases were separated, and the organic phase was washed several times with brine (aqueous sodium chloride solution). The resulting organic solution was subjected to a solvent exchange for toluene via distillation. During this process, the compound according to Formula (V) began to crystallize and could be isolated by filtration. The precipitate was dried at elevated temperature (50 - 60°C) under vacuum. In general, yields at this stage were in the range of 8096% and purities between 95 and 99% area (HPLC).

[0082] For the preparation of material with current good manufacturing practice (cGMP) quality, it has proven beneficial to ultimately mix this product in an isopropanol/water mixture (1:1; 2 to 10 volumes relative to the input material). The material is stirred for 1 to 5 h, preferably 3 h. It is then filtered and washed twice with small amounts of a 1:1 isopropanol/water mixture. The product is dried at high temperature (50-60 °C) under vacuum. In general, yields > 90% and purities > 97 area % (HPLC) are obtained.

[0083] In the following examples in the experimental section, a variant is also described (see example # 2, variant # 3) in which, after treatment with activated carbon, a solvent change is carried out directly to isopropanol. The product is crystallized via addition of water. In this way, the product is obtained directly with very high purity.

[0084] The preparation of the compound according to Formula (VI) was also described in patent application WO 2015/091426. Thereby, 6-(trifluoromethyl)pyridine-2-carboxylic acid (VII) (CAS no.: 21190 87-4) was coupled with the aniline-like compound of Formula (VIII) (methyl-5-amino-1H-indazole -6-carboxylate; CAS nr.: 1000373-79-4) using 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (CAS nr.: 148893-10-1) as coupling agent. The amide (VI) was obtained in 84% yield.

[0085] For process safety reasons, it is not possible to scale up uronium-based coupling reagents, due to their explosive potential. Therefore, an alternative coupling method had to be found.

[0086] The safe and scalable method for preparing a compound similar to Formula (VI) is based on the use of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane- 2,4,6-trioxide; CAS nr.: 68957-94-8) as coupling agent.

[0087] The reaction proceeds smoothly and provides amide-like compound of Formula (VI) in high yields. In a one-bottle process, the carboxylic acid-like compound of Formula (VII) (best used in a slight shortage relative to aniline (VIII), about 0.90-0.95 equivalents) is placed together with 1 .5 equivalents of N,N-diisopropylethylamine in 16 volumes of THF. Subsequently, 2 equivalents of T3P (50% solution in ethyl acetate) are slowly added at 0 to 50°C. The reaction mixture is further stirred for 2 to 4 h, preferably 2 h at 0 to 5 °C.

[0088] The mixture was finished with water, its pH was adjusted with aq. of sodium carbonate to approx. 7.4, and the THF/ethyl acetate mixture was extensively distilled (200 mbar, 45 - 50 °C internal temperature). Subsequently, water and ethanol were added and the pH was adjusted to approx. 7.0 by adding aq. of sodium carbonate. The mixture was stirred for 1 to 5 h, preferably for 1 to 2 h, at 50°C, then cooled to 20-250°C and stirred for 10 to 30 min. The product was isolated by filtration and subsequently washed with a mixture of ethanol and water and finally dried under vacuum at 45°C. With this process, high yields of between 95 and 96% were generally obtained. Purity was in all cases 98 area% (HPLC).

[0089] In some cases, especially when an aniline-like compound of Formula (VIII) of poor optical quality (e.g., dark brown color) was used as the starting material, it proved to be useful in carrying out an activated carbon treatment. This procedure is described in the following section:

[0090] The crude amide (VI) was dissolved in a mixture of methanol and THF (2: 1) and activated carbon was added. The mixture was heated at 60 to 65°C for 1 to 1.5 h. The activated carbon was filtered, and the filtrate was concentrated (up to 2 volumes relative to the input material). Water was added, and the product was precipitated, filtered, washed and dried at 55 to 60 °C (under vacuum).

[0091] The synthesis of compounds of Formulas (VII) and (VIII) has been described in the literature and both are commercially available in large quantities.

[0092] For compounds according to Formula (VII): Cottet, Fabrice; Marull, Marc; Lefebvre, Olivier; Schlosser, Manfred, European Journal of Organic Chemistry, 2003, 8 p. 1559 - 1568; Carter, Percy H.; Cherney, Robert J.; Batt, Douglas G.; Duncia, John V.; Gardner, Daniel S.; Ko, Soo S.; Srivastava, Anurag S.; Yang, Michael G. Patent: US2005/54627 A1, 2005 ; Ashimori; Ono; Uchida; Ohtaki; Fukaya; Watanabe; Yokoyama Chemical and Pharmaceutical Bulletin, 1990, vol. 38, 9 p. 2446 - 2458.

[0093] For compounds according to Formula (VIII): Nissan Chemical Industries, Ltd.; CHUGAI SEIYAKU KABUSHIKI KAISHA, EP2045253 A1, 2009.

[0094] Assessment of the total process:

[0095] Scheme 2 represents the total synthesis of the pure product of Formula (I) from the aniline-like compound of Formula (VIII). The product of Formula (I) is received with a purity of > 99% area (HPLC). When calculating with the best yields obtained for each stage, a total yield of 50% is obtained. This also includes installing the final crystalline form.

[0096] Scheme 2: Total synthesis of the pure product of Formula (I) of the aniline-like compound according to Formula (VIII)

[0097] When comparing this total yield with published prior art data: 1. amide coupling (compound preparation according to Formula (VI)): 84% yield. 2. Grignard reaction followed by chromatographic purification: 45% yield. 3. alkylation with 2-bromoethyl methyl sulfone in a manner analogous to methods known in the literature followed by chromatographic purification: yield 9.68%.

[0098] The advantages of the new process become very clear:

[0099] With the method known from the prior art and as described above, a total yield of only 3.7% could be achieved with the installation of the final crystalline form not included.

[00100] To conclude, the new inventive process provides the compound according to Formula (I) with a total yield > 13 times when compared to the prior art. Furthermore, it includes the targeted and reproducible preparation of the target polymorph for the production of a pharmaceutical composition, such as a tablet.

[00101] It should be emphasized that the reaction of a substituted vinyl sulfone with a highly selective directed preparation of N2-functionalized indazoles is new, without precedence in the literature and, therefore, a highly significant invention for the preparation of these substitution standards.

[00102] Therefore, in a first aspect, the present invention relates to a method for preparing a compound of Formula (I) via the following steps shown in reaction scheme IA, vide infra: (I)

[00103] Scheme IA: Preparation of the compound of Formula (I) from the compound of Formula (VIII) as starting material in which R represents an alkyl group, such as a methyl, ethyl or n-propyl group, for example, or an aryl group, such as a phenyl group, for example, and aromatic hydrocarbon solvent, for example, a solvent such as toluene or xylene.

[00104] In a representation of the first aspect, the present invention relates to a method of preparing a compound of Formula (I) through the following steps shown in reaction scheme I, vide infra:

[00105] Scheme I Preparation of the compound of Formula (I) from the compound of Formula (vIII) as starting material

[00106] In a representation of the first aspect, the present invention relates to a method of preparing a compound of Formula (I):

[00107] which comprises the following step (A): in which a compound of Formula (V):

[00108] can react with a vinyl sulfone compound of Formula (IX'):

[00109] wherein R represents an alkyl group, such as a methyl, ethyl or n-propyl group, for example, or an aryl group, such as a phenyl group, for example, optionally in an aromatic hydrocarbon solvent, such as toluene or xylene, for example, preferably at the reflux temperature of said solvent, thereby providing a said compound of Formula (I).

[00110] In a representation of the first aspect, the present invention relates to a method of preparing a compound of Formula (I) as described above, wherein said aromatic hydrocarbon solvent is toluene.

