EA042116B1 - POLYMORPHIC FORM of N-{6-(2-HYDROXYPROPAN-2-YL)-2-[2-(METHYLSULFONIL)ETHYL]-2H-INDAZOL-5-YL}-6-(TRIFLUOROMETHYL)PYRIDINE-2-CARBOXAMIDE - Google Patents

Description

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 , to processes for their preparation, to pharmaceutical compositions containing them, to intermediates, and to their use in disease control.

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

(I).

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

Human IRAK4 (interleukin-1 receptor-associated kinase 4) plays a key role in the activation of the immune system. Therefore, this kinase is an important therapeutic target molecule for the development of inflammation-inhibiting substances. IRAK4 is expressed by a variety of cells and mediates signal transduction of toll-like receptors (TLRs), with the exception of TLR3, and the interleukin (IL)-1e family of 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).

Neither IRAK4 knockout mice nor human cells from IRAK4-deficient patients respond to stimulation by TLR (with the exception of TLR3) and the IL-1e family (Suzuki, Suzuki, et al., Nature, 2002; Davidson, Currie, et al., The Journal of Immunology, 2006; Ku, von Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).

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

The major role of IRAK4 in the pathology of various inflammatory disorders was shown by direct comparison of wild-type (WT) mice with genetically modified animals having a kinase-inactivated form of IRAK4 (IRAK4 KDKI). IRAK4 KDKI animals have improved clinical performance in an 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; Cameron, Tse, et al., The Journal of Neuroscience, 2012). In addition, deletion of IRAK4 in an animal model has been found to protect against viral-induced myocarditis by an improved antiviral response with concurrently reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013). IRAK4 expression has also been shown to correlate with the degree of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).

In addition to the main role of IRAK4 in innate immunity, there are also indications that IRAK4 influences the differentiation of so-called Th17 T cells, components of acquired immunity. In the absence of IRAK4 kinase activity, fewer IL-17-producing T cells (Th17 T cells) are generated compared to WT mice. Therefore, IRAK4 inhibition is useful in the prevention and/or treatment of atherosclerosis, type 1 diabetes, rheumatoid arthritis, spondyloarthritis, lupus erythematosus, psoriasis, vitiligo, chronic inflammatory bowel disease, and viral disorders, e.g., HIV (human immunodeficiency virus), hepatitis virus ( Staschke, et al., The Journal of Immunology, 2009; Zambrano-Zaragoza, et al., International Journal of Inflammation, 2014).

Because of the major role of IRAK4 in the MyD88-mediated TLR signaling cascade (with the exception of TLR3) and the IL-1 receptor family, inhibition of IRAK4 can be used to prevent and/or treat disorders mediated by these receptors. TLRs, as well as components of the IL-1 receptor family, are involved in the pathogenesis of rheumatoid arthritis, metabolic syndrome, diabetes, osteoarthritis, Sjögren'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; Fresno, Archives Of Physiology And Biochemistry, 2011; Volin and Koch, J. Interferon Cytokine Res., 2011; Akash, Shen, et al., Journal of Pharmaceutical Sciences, 2012; Goh and Midwood, Rheumatology, 2012; Dasu, Ramirez, et al., Clinical Science, 2012; Ramirez and Dasu, Curr Diabetes Rev, 2012; Li, Wang, et al., Pharmacology & Therapeutics, 2013; Sedimbi, Hagglof, et al., Cell Mole Life Sci., 2013; Talabot-Aye, et al., Cytokine, 2014). Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, allergic contact dermatitis, acne inversa, and acne vulgaris are associated with IRAK4-mediated TLR signaling (Gilliet, Conrad, et al., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al. ., Allergy, 2008; Miller, Adv Dermatol, 2008; Terhorst, Kalali, et al., Am. J. Clin. Dermatol., 2010; Viguier, Guigue, et al., Annals of Internal Medicine, 2010; Cevikbas, Steinhoff , J. Invest. Dermatol., 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Dispenza, Wolpert, et al., J. Invest. Dermatol., 2012; Minkis, Aksentijevich, et al., Archives of Dermatology, 2012; Gresnigt and van de Veerdonk, Seminars in Immunology, 2013; Selway, Kurczab, et al., BMC Dermatology, 2013; Sedimbi, Hagglof, et al., Cell Mole Life Sci., 2013; Wollina, Koch, et al., Indian Dermatol. Online, 2013; Foster, Baliwag, et al., The Journal of Immunology, 2014).