[00111] In a representation of the first aspect, the present invention relates to a method for preparing a compound of Formula (I) as described above, wherein said compound of Formula (V):

[00112] is prepared by the following step (B): in which a compound of Formula (VI):

[00113] may react with a methylation reducing agent, such as a methylmetallic agent, such as a methylmagnesium halide, such as methylmagnesium chloride, for example, optionally in the presence of an alkali metal halide, such as lithium chloride, for example, providing , thus, the compound mentioned in Formula (V).

[00114] In a representation of the first aspect, the present invention relates to a method for preparing a compound of Formula (I) as described above, wherein said compound of Formula (VI):

[00115] is prepared by the following step (C): in which a compound of Formula (VIII):

[00116] can react with a compound of Formula (VII):

[00117] optionally in the presence of an organic base, particularly a weak organic base, such as a tertiary amine, such as N,N-diisopropylethylamine, for example, optionally in the presence of a coupling agent, such as 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatrifosphinan 2,4,6-trioxide (T3P), for example, thus providing a compound mentioned in Formula (VI).

[00118] In a further representation of the first aspect, the present invention relates to a method of preparing a compound of Formula (I) as described above, wherein said compound of Formula (I) is purified by crystallization, particularly the from a solvent, such as ethanol or isopropanol, for example.

[00119] In a variant of said representation of the first aspect, said solvent is ethanol.

[00120] In a variant of said representation of the first aspect, said solvent is isopropanol.

[00121] In an embodiment of the first aspect, the present invention relates to a method for preparing a compound of Formula (I) as described above, wherein said compound of Formula (I) is in the form of polymorph B.

[00122] According to a second aspect, the present invention relates to polymorph B of the compound of Formula (I):

[00123] as prepared by the method as described above.

[00124] According to a third aspect, the present invention relates to polymorph B of the compound of Formula (I):

[00125] According to a representation of the third aspect, the present invention relates to said polymorph B as described above, having a maximum XRPD peak [220] (Copper (Cu)) as follows:

[00126] Table 2: XRPD of polymorph A, B and 1,7-hydrate of the compound

[00127] According to a fourth aspect, the present invention relates to the use of a compound selected from:

[00128] to prepare a compound of Formula (I): ,

[00129] or polymorph B of the compound of Formula (I) as described above, by the method as described above.

[00130] According to a fifth aspect, the present invention relates to the use of a vinyl sulfone compound of Formula (IX'):

[00131] wherein R represents an alkyl group, such as a methyl, ethyl or n-propyl group, for example, or an aryl group, such as a phenyl group, for example, to prepare a compound of Formula (I ):

[00132] or polymorph B of the compound of Formula (I) as described above.

[00133] In a representation of the fifth aspect, the present invention relates to the use in which said vinyl compound of Formula (IX') is methyl vinyl sulfone.

[00134] According to a sixth aspect, the present invention relates to the use of crystalline forms of the compound of Formula (I), preferably polymorphic form B for the manufacture of a medicine.

[00135] Treatment method:

[00136] The crystalline forms of the compound of Formula (I), according to the invention, preferably the polymorphic form B, can have pharmacological properties and can be used in the prevention and treatment of disorders in humans and animals. The forms of the compound of Formula (I) according to the invention can open up another treatment alternative and can therefore be a pharmacy enrichment.

[00137] The crystalline forms of the compound of Formula (I) according to the invention, preferably polymorphic form B, can be used suitable for the treatment and prevention of proliferative and inflammatory disorders characterized by an overreactive immune system. Particular mention should be made of the use of crystalline forms of the compound of Formula (I), preferably polymorphic form B, according to the invention for treatment and prevention of neoplastic disorders, dermatological disorders, gynecological disorders, cardiovascular disorders, pulmonary disorders, ophthalmological disorders , neurological disorders, metabolic disorders, liver disorders, kidney disease, inflammatory disorders, autoimmune disorders, and pain. In particular, the use of the crystalline forms of the compound of Formula (I) according to the invention for treatment and for prevention of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, COPD (chronic obstructive pulmonary disease), gout, NASH (non-alcoholic steatohepatitis), liver fibrosis, insulin resistance, metabolic syndrome, chronic kidney disease, nephropathy, spondyloarthritis and rheumatoid arthritis, endometriosis and endometriosis-related pain and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria and dyschezia should be specifically mentioned here.

[00138] The crystalline forms of the compound of Formula (I), according to the invention, preferably polymorphic form B, can be used appropriately for the treatment and prevention of pain as well, including acute, chronic, inflammatory and neuropathic pain, preferably hyperalgesia, allodynia, pain caused by arthritis (such as osteoarthritis, rheumatoid arthritis and spondyloarthritis), pre-menstrual pain, pain associated with endometriosis, post-operative pain, pain caused by interstitial cystitis, CRPS (complex regional pain syndrome), neuralgia trigeminal pain, prostatitis pain, spinal cord injury pain, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain.

[00139] In some representations, the present invention further relates to a method for treating and/or prophylaxis of diseases, in particular, diseases mentioned above, with the use of an effective amount of at least one of the forms of the compound of the Formula ( I) according to the invention.

[00140] In some representations, the present invention further relates to a method of treatment and/or prophylaxis of proliferative and inflammatory disorders characterized by an exaggerated immune system, in particular neoplastic disorders, dermatological disorders, gynecological disorders, cardiovascular disorders, pulmonary disorders , ophthalmological disorders, neurological disorders, metabolic disorders, hepatic disorders, inflammatory disorders, autoimmune disorders and pain using an effective amount of at least one of the forms of the compound of Formula (I) according to the invention.

[00141] The forms of the compound of Formula (I), according to the invention, can be used alone or in combination with other active substances, if necessary. The present invention also relates to medicinal products that contain at least one of the forms of the compound of Formula (I) according to the invention and one or more active substances, in particular for the treatment and/or prophylaxis of the diseases mentioned above. As appropriate, other active substances, the following may be mentioned:

[00142] General mention may be made of active ingredients, such as antibacterial substances (e.g., penicillins, vancomycin, ciprofloxacin), antivirals (e.g., acyclovir, oseltamivir) and antimycotics (e.g., naftifine, nystatin) and gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporine, Methotrexat®, TNF antagonists (e.g. Humira®, Etanercept, Infliximab), IL-1 inhibitors (e.g. Anakinra, Canakinumab, Rilonacept), phosphodiesterase inhibitors (e.g., Apremilast), Jak/STAT inhibitors (e.g., Tofacitinib, Baricitinib, GLPG0634), leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine and sulfasalazine; paracetamol, non-steroidal anti-inflammatory substances (NSAIDS) (aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).