Pulmonary diseases such as pulmonary fibrosis, obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis, and pulmonary hypertension also show association with various TLR-mediated signaling. ways. The pathogenesis of pulmonary diseases can be mediated by processes of either infectious or non-infectious origin (Ramirez Cruz, Maldonado Bernal, et al., Rev. Alerg. Mech., 2004; Jeyaseelan, Chu, et al., Infection and Immunity, 2005; Seki, Tasaka , et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal , 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mole Med., 2012; Deng, Yang, et al., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013). TLRs, as well as members of the IL-1R family, are also implicated in the pathogenesis of other inflammatory disorders such as Behcet's disease, gout, lupus erythematosus, adult Still's disease, and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, and transplant rejection, and therefore, IRAK4 inhibition is the therapeutic approach (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; Heimesaat, Fischer, et al., PLoS ONE, 2007; Kobori, Yagi, et al., J. Gastroenterol., 2010; Shi, Mucsi, et al., Immunological Reviews, 2010; Leventhal and Schroppel, Kidney Int, 2012; Chen, Lin, et al., Arthritis Res Ther, 2013; Hao, Liu, et al., Curr Opin Gastroenterol, 2013; Kreisel and Goldstein, Transplant International, 2013; Li, Wang, et al., Pharmac ology & Therapeutics, 2013; Walsh, Carthy, et al., Cytokine & Growth Factor Reviews, 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 the prophylactic and/or therapeutic use of diseases mediated by TLR and the IL-1R family, such as endometriosis 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; Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Sikora, Mielczarek-Palacz, 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 Gynaecology Research, 2013; Santulli, Borghese, et al., Human Reproduction, 2013; Sedimbi, Hagglof, et al., Cell Mole Life Sci., 2013).

In addition to the diseases already cited, IRAK4-mediated TLR processes have been described in the pathogenesis of eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration, and uveitis (Kaarniranta and Salminen, J. Mole Med. (Berl) , 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J. Leukoc. Biol., 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012; Guo, Gao, et al., Immunol. Cell Bio.l, 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao, et al., Investigative Ophthalmology & Visual Science, 2014).

Due to the central role of IRAK4 in TLR-mediated processes, inhibition of IRAK4 also provides treatment and/or prevention of cardiovascular and neurological disorders, such as myocardial reperfusion injury, myocardial infarction, hypertension (Oyama, Blais, et al., Circulation, 2004; Timmers , Sluijter, et al., Circulation Research, 2008; Fang and Hu, Med. Sci. Monit., 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al., Clin. Sci. (Lond) , 2012; Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin. Sci. (Lond), 2013), as well as Alzheimer's disease, stroke, traumatic brain injury and Parkinson's disease (Brough , Tyrrell, et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical

Pharmacology, 2011; Denes, Kitazawa, Cheng, et al., The Journal of Immunology, 2011; Lim, Kou, et al., The

American Journal of Pathology, 2011; Beraud 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).

Due to the involvement of TLR signaling and IL-1 receptor family-mediated signaling through IRAK4 in pruritus and pain, e.g. cancer pain, postoperative pain caused by inflammation and chronic pain, a therapeutic effect in these indications could be expected as a result of 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; Kwok, Hutchinson, et al., PLoS ONE, 2012; Nicotra, Loram, et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake, et al., Neurobiology of Disease, 2013; Han, Zhao, et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung, et al., Journal of Neuroinflammation, 2013; Zhao, Zhang, et al., Neuroscience, 2013; Liu, Y. Zhang, et al., Cell Research, 2014).

This also applies to some cancers. Certain lymphomas, such as ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma), mantle cell lymphoma, and Waldenström's disease, as well as chronic lymphatic leukemia, melanoma, and hepatocellular carcinoma, are characterized by mutations in MyD88 or changes in activity MyD88 that can be treated with 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; (Liang, Chen, et al., Clinical Cancer Research, 2013) In addition, MyD88 plays an important role in ras-dependent tumors, and such IRAK4 inhibitors are also suitable for their treatment (Kfoury, A., K.L. Corf, et al., Journal of the National Cancer Institute, 2013).

Treatment of inflammatory diseases such as CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold autoinflammatory syndrome), MWS (Muckle-Wales syndrome), NOMID (multisystem inflammatory disease of neonatal age) and CONCA (chronic infantile neurological cutaneous articular) syndrome; FMF (familial Mediterranean fever), HIDS (hyper-IgD syndrome), TRAPS (tumor necrosis factor receptor 1-associated periodic syndrome), juvenile idiopathic arthritis, adult Still's disease, Adamantiad-Behcet's disease, rheumatoid arthritis, osteoarthritis, keratoconjunctivitis sicca, and Sjögren's syndrome, carried out by blocking the IL-1 signaling pathway; accordingly, in this case, an IRAK4 inhibitor is also suitable for the treatment of these 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; Pettersson, Annals of MedicinePetterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordstrom, Knight, et al., The Journal of Rheumatology, 2012 ; Vijmasi, Chen, et al., Mole Vis, 2013; Yamada, Arakaki, et al., Opinion on Therapeutic Targets, 2013). The IL-33R ligand, IL-33 is particularly implicated in the pathogenesis of acute renal failure, and therefore inhibition of IRAK4 for prevention and/or treatment is an acceptable therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011 ). IL-1 receptor family components are associated with myocardial infarction, various lung diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis, and acute respiratory distress syndrome (ARDS), and therefore should be expected for these indications with IRAK4 inhibition. preventive and/or therapeutic effect (Kang, Homer, et al., The Journal of Immunology, 2007; Imaoka, Hoshino, et al., European Respiratory Journal, 2008; Couillin, Vasseur, et al., The Journal of Immunology, 2009 ; Abbate, Kontos, et al., The American Journal of Cardiology, 2010; Lloyd, Current Opinion in Immunology, 2010; Pauwels, Bracke, et al., European Respiratory Journal, 2011; Haenuki, Matsushita, et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li, et al., Clinical & Experimental Immunology, 2012; Abbate, Van Tassell, et al., The American Journal of Cardiology, 2013; Alexander-Brett, et al., The Journal of Clinical Investigation, 20 13; Bunting, Shadie, et al., BioMed Research International, 2013; Byers, Alexander-Brett, et al., The Journal of Clinical Investigation, 2013; Kawayama, Okamoto, et al., J. Interferon Cytokine Res, 2013; Martinez-Gonzalez, Roca, et al., American Journal of Respiratory Cell and Molecular Biology, 2013; Nakanishi, Yamaguchi, et al., PLoS ONE, 2013; Qiu, Li, et al., Immunology, 2013; Li, Guabiraba, et al., Journal of Allergy and Clinical Immunology, 2014; Saluja, Ketelaar, et al., Molecular Immunology, 2014).

A variety of IRAK4 inhibitors have been disclosed in the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133).

US 8293923 and US 20130274241 disclose IRAK4 inhibitors with a 3-substituted indazole structure. There is no description of 2-substituted indazoles.

WO 2013/106254 and WO 2011/153588 disclose 2,3-disubstituted indazole derivatives.

WO 2007/091107 describes 2-substituted indazole derivatives for the treatment of Duchenne muscular dystrophy. The disclosed compounds do not have a 6-hydroxyalkyl substitution.

WO 2015/091426 describes indazoles whose alkyl group is substituted in position 2 with a carboxamide structure.

WO 2015/104662 describes indazole compounds of formula (I)

which are therapeutically useful as a kinase inhibitor, in particular IRAK4 inhibitors, and their pharmaceutically acceptable salts or stereoisomers which are useful in the treatment and prevention of diseases or disorders, in particular their use in the treatment of diseases or disorders mediated by a kinase enzyme, in particular the IRAK4 enzyme .

WO 2016/083433, published after the priority date of the application for this invention, describes new substituted indazoles of the following formula:

methods for their preparation, their use alone or in combination for the treatment and/or prevention of diseases and their use for the manufacture of drugs for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of endometriosis and endometriosis-related pain and other symptoms, associated with endometriosis, such as dysmenorrhea, dyspareunia, dysuria and dyschezia, lymphomas, rheumatoid arthritis, spondyloarthritis (particularly psoriatic spondyloarthritis and ankylosing spondylitis), lupus erythematosus, multiple sclerosis, macular degeneration, COPD, gout, fatty liver disease, resistance to insulin, tumor diseases and psoriasis.

Accordingly, there is a need to obtain crystalline forms of the compound of formula (1) with good physicochemical properties, which can be advantageously used in pharmaceutical production and pharmaceutical compositions.

The novel IRAK4 inhibitor should be particularly useful in the treatment and prevention of proliferative and inflammatory diseases that are characterized by an over-reaction of the immune system. In this context, mention should be made in particular of inflammatory skin lesions, cardiovascular diseases, lung diseases, eye diseases, autoimmune disorders, gynecological disorders, especially endometriosis and cancer.

A process is to be disclosed that allows the production of indazole (I) on an industrial scale, with particular reference to the following requirements:

scaling/scalability of the production process;

high regioselectivity of the N2-alkylation reaction;

elimination of chromatographic separation and purification steps;

final processing by crystallization;

final adjustment of the polymorph using grade 3 solvents (according to FDA guidelines).

Surprisingly, a method can be disclosed that meets all the requirements mentioned above.