[00143] The following should be mentioned for tumor therapy: immunotherapy (e.g., aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab tiuxetan, imiquimod, interferon-alpha, interferon beta , interferon-gamma, ipilimumab, lenalidomide, lenograstim, mifamurtide, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermin, teceleukin, tocilizumab), aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, nileukin diftitox , eculizumab, edrecolomab, gentuzumab, ibritumomab tiuxetan, imiquimod, interferon-alpha, interferon beta, interferon-gamma, ipilimumab, lenalidomide, lenograstim, mifamurtide, ofatumumab, oprelvecin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, sonermine , teceleukin, tocilizumab), antiproliferative substances, for example, but not exclusively, ansacrine, arglabine, arsenic trioxide, asparaginase, bleomycin, busulfan, dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, obinutuzumab, ofatumumab, tositumomab, inhibitors aromatase (e.g., exemestane, fadrozole, formestane, letrozole, anastrozole, vorozole), antiestrogens (e.g., chlormadinone, fulvestrant, mepitiostane, tamoxifen, toremifene), estrogens (e.g., estradiol, polyestradiol phosphate, raloxifene ), gestagens (e.g., medroxyprogesterone, megestrol), topoisomerase I inhibitors (e.g., irinotecan, topotecan), topoisomerase II inhibitors (e.g., amrubicin, daunorubicin, eliptinium acetate, etoposide, idarubicin, mitoxantrone, teniposide) , microtubule-active substances (e.g., cabazitaxel, eribulin, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine), telomerase inhibitors (e.g., imetelstat), alkylating substances and histone deacetylase inhibitors (e.g., bendamustine, carmustine, chlormethine, dacarbazine, estramustine, ifosfamide, lomustine, mitobronitol, mitolactol, nimustine prednimustine, procarbazine, ranimustine, streptozotocin, temozolomide, thiotepa, treosulfan, trofosfamide, vorinostat, romidepsin, panobinostat); substances that affect cell differentiation processes, such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptide mimetic, non-peptide mimetic and tetracyclines, e.g. marimastat, BAY 12-9566, BMS-275291, clodronate, prinomastat, doxycycline), mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus, zotarolimus), antimetabolites (e.g., clofarabine, doxifluridine, methotrexate, 5-fluorouracil, cladribine, cytarabine, fludarabine, mercaptopurine, methotrexate, pemetrexed, raltitrexed, tegafur, thioguanine ), platinum compounds (e.g., carboplatin, cisplatin, cisplatinum, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin); antiangiogenic compounds (e.g., bevacizumab), antiandrogenic compounds (e.g., bevacizumab, enzalutamide, flutamide, nilutamide, bicalutamide, cyproterone, cyproterone acetate), proteasome inhibitors (e.g., bortezomib, carfilzomib, oprozomib, ONYX0914) , gonadoliberin agonists and antagonists (e.g., abarelix, buserelin, deslorelin, ganirelix, goserelin, histrelin, triptorelin, degarelix, leuprorelin), methionine aminopeptidase inhibitors (e.g., bengamid derivatives, TNP-470, PPI-2458 ), heparanase inhibitors (e.g., SST0001, PI-88); inhibitors against genetically modified Ras protein (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, IPI-493, AUY922, BIIB028, STA-9090, KW-2478), kinesin spindle protein inhibitors (e.g., SB715992, SB743921, pentamidine/chlorpromazine), MEK (medium-activated protein kinase) inhibitors mitogens) - e.g., trametinib, BAY 86-9766 (refametinib), AZD6244), kinase inhibitors (e.g., sorafenib, regorafenib, lapatinib, Sutent®, dasatinib, cetuximab, BMS-908662, GSK2118436, AMG 706 , erlotinib, gefitinib, imatinib, nilotinib, Pazopanib, roniciclib, sunitinib, vandetanib, vemurafenib), hedgehog signaling inhibitors (e.g., cyclopamine, vismodegib), BTK (Bruton's tyrosine kinase) inhibitor - e.g., ibrutinib) , JAK/pan-JAK (janus kinase) inhibitor - e.g., SB-1578, baricitinib, tofacitinib, pacritinib, momelotinib, ruxolitinib, VX-509, AZD-1480, TG-101348), PI3K inhibitor (e.g. ., BAY 1082439, BAY 80-6946 (copanlisib), ATU-027, SF-1126, DS-7423, GSK-2126458, buparlisib, PF-4691502, BYL-719, XL-147, XL-765, idelalisib), SYK inhibitors (spleen tyrosine kinase - e.g. fostamatinib, Excellair, PRT-062607), p53 gene therapy, bisphosphonates (e.g. etidronate, clodronate, tiludronate, pamidronate, alendronic acid, ibandronate, risedronate, zoledronate). For a combination, the following active ingredients should also be mentioned as an example, but not exclusively: rituximab, cyclophosphamide, doxorubicin, doxorubicin in combination with estrone, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 1311-chTNT, abiraterone, aclarubicin , alitretinoin, bisantrene, calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, chrysantaspase, darbepoetin alfa, decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitiostanol, epoetin alfa, filgrastim, fotemustine, nitrate gallium, gemcitabine, glutoxim, histamine dihydrochloride, hydroxycarbamide, improsulfan, ixabepilone, lanreotide, lentinan, levadamisole, lisuride, lonidamine, masoprocol, methyltestosterone, methoxsalen, methyl aminolevulinate, miltefosine, mitoguazone, mitomycin, mitotane, Nelarabine, nimotuzumab, nitracrine, omeprazole, palifermin, panitumumab, pegaspargase, PEG epoetin alfa (methoxy- PEG betaepoetin), pegfilgrastim, peg interferon alfa-2b, pentazocine, pentostatin, perfosfamide, pirarubicin, plicamicin, poliglusam, porfimer sodium, pralatrexate, quinagolide, razoxan, sizophyran , sobuzoxane, glycididazole sodium, tamibarotene, the combination of tegafur and gimeracil and oteracil, testosterone, tetrofosmin, thalidomide, thymalfasin, trabectedin, tretinoin, trilostane, tryptophan, ubenimex, vapreotide, yttrium-90 glass microspheres, zinostatin, zinostatin estimalamer.

[00144] Also suitable for tumor therapy is the combination of drug-free therapy, such as chemotherapy (e.g., azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin), radiotherapy (e.g., 1- 125, palladium-103 seed, radium-223 chloride) or phototherapy (e.g., temoporfin, talaporfin) that is accompanied by drug treatment with the inventive IRAK4 inhibitors or that, following drug-free tumor therapy, Once chemotherapy, radiotherapy or phototherapy has ended, they are supplemented by drug treatment with the inventive IRAK4 inhibitors.

[00145] In addition to those mentioned above, the inventive IRAK4 inhibitors can be combined with the following active ingredients:

[00146] active ingredients for Alzheimer's therapy, e.g., acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, tacrine), NMDA receptor antagonists (N-methyl-D-aspartate) - e.g., memantine); L-DOPA/carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors - e.g. entacapone), dopamine agonists (e.g. ropinirole, pramipexole, bromocriptine), dopamine inhibitors MAO-B (monoamine oxidase-B) - e.g., selegiline), anticholinergics (e.g., trihexyphenidyl) and NMDA antagonists (e.g., amantadine) for the treatment of Parkinson's; beta-interferon (IFN-beta) (e.g., IFN beta-1b, IFN beta-1a Avonexk and Betaferonk), glatiramer acetate, immunoglobulins, natalizumab, fingolimod, and immunosuppressants such as mitoxantrone, azathioprine, and cyclophosphamide for the treatment of sclerosis multiple; substances for the treatment of pulmonary disorders, e.g. beta-2-sympathomimetics (e.g. salbutamol), anticholinergics (e.g. glycopyrronium), methylxanthines (e.g. theophylline), leukotriene receptor antagonists (e.g. , montelukast), PDE-4 (phosphodiesterase type 4) inhibitors - e.g. roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, preparations containing cortisol; substances for treating osteoarthritis, such as non-steroidal anti-inflammatory substances (NSAIDs). In addition to the two therapies mentioned, methotrexate and biologics for B-cell and T-cell therapy (e.g., rituximab, abatacept) should be mentioned for rheumatoid disorders, e.g., rheumatoid arthritis, spondyloarthritis, and juvenile idiopathic arthritis. Neurotrophic substances, such as acetylcholinesterase inhibitors (e.g. donepezil), MAO (monoamine oxidase) inhibitors - e.g. selegiline), interferons and anticonvulsants (e.g. gabapentin); active ingredients for the treatment of cardiovascular disorders, such as beta-blockers (e.g., metoprolol), ACE inhibitors (e.g., benazepril), angiotensin receptor blockers (e.g., losartan, valsartan), diuretics (e.g., hydrochlorothiazide), calcium channel blockers (e.g. nifedipine), statins (e.g. simvastatin, fluvastatin); antidiabetic drugs, e.g. metformin, glinides (e.g. nateglinide), DPP-4 (dipeptidyl peptidase-4) inhibitors - e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT2 (sodium cotransporter/ glucose 2)/ gliflozin (e.g., dapagliflozin, empagliflozin), incretin mimetics (hormone glucose-dependent insulinotropic peptide (GIP) analogues/agonists and glucagon-like peptide 1 (GLP-1) - e.g., exenatide, liraglutide, lixisenatide), α-glucosidase inhibitors (e.g., acarbose, miglitol, voglibiose) and sulfonylureas (e.g., glibenclamide, tolbutamide), insulin sensitizers (e.g., pioglitazone) and insulin therapy (e.g. ., NPH insulin, insulin lispro), substances for the treatment of hypoglycemia, for the treatment of diabetes and metabolic syndrome. Lipid-lowering medicines, e.g., fibrates (e.g., bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (e.g., nicotinic acid/laropiprant), ezetimibe, statins (e.g., simvastatin, fluvastatin ), anion exchangers (e.g., cholestyramine, colestipol, colesevelam). Active ingredients such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL#3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei, Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle 1917), antibiotics, e.g. ciprofloxacin and metronidazole, anti-diarrheal medicines, e.g. loperamide or laxatives (bisacodyl) for the treatment of chronic inflammatory bowel diseases. Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory substances (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus. Examples include, but not limited to, calcineurin inhibitors (e.g., tacrolimus and cyclosporine), cell division inhibitors (e.g., azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus), rapamycin, basiliximab, daclizumab , anti-CD3 antibodies, anti-T-lymphocyte globulin/anti-lymphocyte globulin for organ transplantation. Vitamin D3 analogues, e.g. calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate, efalizumab for dermatological disorders.