Surprisingly, the following crystalline forms of the compound of formula (I) have been identified, which are the A polymorph, the B polymorph, and the 1,7-hydrate crystalline pseudopolymorph. In this context of modification, polymorphic forms and polymorphs have the same meaning. In addition, there is an amorphous form. Collectively, the polymorphic forms, the pseudopolymorphic form and the amorphous form are the various solid forms of the compound of formula (I).

The compound of formula (I) in its polymorphic form B was described in priority application EP 16167652.3, filed 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, p. 8-9, the designation and naming of the polymorphs is usually carried out according to the order of their melting points, starting with those having the highest melting point, called the A polymorph. I), which is described in priority application EP 16167652.3, is a form with a lower melting point compared to the other polymorph, whereby the applicant corrects the name of that compound, which is described in EP 16167652.3, filed April 29, 2016, as form A to polymorph form B of the compound of formula (I).

Polymorph form B of the compound of formula (I) is a thermodynamically stable form. Surprisingly, polymorph Form B of the compound of formula (I) exhibits advantageous properties over 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, appearance, bioavailability, side effects, pharmacokinetic behavior, potency, advantageous properties during chemical synthesis (e.g. , in relation to processing or isolation, which may represent, for example, improved filtration capacity) and/or useful properties during the manufacture of the pharmaceutical composition.

Thus, polymorph 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 the manufacture of tablets containing polymorph form B of the compound of formula (I).

In particular, the polymorph form B of the compound of formula (I) provides for the prevention of undesirable conversion to another form of the compound of formula (I) and the associated change in the properties described above. Does this improve the safety and quality of formulations containing the compound of formula (I)? and the risk to the patient is reduced.

The compound of formula (I) in polymorph form B can be isolated by crystallization from solution using acetonitrile, tetrahydrofuran or acetone by evaporation at room temperature or evaporation under refrigerated conditions (refrigerator or freezer).

Embodiments of the present invention are not only a single crystalline form of the compound of formula (I), which is a polymorph form A, a polymorph form B and a 1,7-hydrate of the compound of formula (I), but also mixtures containing two or three crystalline forms of the above .

The pharmaceutical composition according to the present invention contains a crystalline form of the compound of formula (I) selected from the group consisting of its polymorph form A, its polymorph form B, its 1,7-hydrate and a mixture thereof, and other pharmaceutically acceptable excipients.

The pharmaceutical composition according to the present invention preferably contains only one of the crystalline forms selected from the group consisting of polymorph form A, polymorph form B and mainly 1,7-hydrate of the compound of formula (I) and does not contain significant fractions of another form of the compound of formula ( I). More preferably, the pharmaceutical composition contains more than 85 wt.%, more preferably more than 90 wt.%, most preferably more than 95 wt.% of the polymorph form B of the compound of formula (I) in terms of the total amount of all forms of the compound of formula (I) present in compositions.

Preference is given to a pharmaceutical composition containing the compound of formula (I) essentially in polymorph form B and not containing significant fractions of another solid form of the compound of formula (I), for example another polymorph or pseudopolymorph of the compound of formula (I). The pharmaceutical composition preferably contains more than 80 wt.%, preferably more than 90 wt.%, most preferably more than 95 wt.% of the polymorph form B of the compound of formula (I) in terms of the total amount of all forms of the compound of formula (I) present in compositions.

In addition, preference is given to a pharmaceutical composition containing the compound of formula (I) essentially in polymorph form A and not containing significant fractions of another solid form of the compound of formula (I), for example another pseudopolymorph of the compound of formula (I). The pharmaceutical composition preferably contains more than 80% by weight, more preferably more than 90% by weight, most preferably more than 95% by weight of the compound of formula (I) in polymorph form A, based on the total amount of all forms of the compound of formula (I) present in composition.

In addition, preference is given to a pharmaceutical composition containing essentially the 1,7-hydrate of the compound of formula (I) and not containing significant fractions of another solid form of the compound of formula (I), for example another pseudopolymorphic form of the compound of formula (I). The pharmaceutical composition preferably contains more than 85 wt.%, more preferably more than wt.%, more preferably more than 95 wt.% of the compound of formula (I) in the form of a 1,7-hydrate, calculated on the total amount of all forms compounds of formula (I) present in the composition.

The various forms of the compound of formula (I) can be distinguished by X-ray powder diffraction, differential scanning calorimetry (DSC), IR, Raman, NIR, DIC and ¹³ C solid state NMR spectroscopy.

The various forms of the compound of formula (I) were characterized by X-ray powder diffraction, DSC and TGA thermograms.

Fig. 1: X-ray powder diffraction pattern of polymorph form B of compound (I).

Fig. 2: X-ray powder diffraction pattern of the polymorph Form A of compound (I).

Fig. 3: X-ray powder diffraction pattern of 1,7-hydrate compound (I).

Fig. 4: DSC and TGA thermogram of polymorph form B of compound (I).

Fig. 5: DSC and TGA thermogram of polymorph form A of compound (I).

Fig. 6: DSC and TGA thermogram of compound (I) 1,7-hydrate.

The polymorph form B of the compound of formula (I) can be clearly characterized by an X-ray powder diffraction pattern (at 25°C and with copper K (Cu-K) alpha 1 as the radiation source) which displays 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, more preferably at least the following reflections: 9.7, 10.1, 15.4, 16.1, 20.2, 22.3, most preferably at least the following reflections: 9.7, 10.1 , 15.4, 16.1, 20.2, 22.3, 25.2, each of them is indicated as a value of 2Theta ± 0.2°. The compound of formula (I) in polymorph form B can also be clearly characterized by an X-ray powder diffraction pattern (at 25° C. and with Cu-K alpha 1 as the radiation source) as shown in FIG. 1.

The polymorph form A of the compound of formula (I) can be clearly characterized by an X-ray powder diffraction pattern (at 25° C. with copper K alpha 1 as radiation source) which shows 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, 9.8, 19.3, 20.4, 20.7, 21.6, most 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 of them is indicated as a value of 2Theta ± 0.2°. The compound of formula (I) in polymorph form A can also be clearly characterized by an X-ray powder diffraction pattern (at 25° C. and with Cu-K alpha 1 as the radiation source) as shown in FIG. 2.

The 1,7-Hydrate of the compound of formula (I) can be clearly characterized by an X-ray powder diffraction pattern (at 25° C. and with Cu-K alpha 1 as the radiation source) which displays 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, most preferably at least the following reflections: 10.6, 11.8 , 14.5, 14.9, 15.1, 17.6, 18.7, 19.8, each of them is indicated as a value of 2Theta ± 0.2°. The 1,7-Hydrate of the compound of formula (I) can also be clearly characterized by an X-ray powder diffraction pattern (at 25° C. and with Cu-K alpha 1 as the radiation source) as shown in FIG. 3.

How to obtain

The preparation of compound (I) by a remarkably highly selective N2 alkylation is described in the following:

(I)

Preparations of N2-substituted indazoles have been previously described in the literature. However, these techniques have significant drawbacks, making them unsuitable for the technical scale. N2-Substituted indazoles can be produced selectively by complex synthetic step sequences that do not involve a direct alkylation step. However, these sequences are long and laborious and involve significant losses, which ultimately results in a low overall yield. Therefore, the most interesting are the synthesis methods that provide direct preparation of N2-substituted indazoles from 1H-indazole precursors by direct and selective alkylation on N2. When attempting direct alkylation of the 1H-indazole precursor of general formula (II), as a rule, a mixture is obtained consisting of N1-(IIIa) and N2-alkylated (III) regioisomers:

- 6 042116

Indazole and its derivatives, a typical class of aromatic N-heterocycles, have generated considerable interest in synthetic and medicinal chemistry due to their diverse biological activities. In addition, various heterocyclic structures can be accessed from indazole derivatives of N-heterocyclic carbenes. Among indazoles, N1/N2-substituted indazoles are widely used as anticancer, anti-inflammatory, anti-HIV and antimicrobial drugs. As a rule, the synthesis of N-substituted indazoles includes cyclization procedures from various starting materials. Unfortunately, there are no general methodologies in the literature. As a result, only moderate yields were obtained.

With regard to the state of the art, several publications are known and will be discussed in the next section. None of the published procedures present reaction conditions that lead to direct N-selective alkylation using methyl vinyl sulfone as the alkylating agent. Either no conversion or selectivity is observed and the yield is low. A problem with prior art techniques is the use of relatively simple alkylating agents bearing unstable functional groups. These agents are generally attached to 1H-indazole by nucleophilic substitution of their halides, tosylates, triflates or mesylates. When more functional moieties are used, the yield and selectivity are drastically reduced. The following section provides reasons why these prior art techniques are not applicable to the problem at hand.

1. WO 2011/043479: The reactions are carried out in THF at reflux (see Scheme 2). This does not work for the case in question (methyl vinyl sulfone). Obtaining the corresponding triflate, for example, from alcohol is impossible, since its decomposition occurs instantly. In addition, only a simple substrate with no functionality in the side chain was used.