[00147] Pharmaceutical compositions:

[00148] It is possible that the crystalline forms of the compound of Formula (I) have systemic and/or local activity. For this purpose, they may be administered in a suitable manner, such as, for example, orally, parenterally, pulmonaryly, nasally, sublingually, lingually, buccally, rectally, vaginally, cutaneously, transcutaneously, conjunctively or optically or as an implant or stent.

[00149] For these routes of administration, it is possible that crystalline forms of the compound of Formula (I) are administered in suitable administration forms.

[00150] For oral administration, it is possible to formulate crystalline forms of the compound of Formula (I) into dosage forms known in the art that release the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets, ( coated or uncoated tablets, e.g., with enteric or controlled-release coatings that are delayed-dissolving or insoluble), orally disintegrating tablets, films/wafers, films/lyophilisates, capsules (e.g., hard or soft gelatin capsules ), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, It is possible to incorporate the compounds according to the invention in crystalline and/or amorphized and/or dissolved form in said dosage forms,

[00151] Parenteral administration can be carried out avoiding an absorption step (for example, intravenously, intra-arterially, intracardiac, intraspinally) or with absorption included (for example, intramuscularly, subcutaneously, intracutaneously, percutaneously). or intraperitoneal), Forms of administration that are suitable for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterilized powders,

[00152] Examples that are suitable for other routes of administration are pharmaceutical forms for inhalation [inter alia, powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear rinses, ear plugs; vaginal capsules, aqueous suspensions (lotions, stirring mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents,

[00153] The crystalline forms of the compound of Formula (I) can be incorporated into the indicated administration forms. This can be carried out in a known manner by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel®), lactose, mannitol, starch, calcium phosphate (e.g. Di-Cafos® )), • ointment bases (e.g. petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyalkylene glycols), • suppository bases (e.g. polyalkylene glycols , cocoa butter, hard fat), • solvents (e.g. water, ethanol, isopropanol, glycerol, propylene glycol, medium chain length triglyceride fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or humectants (e.g. sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g. Lanette®), sorbitan fatty acid esters (e.g. Span®), polyoxyethylene fatty acid esters sorbitan (e.g. polyoxyethylene sorbitan fatty acid esters (e.g. Tween®), polyoxyethylene fatty acid glycerides (e.g. Cremophor®), polyoxyethylene fatty acid ethers, fatty alcohol ethers polyoxyethylene, glycerol fatty acid esters, poloxamers (e.g. Pluronic®), • buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonic agents (e.g. glucose, sodium chloride), • adsorbents (e.g. highly dispersible silicas), • viscosity increasing agents, gel formers, thickeners and/or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (e.g., Carbopol®); alginates, gelatin), • disintegrants (e.g. modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g. Explotabk), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g. AcDiSol®)), • flow regulators, lubricants, glidants and rust release agents (e.g. magnesium stearate, stearic acid, talc, highly diverse silicas (e.g. Aerosilk)), • coating materials (e.g. sugar, gum - lacquer) and film formers for diffusion films or membranes that dissolve quickly or in a modified manner (e.g. polyvinylpyrrolidones such as Kollidon®) polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, e.g. Eudragitk), • capsule materials (e.g. gelatin, hydroxypropyl methylcellulose), • synthetic polymers (e.g. polyactides, polyacrylates, polymethacrylates (e.g. Eudragitk), polyvinyl pyrrolidones (e.g. e.g. Kollidonk), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyalkylene glycols and their copolymers and block copolymers), • plasticizers (e.g. polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), • penetration enhancers, • stabilizers (e.g. antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), • preservatives (e.g. parabens, sorbic acid, thiomersal , benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colorants (e.g. inorganic pigments, e.g. iron oxides, titanium dioxide), • flavorings, sweeteners, flavor and/or aroma masking agents .

[00154] The present invention further relates to a pharmaceutical composition, which comprises at least one crystalline form of the compound of Formula (I), conventionally together with one or more pharmaceutically suitable excipients, and to its use in accordance with the present invention .

[00155] Dosage of the pharmaceutical compositions of the present invention:

[00156] Based on known laboratory techniques in the evaluation of compounds useful for the treatment of disorders, by pharmacological tests to determine the treatment of the conditions identified above in mammals and by comparing these results with the results of known medicines that are used to treat these conditions, the effective dosage of the compounds of this invention can actually be determined for the treatment of each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the subject. patient treated and the nature and extent of the condition treated.

[00157] The total amount of active ingredient to be administered will generally vary between about 5 and 2000 mg per day, preferably 15 to 750 mg per day, more preferably 15 to 200 mg per day. A unit dosage may contain from about 15 to 750 mg, preferably from 15 to 120 mg of active ingredient, and may be administered one or more times per day.

[00158] Of course, the specific initial and continued dosage administration for each patient will vary according to the severity of the condition as determined by the attending diagnostician, the activity employed in the specific compound, the age and general condition of the patient, the time of administration, route of administration, drug excretion rate, drug combinations and the like. The mode of treatment and the desired number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be verified by the person skilled in the art using conventional treatment tests.

[00159] Weight data in tests and examples which, below, are, unless otherwise indicated, percentages by weight; parts are parts by weight. The solvent ratios, dilution ratios, and concentration data for the liquid/liquid solutions in each case are based on volume.

[00160] Processing examples

[00161] The following examples illustrate the present invention.

[00162] Methods:

[00163] DSC thermograms were recorded using Differential Scanning Calorimeters (model DSC7, Pyris-1 or Diamond) from Perkin-Elmer. Measurements were carried out with a heating rate of 20 Kmin-1 [using non-gas-tight aluminum pans. The flow gas was nitrogen. There was no sample preparation.

[00164] TGA thermograms were recorded using thermobalances (model TGA7 and Pyris 1) from Perkin-Elmer. Measurements were carried out at a heating rate of 10 Kmin-1 using open platinum pans. The flow gas was nitrogen. There was no sample preparation.

[00165] X-ray diffraction patterns were recorded at room temperature using XRD X'Pert PRO (PANalytical) and STOE STADI-P diffractometers (Cu-K alpha 1 radiation, wavelength 1.5406 A). There was no sample preparation. All X-ray reflections are quoted as °2Theta values with a resolution of ±0.2°.