2.S.R. Baddam, N.U. Kumar, A.P. Reddy, R. Bandichhor, Tetrahedron Lett. 2013, 54, 1661: Only simple indazoles without functional groups were used in the reaction. Only methyltrichloroacetimidate was used as the alkylating agent. Attempts to transfer acid-catalyzed conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone failed. This technique cannot be easily scaled up.

3. Q. Tian, Z. Cheng, H.H. Yajima, S.J. Savage, K.L. Green, T. Humphries, M.E. Reynolds, S. Babu, F. Gosselin, D. Askin, Org. Process Res. dev. 2013, 17, 97: A THP ether preparation is presented with a preference for N2 indazole. This reaction follows a different mechanism and is not a general method because the THP ester product cannot be easily converted further. In addition, selective methods for the protection of indazoles using p-methoxybenzyl derivatives under acidic conditions are presented.

Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

4. D.J. Slade, N.F. Pelz, W. Bodnar, J.W. Lampe, P.S. Watson, J. Org. Chem. 2009, 74, 6331: THP ether and PMB protection using acidic conditions (PPTS: pyridinium p-toluenesulfonate), see Scheme 2; attempts to transfer these conditions to the selective introduction of a methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone have been unsuccessful.

5. M. Cheung, A. Boloor, J.A. Stafford, J. Org. Chem. 2003, 68, 4093: Highly reactive and highly carcinogenic salts of Meerwein were used as alkylating agents (see Scheme 2). This method includes only Meerwein's simple non-functionalized ethyl and methyl salts. The reaction takes place in polar ethyl acetate at ambient temperature. These conditions could not be transferred to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone.

Scheme 1

N-Alkylation of 1H-indazoles

- 7 042116

Scheme 2

Methods for N-alkylation of indazoles known in the art

6. M.-N. Lin, H.-J. Liu, W.-C. Lin, S.-K. Kuo, T.-H. Chuang, Org. Biomol. Chem. 2015, 13, 11376: The technique is N2 selective; however, it cannot be scaled up using Ga and Al metals used in stoichiometric amounts. Under the reaction conditions described, Bronsted acids are formed which react with the corresponding metals to release hydrogen gas. Only relatively simple substrates (without a sulfonic group) are used as alkylating agents. When using more functionalized substrates, a significant decrease in yield was observed. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone were unsuccessful.

7. G. Luo, L. Chen, G. Dubowchick, J. Org. Chem. 2006, 71, 5392: 2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl) in THF has been used to replace indazoles with N2. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful. The corresponding products described in this publication are ethers and are not associated with the Applicant's target molecule. The use of the highly carcinogenic 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl), as well as benzyloxymethyl chloride (BOM-Cl), is not a scalable option to obtain 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. Little selectivity has been reported. A slight preference for N1-alkylation in indazole was noted.

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, for example, the combination of formaldehyde with protonated methanol, results in only the N1-substituted product (ether).

10.V.G. Tsypin et al., Russ. J. Org. Chem. 2002, 38, 90: The reaction takes place in sulfuric acid and chloroform. Only conversions of simple indazoles with adamantyl alcohol as the sole alkylating agent have been described. These conditions cannot be transferred to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone.

11. S.K. Jains et al. RSC Advances, 2012, 2, 8929: This publication provides an example of N-benzylation of indazoles with low selectivity for N1 substitution. This method, catalyzed by KF-/alumina, cannot be used effectively for the synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone were unsuccessful.

12 L. Gavara et al. Tetrahedron, 2011, 67, 1633: Only relatively simple substrates are used. The described acidic THP ester formation and reflux benzylation of THP do not apply to Applicant's substrate. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

13. M. Chakrabarty et al. Tetrahedron, 2008, 64, 6711: N2-alkylation was observed, but predominantly an N1-alkylated product was obtained. Described conditions for the use of aqueous hydroxide

- 8 042116 sodium and phase transfer catalyst in THF are not applicable to 2-substituted indazoles. Attempts to transfer these conditions into the Applicant's system (methyl vinyl sulfone) have been unsuccessful.

14. M.T. Reddy et al. Der Pharma Chemica, 2014, 6, 411: The reaction was carried out in an appropriate alkylating agent as a solvent. As an alkylating agent, only highly reactive ethyl bromoacetate has been reported. Selectivity data are not available. These conditions do not apply to the selective synthesis of N-substituted indazoles. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

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 the base and the reaction was obtained in a mixture of N1- and N2-alkylated products. These conditions do not apply to compounds such as 2-indazoles. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain in the N2 position of the indazole core structure by reaction with methyl vinyl sulfone were unsuccessful.

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 base into DMF. Mixtures are obtained from N1- and N2-alkylated products. The conditions do not apply to the selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

17. C. Marminon et al. Tetrahedron, 2007, 63, 735: The ortho substituent R at position 7 in indazole directs alkylation towards N2 by shielding N1 from electrophilic attacks. The conditions, sodium hydride as a base in THF, are not applicable to the selective synthesis of N2-substituted indazoles, since they predominantly lead to alkylation at N1 in the absence of a substituent at position 7 of the indazole. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

18.D.A. Nicewicz et al. Angew. Chem. Int. Ed. 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 the general selective synthesis of N2-substituted indazoles. Under radical reaction conditions, very specific styrene derivatives are used. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

19 A. Togni et al. Angew. Chem. Int. Ed. 2011, 50, 1059: This publication exclusively describes a particular type of substituent (hypervalent iodine as a trifluoromethylating agent in combination with acetonitrile). This particular case is not applicable to the 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 a melt of α-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 the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone were unsuccessful.

21.K.W. Hunt, D.A. Moreno, N. Suiter, S.T. Clark, G. Kim, Org. Lett. 2009, 11, 5054: This publication mainly describes the method of N1-selective alkylation with the addition of various bases. Simple substrates were used. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

22. J. Yang et al. Synthesis, 2016, 48, 48, 1139: This publication describes the N1-selective base-catalyzed aza-Michael reaction. Substitutions in N2 were not observed. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

23.P.R. Kym et al. J. Med. Chem. 2006, 49, 2339: N1-alkylations are generally described. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

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 a preference for N1 substitution and is therefore not applicable to the selective synthesis of N2-substituted indazoles. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

25 P. Bethanamudi et al. E-Journal of Chemistry, 2012, 9, 1676: The use of ionic liquids along with potassium carbonate as a base provides mixtures of N1- and N2-alkylated indazoles in low yields. Selectivity shows a trend towards substitution in N1. Application of ionic

- 9 042116 liquid cannot be transferred to the applicant's system. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

26 S. Palit et al. Synthesis, 2015, 3371: The reaction described there is essentially non-selective with a slight preference for indazole substitution at N1. Only simple non-functionalized alkyl groups were used. Sodium hydride and similar strong bases were used. Attempts to transfer these conditions to the selective introduction of the methyl ethyl sulfone side chain at the N2 position of the indazole core structure by reaction with methyl vinyl sulfone proved unsuccessful.

It has been proven that the compound of formula (I) can be synthesized analogously to methods previously published in the literature by, for example, direct alkylation using 2-bromoethyl-methyl-sulfone. However, a mixture of N1- and N2-alkylated products was obtained preferably for the N1-regioisomer (N1:N2 = approximately 2:1). The target N2-alkylated indazole of formula (I) can also be obtained in very low yield as described in WO 2016/083433 published after the priority date of the application for this invention, with the following reaction procedure: 160 mg (0.44 mmol) N-[ 6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6(trifluoromethyl)pyridine-2-carboxamide (Intermediate 5-1) was suspended together with 182 mg of potassium carbonate and 36 mg of potassium iodide in 1.0 ml 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, filtered through a hydrophobic filter and concentrated. Purification of the residue by preparative HPLC provided 20 mg (9.7% yield) of the title compound.

Expensive preparative HPLC proved to be indispensable for efficient separation of N1-/N2-regioisomers. The aim of this new process according to the invention is to abandon the HPLC separation by achieving better reaction selectivity in favor of N2 displacement followed by the new recrystallization procedure according to the invention.

The present invention provides a process for preparing compounds of general formula (III) from compounds of general formula (II):

(II) (III) in which R ¹ means 2-(methylsulfonyl)ethyl;

R ⁴ means difluoromethyl, trifluoromethyl or methyl;

R ⁵ means hydrogen or fluorine;

preferably R ⁴ = trifluoromethyl and R ⁵ = H:

(V) (I)

Surprisingly, the inventors have found that methyl vinyl sulfone (IX) can replace the corresponding alkyl halide in the reaction. The use of vinyl sulfones for the alkylation of indazoles at N2 is unexpectedly unprecedented and therefore highly inventive. When reacting compounds of general formula (II) with methyl vinyl sulfone in toluene, optionally with the addition of an organic base such as N,N-diisopropylethylamine or triethylamine, the target N2 isomer according to formulas (III) and (I) obtained with very high selectivity. The selectivity in the reaction mixture was found to be in the range of 8:1 to 10:1 in favor of the N2-alkylated product (III) as well as (I). The unwanted N1-substituted by-product remained largely in the mother liquor after working up the reaction mixture (mainly <2% after crystallization).

The reaction proceeds without the use of an additional base. The compound of general formula (II) or (V) is placed in a reaction vessel.