[00166] Raman spectra are recorded at room temperature using FT-Raman spectrophotometers (model RFS 100 and MultiRam) from Bruker. The resolution was 2 cm-1. Measurements are carried out in glass flasks or aluminum discs. There is no sample preparation.

[00167] IR-ATR spectra are recorded at room temperature using an FT-IR spectrophotometer with a Perkin-Elmer universal diamond ATR device. The resolution was 4 cm-1. There is no sample preparation.

[00168] HPLC

[00169] Method A

[00170] Device: Agilent Technology 1260 Infinity with 1290 Infinity Sampler and Agilent 1100 Series

[00171] Zorbax SB-AQ, 50*4.6 mm, 1.5 pm

[00172] Buffer: pH of ammonium dihydrogen phosphate: 2.4

[00173] Acetonitrile

[00174] 0 min., 5% buffer

[00175] 8.3 min., 80% buffer

[00176] 11 min., 80% buffer

[00177] 210nm/4nm

[00178] 1.2 mL/min.

[00179] Method B A.

[00180] GC-HS

[00181] Residual solvent analysis via headspace gas chromatography (GC-HS)

[00182] Agilent 6890 gas chromatograph with subdivided injection and FID (column: Restek Rxi Sil MS; extension: 20 m; internal diameter: 0.18 mm; df = 1 µm). Injector temperature 160°C, flow 1.2 mL/min (H2) Split ratio 18, oven temperature 40°C (4.5min) - 14°C/min - 70°C - 90°C/min - 220°C (1.69 min). Detector: temp 300°C, 400 mL/min (synthetic air), 40 mL/min (H2), 30 mL/min (N2), rate 20 Hz.

[00183] Perkin Elmer Turbomatrix 40 headspace sampler: 80 °C oven, 150 °C needle, 160 °C transfer line, system pressure 140 kPa, equilibration time 32 min, pressurization 4.0 min, injection time 0 .04 min (Sampler) 0.05 min (GC).

[00184] Sample concentration: 20 mg of substance in 2 mL of DMF Preparation of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H- indazol-5- yl}-6-(trifluoromethyl)pyridine-2-carboxamide (I)

[00185] Example n0 1

[00186] Methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazol-6-carboxylate (VI)

[00187] 2000 g (10.46 mol) of methyl 5-amino-1H-indazol-6-carboxylate, 1899 g (9.94 mol) 6-(trifluoromethyl)pyridine-2-carboxylic acid and 2028 g (15. 69 mol) N,N-diisopropylethylamine are mixed in 14.2 kg of THF. At 0 to 5°C, 13.3 kg of a solution of T3P in ethyl acetate (50% by weight) was added dropwise over 30 min. Stirring continued for 2 hours at the same temperature.

[00188] Preparation:

[00189] The reaction mixture was heated to room temperature (20°C). 3000 g of water is added while the temperature is maintained at 20 - 25 °C. Stirring continues for 10 min. The pH is adjusted to ca. 7.4 (78) using 4 N aqueous sodium carbonate solution. Stirring continues for 10 min. If necessary, the pH is adjusted again to 7.4 using aq. 4 N sodium carbonate.

[00190] The solvents (THF/ethyl acetate) are evaporated under reduced pressure (approx. 200 mbar, 45 - 50 °C internal temperature) until the agitation limit is reached. A mixture of 4.7 kg of ethanol and 14.0 kg of water is added, and the pH is again adjusted to pH 7.4 (7-8) using aq. 4 N sodium carbonate.

[00191] The mixture is stirred for 1 h at 50 0C, subsequently cooled to 20 to 25 0C. Stirring continues for 10 min. at the same temperature. The precipitated crystals are filtered, washed with a mixture of ethanol and water (1.3 kg of ethanol with 4 kg of water) and dried under vacuum in a drying oven (45°C, N2 flow, at least 12 hours). .

[00192] According to the procedure described above, four batches using 2 kg of starting material (methyl 5-amino-1H-indazole-6-carboxylate) were produced in the technical laboratory:

[00193] Yields:

[00194] Lot no. 1: 3476 g (95%)

[00195] Lot no. 2: 3449 g (95%)

[00196] Lot no. 3: 3476 g (95%)

[00197] Lot no. 4: 3494 g (96%)

[00198] The purities of all batches were determined to be > 98% area (HPLC).

[00199] HPLC (Method A): Rt = 6.5 min.

[00200] MS (ESI pos): m/z = 365 (M+H)+

[00201] 1H NMR (500 MHz, DMSO-d6): d [ppm]: 3.98 (s, 3 H), 8.21 (d, 1H), 8.25 (s, 1H), 8.31 (s, 1H), 8.39 (t, 1H), 8.48 (d, 1H), 9.16 (s, 1H), 12.57 (s, 1H), 13.45 (br s, 1H ).

[00202] 1H NMR (300 MHz, DMSO-d6): d [ppm] = 3.97 (s, 3 H), 8.13 - 8.27 (m, 2 H), 8.30 (s, 1 H), 8.33 - 8.45 (m, 1 H), 8.45 - 8.51 (m, 1 H), 9.15 (s, 1 H), 12.57 (s, 1 H) , 13.44 (br s, 1 H). Example n0 2

[00203] N-[6-(2-hydroxypropan-2-yl)-1 H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (V)

[00204] In the following section, different variants of the reaction procedure and procedure are described. These procedures are guided by the conditions presented in the respective technical plans.

[00205] The following experiments were carried out excluding water and air using inert gas (N2 or Ar).

[00206] Variant no. 1

[00207] 50 g (137.255 mmol) of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (VI) were dissolved in 800 mL of THF. Under normal pressure (1 atm) ca. 300 mL of THF was distilled at 70 °C. The solution was cooled to 0 to 3°C.

[00208] The solution was maintained at this temperature and added dropwise over 120 min to a cooled mixture of 457.5 mL (1372.6 mmol) of 3M methylmagnesium chloride in THF and 29.1 g of lithium chloride (686 .3 mmol) at 0-3 °C. After the addition was complete, a sample of the mixture was taken and subjected to HPLC analysis showing that the conversion was completely complete. The mixture was carefully poured for 25 min at 0 to 3°C into 500 mL of aq. of sodium chloride half sat. (attention: exothermic! During the first 50 mL, a strong rise in temperature to 29 °C was observed!). A suspension was received which dissolved when 358 ml of 20% by weight aq. were added (pH dropped from 8.08 to 4.28). Stirring continued for 10 min at 20 to 25°C. 500 mL of ethyl acetate was added and stirring was continued for 10 min. The phases were separated. The sediment was added to the organic phase. 5 g of activated carbon were added to the organic phase. The mixture was heated to 78°C (internal temperature), stirred for 30 min at that temperature and subsequently cooled to 50°C (internal temperature). The hot solution was filtered through celite and washed twice with 125 mL of ethyl acetate. The mixture was concentrated to ca. 150 mL at ambient pressure (1 atm) and 110°C. 350 mL of toluene were added and 200 mL were distilled at ambient pressure (1 atm) and 110°C. The product was precipitated. At an internal temperature of 60°C, 200 mL of n-heptane were added over 45 min. The mixture was cooled to 0 to 3°C and stirred for 2 h at that temperature. The product was filtered and washed twice with a mixture of 50 mL of toluene/n-heptane (1:1). The precipitated product was dried in a drying oven at 40°C and 20 mbar for > 48 h.

[00209] Yield: 39.42 g (78.83%, purity 97.84% area by HPLC)

[00210] HPLC (Method A): Rt = 5.8 min.

[00211] MS (ESlpos): m/z = 365 (M+H)+

[00212] 1H-NMR (400MHz, DMSO-d6): d [ppm] = 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 ( s, 1H),

[00213] 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12, 97 (br s, 1H).

[00214] 13 batches were produced following the procedure of variant nr. 1. Table 3 below summarizes the respective income. Reactions were performed at the 1 kg scale using methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (Vl) as starting material. In most cases, two of the batches were joined together after treatment with activated carbon:

[00215] Table 3: Yields obtained for batches 1 to 13 of the synthesis of (V) of (Vl)

[00216] *) single batch

[00217] Variant no. two

[00218] 30 g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazol-6-carboxylate (VI) were dissolved in 480 mL of THF . Under normal pressure (1 atm) ca. 180 mL of THF was removed by distillation at 70°C. The mixture (light suspension) was then cooled to 0 to 3°C.

[00219] The solution was maintained at this temperature and added dropwise over 120 min to a cooled mixture of 274.5 mL (823.5 mmol) of 3M methylmagnesium chloride in THF and 17.5 g of lithium chloride (411 .8 mmol) at 0-3oC. 15 min after the addition was completed, a sample was removed from the mixture and subjected to HPLC analysis showing that (VI) was completely converted. The mixture was carefully poured over 15 min at 0 to 3 °C into 300 mL of water (caution: exothermic! During the first 50 mL, a strong rise in temperature was observed!). 310 mL of aq. citric acid. at 20% by weight were added (pH dropped to 4.05). Stirring continued for 60 min at 20 to 25°C. 300 mL of ethyl acetate was added and stirring was continued for 30 min. The phases were separated. The sediment was added to the organic phase. The organic phase was washed twice with 450 ml of water. The organic phase was concentrated in 350 mL at 65 °C (internal temperature) and ambient pressure (1 atm). 250 ml of ethyl acetate were added. 6 g of activated carbon were added to the organic phase. The mixture was heated to 65 °C (internal temperature), stirred for 120 min at that temperature and subsequently cooled to 50 °C (internal temperature). The hot solution was filtered through celite and washed twice with 125 mL of ethyl acetate. The mixture was concentrated to ca. 150 mL at ambient pressure (1 atm) and 110 °C. 300 mL of toluene was added and 200 mL was distilled at ambient pressure (1 atm) and 110 °C. The product was precipitated. At an internal temperature of 60°C, 200 mL of n-heptane were added over 45 min. The mixture was cooled to 0-3°C and stirred for 2h at that temperature. The product was filtered and washed twice with a mixture of 50 ml of toluene/n-heptane (1:1). The precipitated product was dried in a drying oven at 40°C and 20 mbar for >48 h.

[00220] Yield: 24.0 g (80%, purity: 95.8% area by HPLC)

[00221] HPLC (Method A): Rt = 5.8 min.

[00222] MS (ESI pos): m/z = 365 (M+H)+

[00223] 1H-NMR (400MHz, DMSO-d6): d [ppm] = 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 ( s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).

[00224] Variant no. 3

[00225] 30 g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazol-6-carboxylate (VI) were dissolved in 600 mL of THF . Under normal pressure (1 atm) ca. 150 mL of THF was removed by distillation at 70 °C. The mixture (light suspension) was then cooled to 0-3°C.

[00226] The solution was maintained at this temperature and added in drops within 120 min. to a cooled mixture of 274.5 mL (823.5 mmol) of 3 M methylmagnesium chloride in THF and 17.5 g (411.8 mmol) of lithium chloride at 0 - 3 °C. The dripping funnel was rinsed twice with 10 mL of THF. 15 minutes after the addition was completed, a sample of the mixture was taken, and analysis was submitted by HPLC showing that (VI) was completely converted. The mixture was carefully poured over 10 min at 0 - 3 °C into 300 mL of water (attention: exothermic! During the first 50 mL, a strong rise in temperature to 25 °C was observed!). 250 mL of aq citric acid. at 20% by weight were added (pH dropped from 8 to 4). Stirring continued for 30 min at 20 - 25°C. 300 mL of ethyl acetate was added and stirring was continued for 10 min. The phases were separated. The sediment was added to the organic phase. The organic phase was washed twice with 200 mL of aq. of sodium chloride at 1% by weight. The phases were separated. The organic phase was concentrated to 250 mL at 65 °C (internal temperature) and ambient pressure (1 atm). 150 mL of ethyl acetate and 6 g of activated carbon were added to the organic phase. The mixture was heated to 65 °C (internal temperature), stirred for 120 min at that temperature and subsequently cooled to 50 °C (internal temperature). The hot solution was filtered through celite and washed twice with 50 mL of ethyl acetate. The mixture was concentrated to ca. 100 mL at ambient pressure (1 atm) and 110 °C. 300 mL of isopropanol were added. 300 mL were distilled at ambient pressure (1 atm) and 110 °C. 300 mL of isopropanol was added again and distilled (ca. 355 mL) at 110 °C. The resulting suspension was cooled to 20-25. 45 mL of water was added over 45 min. The mixture was stirred for 1 h. The precipitated product was filtered and washed with 50 ml of a water/isopropanol mixture (1:1). The precipitated product was dried in a drying oven at 50°C and 20 mbar for 48 h.

[00227] Yield: 24.9 g (83%, purity: 97.84% area by HPLC)

[00228] HPLC (Method A): Rt = 5.8 min.

[00229] MS (ESI pos): m/z = 365 (M+H)+

[00230] 1 H-NMR (400MHz, DMSO-d6): d [ppm] = 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H) , 12.97 (br s, 1H). Variant no. 4

[00231] This variant was used for the production of technical batches on the kg scale (> 10 kg) (see table 4).

[00232] 60 g (164.7 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazol-6-carboxylate (VI) were dissolved in 1500 mL of THF . Under normal pressure (1 atm) ca. 600 mL of THF was removed by distillation at 70°C. The mixture (yellow solution) was cooled to 0-3°C.

[00233] The solution was maintained at this temperature and added dropwise over 120 min to a cooled mixture of 550 mL (1647.1 mmol) of 3M methylmagnesium chloride in THF and 35 g of lithium chloride (823.5 mmol) at 0-3°C. 15 min after the addition was completed, a sample of the mixture was taken and subjected to HPLC analysis showing that (VI) was completely converted. The mixture was carefully poured over 15 min at 0 - 3°C into 600 mL of water (attention: exothermic! During the first 50 mL, a strong rise in temperature was observed!). 600 mL of aq citric acid. at 20% by weight were added (pH dropped to 4). Stirring continued for 30 min at 20 - 25°C. The phases were separated. The organic phase was washed twice with 400 mL of aq. of sodium chloride at 1% by weight. The sediment was added to the organic phase. The phases were separated. The organic phase was concentrated to 700 mL at 65 °C (internal temperature) and ambient pressure (1 atm). 500 mL of ethyl acetate and 12 g of activated carbon were added to the organic phase. The mixture was heated to 65°C (internal temperature), stirred for 120 min at that temperature and subsequently cooled to 50°C (internal temperature). The hot solution was filtered through celite and washed twice with 200 mL of ethyl acetate. Concentration was continued under reduced pressure (200 mbar). A solvent exchange was performed for toluene (remaining volume ca. 850 mL). The resulting suspension was cooled to 03°C. The precipitated product was filtered and washed with 50 ml of toluene. The precipitated product was dried in a drying oven at 50°C and 20 mbar for 48 h. Yield: 51.2 g (85.3%, purity 96.51 area % by HPLC)

[00234] HPLC (Method A): Rt = 5.8 min.

[00235] MS (ESI pos): m/z = 365 (M+H)+

[00236] 1 H-NMR (400MHz, DMSO-d6): d [ppm] = 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 (s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H) , 12.97 (br s, 1H).

[00237] Variant no. 5

[00238] Purification via agitation in isopropanol/water

[00239] Depending on the purity of the raw product, it is possible to carry out an additional purification step by stirring in mixtures of isopropanol and water, preferably 1:1. Depending on the purity of the raw product, stirring is carried out in a range of 2-10 volumes relative to the raw starting material. The following example describes stirring in 3 volumes of isopropanol/water:

[00240] 7.5 g of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl) pyridine-2-carboxamide (V) with a purity of 95 % area (HPLC) 22.5 mL of a 1:1 (vol) mixture of water and isopropanol are stirred for 2 hours at 20°C. The suspension was then filtered, and the product was washed with 4 ml of the same solvent mixture. The product was dried in a drying oven at 50°C under vacuum (<100 mbar).

[00241] Yield: 6.8 g (90.7%, purity > 98% area by HPLC)

[00242] HPLC (Method A): Rt = 5.8 min.

[00243] MS (ESIpos): m/z = 365 (M+H)+

[00244] 1H-NMR (400MHz, DMSO-4): d [ppm] = 1.63 (s, 6H), 5.99 (s, 1H), 7.50 (s, 1H), 8.06 ( s, 1H), 8.17 (d, 1H), 8.37 (t, 1H), 8.46 (d, 1H), 8.78 (s, 1H), 12.33 (s, 1H), 12.97 (br s, 1H).

[00245] A combination of variants nr. 4 and nr. 5 was performed at the 44 kg scale (see table 4 below).

[00246] Table 4: Compound manufacturing according to Formula (V) following the protocols of variants 4 and 5

[00247] Example n0 3

[00248] N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide (I )

[00249] Variant no. 1

[00250] This variant was used for the production of technical batches on the kg scale and follows the protocol described in document WO2016/083433.

[00251] 2.5 kg (6.86 mol) N-[6-(2-hydroxypropan-2-yl)-1 H-indazol-5-yl]- 6-(trifluoromethyl) pyridine-2-carboxamide (V ) were suspended in 33 L (28.6 kg) of toluene. The mixture was heated to reflux and approx. 8 l of toluene was distilled from the mixture. The mixture was cooled to 90 °C and 44 g (0.34 mol) of N,N-diisopropylethylamine were dosed into the mixture. The mixture was stirred for a further 15 min at 90°C before 1.17 kg (10.98 mmol) of methyl vinyl sulfone was added. The reaction mixture was maintained at 112°C (refluxing toluene) and stirred for at least 72 h. The mixture was cooled to 20 °C. Then the mixture was heated to reflux and 8 liters of toluene were distilled from the mixture. The mixture was then cooled to 70 °C and 12.6 kg of methyl tert-butyl ether (MTBE) was added within 30 min. The mixture was cooled to 20 °C within 2 h and stirred at 20 °C overnight. It was then cooled to 0°C and stirred for 1 h. The precipitate was filtered and washed twice with 3 l of cold MTBE. The crystalline product was dried in a drying oven at 50°C under vacuum.

[00252] Yield: 2.39 kg (73.9%, purity: 97.8% area by HPLC)

[00253] HPLC (Method B): Rt = 3.07 min.

[00254] MS (ESI pos): m/z = 471 (M+H)+

[00255] 1H NMR (400 MHz, DMSO-d6): d [ppm] = 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4 .86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.13 - 8.19 (m, 1 H), 8.37 (s, 1 H), 8.41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H).

[00256] Table 5: Yields and purity (in % after HPLC) obtained for three batches of (I) and (V)

[00257] * Method B

[00258] To obtain material with very high purity and a defined crystalline form (polymorph B), an additional purification step was introduced.

[00259] 1.85 kg of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl) ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine- Crude 2-carboxamide (I) were dissolved in 36.6 kg (46.3 l) of acetone at room temperature. The resulting solution was dosed into refluxing ethanol for 2.5 h. During the dosing process, 54 l of solvent was distilled and an internal temperature of 63 °C was reached. An additional 20.8 L of ethanol was added and 27 liters of solvents were distilled from the mixture. Additionally, 10.2 L of additional ethanol was added and 9.3 L was distilled from the mixture. Finally, an additional 10.2 L of additional ethanol was added and 10.2 L of solvents were distilled from the mixture. The mixture was cooled to 20 °C in 3 h and stirred overnight. The mixture was cooled to 0 - 2°C within 1.5 h and stirred at that temperature for a further 3 h. The suspension was filtered and the precipitate was washed with 2x 0.93 l of cold ethanol. The product was dried in a drying oven at 50°C under vacuum.

[00260] Yield: 1.59 kg (85.7%, purity: 99.0% area by HPLC)

[00261] HPLC (Method B): Rt = 3.07 min.

[00262] MS (ESI pos): m/z = 471 (M+H)+

[00263] 1H NMR (400 MHz, DMSO-d6): d [ppm] = 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4 .86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.16 (d, 1 H), 8.37 (t, 1 H), 8 .41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H).

[00264] Table 6: Yield and purity obtained from the synthesis as well as purity (%) after HPLC for (I) synthesized from (V)

[00265] Variant no. two

[00266] This variant was used for the production of technical batches on the kg scale.

[00267] 10 g (27.448 mmol) N-[6-(2-hydroxypropan-2-iI)-1H-indazoI-5-iI]-6-(trifIuoromethyl) pyridine-2-carboxamide (V) were suspended in 100 mL of toluene. 3.496 g (32.937 mmol) of methyl vinyl sulfone were added. The reaction mixture was heated to 110°C (reflux toluene) and stirred for at least 15 h. An additional portion of 583 mg (5.49 mmol) of methyl vinyl sulfone was added, and the reaction mixture was stirred for 7 h at reflux. An additional 583 mg (5.49 mmol) of methyl vinyl sulfone was added and the reaction mixture was stirred for > 15 h. According to HPLC analysis, 2.5% of the starting material (V) was still in the reaction mixture. The N1/N2 selectivity was 1:8. 30 mL toluene was distilled. The mixture was cooled to 70 °C. At this temperature, 70 mL of MTBE was added dropwise over 5 min to the mixture resulting in a suspension. The mixture was cooled to 20 °C overnight. It was then cooled to 0oC and stirred for 2 h. The precipitate was filtered and washed twice with 10 mL of cold MTBE. The crystalline product was dried in a drying oven for at least 48 hours at 50°C and <100 mbar.

[00268] Yield: 8.6 g (66.6%, purity: 94.7% area by HPLC)

[00269] HPLC (Method B): Rt = 3.07 min.

[00270] MS (ESI pos): m/z = 471 (M+H)+

[00271] 1H NMR (400 MHz, DMSO-d6): d [ppm] = 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2 H), 4 .86 (t, 2 H), 5.97 (s, 1 H), 7.59 (s, 1 H), 8.16 (d, 1 H), 8.37 (t, 1 H), 8 .41 - 8.48 (m, 2 H), 8.74 (s, 1 H), 12.37 (s, 1 H). Technical scale lots:

[00272] Following the procedure described as batches of variant nr. 2 in the scales of 3.396 kg and 1.699 kg relative to the initial material (V) were produced:

[00273] Table 7: Yield for compound (I) synthesized from compound (V)

[00274] Preparation of polymorphic forms of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine- 2-carboxamide (I)

[00275] Preparation of polymorphic forms of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine- 2-carboxamide (I)

[00276] When the term "room temperature" is used in the following synthesis protocols, a temperature of about 20 to 25 °C is meant.

[00277] Example 0

[00278] For the production of cGMP grade material and to adjust the crystalline form for tablet production, an additional purification step was introduced.

[00279] 1500 kg of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2- crude carboxamide (I) were dissolved in 45 kg of acetone and subjected to clarification filtration (filter cartridge: 3.0 am ^ GMP filtration). The filtrate was concentrated and a solvent change to ethanol was performed. Thus, ethanol was added during simultaneous distillation until an internal temperature of 77 °C was reached. The solution was concentrated to 6 to 7 volumes of ethanol relative to the initial volume. The mixture was cooled to 20 °C and stirred for 12 h at that temperature. It was then cooled to 0°C and stirred for a further 3 h. The product was filtered and washed twice with 1 kg of cold ethanol. The product was dried in a drying oven at 60 oC under vacuum (<100 mbar).

[00280] Yield: 1370 g (91.33%). Analogous to the procedure described, three batches were carried out on a technical scale, see table 7.

[00281] Table 8: Yield of pure compound (I) obtained by purification described above of crude (I)

[00282] Table 9: Analytical data from three combined batches, as shown in table 8

[00283] * Method B; "GC-HS

[00284] Example 1

[00285] Preparation of polymorphic form A of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine -2-carboxamide A) 400 mg N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine- 2-carboxamide were dissolved in 40 mL of THF under reflux. The solution was filtered. Evaporation of the clear solution until drying was done by storage at room temperature or in the refrigerator or freezer. B) 400 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 40 mL of acetone under reflux. The solution was filtered. The clear solution was evaporated until dry by storing it at room temperature or in the refrigerator. C) 400 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 40 mL of acetone under reflux and 20 mL of water were added to the solution. Evaporation of the clear solution until drying was done by storage at room temperature.

[00286] Example 2

[00287] Preparation of polymorphic form B of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine -2-carboxamide A) 400 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine -2- carboxamide were dissolved in 40 mL of acetonitrile under reflux. The solution was filtered, and the clear solution was evaporated to dryness by storage at room temperature. B) 400 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 40 mL of acetone under reflux. The solution was filtered, and the clear solution was evaporated to dryness by storage in a freezer. C) 400 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide were dissolved in 40 mL of tetrahydrofuran under reflux and 20 mL of n-heptane were added to the solution and then it was evaporated to dryness by storage at room temperature. Example 3

[00288] Preparation of pseudopolymorphic form (1,7 Hydrate) of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6 - (trifluoromethyl)pyridine-2-carboxamide

[00289] 100 mg of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2- carboxamide were suspended in 1 mL of a 1:1 ethanol/water mixture and stirred for two weeks at room temperature. The solid was filtered and dried by storage at room temperature.

[00290] XRPD data for polymorph A, B and 1,7-hydrate of compound (I) are presented in table 2 and in Figures 1, 2 and 3.

[00291] X-ray powder diffraction; measurement conditions: Anode material Ass

[00292] Example 4

[00293] Pharmaceutical composition containing one of the polymorphic forms A or B or the pseudopolymorphic form (1,7-hydrate) of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl] -2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[00294] The granulation liquid by mixing the micronized form of the compound of Formula (I), sodium lauryl sulfate, hypromellose 3 cP and purified water in bulk. Mannitol, microcrystalline cellulose and croscarmellose sodium are mixed. This mixture is granulated with the granulation liquid in the fluidized bed granulator. The granules are dried and sieved.

[00295] The granules are mixed with sifted magnesium stearate in a mixer which results in the mixture ready for pressing. The ready-to-press mixture is compressed into tablets. Uncoated tablets are tested for mass uniformity, thickness, resistance to crushing, disintegration and brittleness. Hypromellose 5 cP, macrogol 3350, talc, titanium dioxide and ferric oxide red are combined with bulk purified water to result in a homogeneous coating suspension, which is sprayed onto the tablets in a suitable coating device, e.g. coater perforated drum.

[00296] Table 10: Tablet composition

[00297] Tablets each containing 15 and 120 mg of the polymorphic form B of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)-ethyl]-2H- indazol-5-yl }-6-(trifluoromethyl)pyridine-2-carboxamide were prepared following the protocol presented in example 4.

[00298] Test for stability of a pharmaceutical composition containing one of the polymorphic forms A or B or the pseudopolymorphic form (1,7-hydrate) of N-{6-(2-Hydroxypropan-2-yl)-2-[2- (methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide

[00299] Coated tablet containing 15 mg or 120 mg of the polymorphic form B of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)-ethyl]-2H-indazol-5-yl }-6-(trifluoromethyl)pyridine-2-carboxamide (drug substance) are packaged in HDPE (High Density Polyethylene) bottles with child-resistant white polypropylene/polyethylene screw cap closures. This packaging configuration provides sufficient protection from light and moisture.

[00300] Stability studies are carried out with tests of parameters indicating stability, appearance, dissolution, degradation products and drug content at regular intervals to confirm the stability of the coated tablet containing 15 mg or 120 mg of the substance during the duration of the proposed study.

[00301] Coated tablet samples (15 mg or 120 mg) packed in HDPE bottles are stored at 25 °C/60% relative humidity, 30 °C/75% relative humidity and 40 °C/75% relative humidity. relative humidity as well as 2 - 8°C. Experiments to investigate stability are carried out regularly.

[00302] Coated tablets containing 15 mg or 120 mg of the polymorphic form B of N-{6-(2-Hydroxypropan-2-yl)-2-[2-(methylsulfonyl)-ethyl]-2H-indazol-5-yl }-6-(trifluoromethyl)pyridine-2-carboxamide (drug substance) are stable under all investigated conditions. During this storage period, neither an increase in degradation products nor a decrease in the drug substance content were observed.

Claims (7)

1. Crystalline form, characterized by the fact that it is the compound of Formula (I), which is polymorph B, defined by an X-ray powder diffraction diagram at 25 °C and with Cu-K alpha 1, as a radiation source, presenting at least the following reflections, cited as a value of 2Theta ± 0, 2nd: 9.7, 10.1, 15.4. 2. Crystalline form, according to claim 1, characterized by the fact that it is polymorph B, defined by an X-ray powder diffraction diagram at 25 °C and with Cu-K alpha 1, as a radiation source, presenting at least the following reflections, cited as a value of 2Theta ± 0.2°: 9.7, 10.1, 15.4, 16.1, 20.2. 3. Crystalline form, according to claim 1, characterized by the fact that it is polymorph B, defined by an X-ray powder diffraction diagram at 25 °C and with Cu-K alpha 1, as a radiation source, presenting at least the following reflections, cited as a value of 2Theta ± 0.2°: 9.7, 10.1, 15.4, 16.1, 20.2, 22.3. 4. Crystalline form, according to claim 1, characterized by the fact that it is polymorph B, defined by an X-ray powder diffraction diagram at 25 °C and with Cu-K alpha 1 as a radiation source presenting at least minus the following reflections, cited as a value of 2Theta ± 0.2°: 9.7, 10.1, 15.4, 16.1, 20.2, 22.3, 25.2. 5. Crystalline form, according to any one of claims 1 to 4, characterized by the fact that it is for treatment and/or prophylaxis of neoplastic disorders, dermatological disorders, gynecological disorders, cardiovascular disorders, pulmonary disorders, ophthalmological disorders, neurological disorders, metabolic disorders, liver disorders, inflammatory disorders, autoimmune disorders and pain. 6. Crystalline form, according to any one of claims 1 to 4, characterized by the fact that it is for treatment and/or prophylaxis of lymphoma, macular degeneration, psoriasis, lupus erythematosus, multiple sclerosis, obstructive pulmonary disease (COPD), gout, non-alcoholic steatohepatitis (NASH), liver fibrosis, insulin resistance, metabolic syndrome, spondyloarthritis and rheumatoid arthritis, endometriosis and endometriosis-related pain, and other symptoms associated with endometriosis such as dysmenorrhea, dyspareunia, dysuria and dyschesia. 7. Invention, characterized by the fact that it falls under any of its embodiments or categories of claims, for example, product or process or use encompassed by the matter initially described, disclosed or illustrated in the patent application.