Add 1-2 eq. methyl vinyl sulfone and the reaction mixture is refluxed in toluene (approximately 110° C. internal temperature). The reaction can be carried out using 5 to 30 volumes of toluene relative to the amount of starting material (II) or (V). Preferably, the reaction proceeds with 8-15 volumes and preferably 10 volumes of toluene. The reaction time is from 12 to 100 hours. Preferably, it is from 48 to 72 hours. In some cases, it was

- 10 042116 would be advantageous to add methyl vinyl sulfone to the reaction mixture in parts, for example, starting with 1 eq., and then adding 0.3 eq. after 24 hours and another 0.3 eq. after 48 hours

Optionally, the reaction proceeds with catalytic amounts of an organic auxiliary base, such as N,N-diisopropylethylamine. The compound of general formula (II) or (V) is placed in a reaction vessel together with a solvent (toluene or xylene) and catalytic amounts of an organic base.

Auxiliary organic base, for example N,N-diisopropylethylamine, N,N-dicyclohexylamine or triethylamine can be added in amounts from 0.01 to 1 eq. The reaction proceeds with from 0.01 to 0.1 equiv. grounds.

It is noteworthy and certainly surprising that when using chloro- or ethylbenzene as solvent at the same reaction temperature, or xylene as solvent at a higher reaction temperature, the alkene (IV) was obtained in large quantities by removing water. Surprisingly, this removal was observed only in very small amounts when toluene was used as the solvent. Therefore, toluene should be considered as proposed in the invention of the solvent with unique and completely unforeseen properties in relation to this particular reaction. It was also found that the formation (IV) depends on the quality (V). When using (V), which had a higher than usual water content (1 wt.% instead of <0.5 wt.%), a larger amount of (IV) was obtained in the reaction. It should be noted that the formation of the elimination product (VI) can be effectively suppressed by removing excess water from (V) by azeotropic distillation with toluene and by adding catalytic amounts of an organic base, in particular Ν,Ν-diisopropylethylamine:

(iv)

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

It should be emphasized that the reaction of substituted vinyl sulfone for the targeted highly selective production of N2-functionalized indazoles is new, has no precedent in the literature, and therefore represents a scientifically significant invention for obtaining such substitution patterns.

Obtaining a GMP substance, which will also be used in clinical trials, requires an additional purification step. Moreover, since the active pharmaceutical ingredient will be used to manufacture a pharmaceutical composition such as a tablet, a procedure is required that reproducibly provides an identical crystal habit. Surprisingly, this can be realized using ethanol or isopropanol as a recrystallization solvent. The preferred solvent is ethanol. Therefore, the compound is first dissolved in acetone and then passed through a particulate filter (GMP filtration). The solvent change from acetone to ethanol is then carried out by distillation. Distillation is continued until a final volume of 6 to 7 volumes of ethanol relative to the starting material is reached. Distillation is canceled when reaching the boiling point of ethanol (approximately 77-78°C), ensuring the distillation of all acetone. The mixture is then cooled, stirred and the crystallized products are isolated by filtration and dried in vacuo at elevated temperature. The crystallization yield is typically >90%. The product obtained from this crystallization procedure has the required polymorphism properties necessary for the preparation of a pharmaceutical composition such as a tablet. The product exhibits very high purity as well as a very high content. The most important analytical data for typical batches are given in table. 1.

Table 1

Analytical data of sample batches, as shown in Table. 7

Purity (HPLC) > 99% (area) Content (analysis for application) > 97.7% (May) ethanol < 0.25% (May) Pd < 1 ppm

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

The preparation of compounds according to the general formula (II) as well as (V) is described in WO 2015/091426. This new method according to the invention focuses on the compound represented by formula (V)

In published patent application WO 2015/091426, a compound according to formula (V) is obtained by reacting a methyl ester of a compound according to formula (VI)

using a solution of methylmagnesium bromide in diethyl ether.

After treatment, the crude product was purified by column chromatography to obtain a compound according to formula (V) in 45% yield.

WO 2016/083433, published after the priority date of the application for this invention, describes a synthetic route for obtaining a compound according to formula (V) and also starting from a compound according to formula (VI) by Grignard reaction using suitable alkylmagnesium halides , for example methylmagnesium chloride or methylmagnesium bromide in THF or diethyl ether or in mixtures of THF and diethyl ether.

This procedure is not suitable for obtaining the compound of formula (V) on an industrial scale due to the following disadvantages.

Diethyl ether should be avoided due to its low flash point and explosive potential.

The relatively expensive methylmagnesium bromide has been used in place of the more common methylmagnesium chloride, which is easier to prepare.

On an industrial scale, chromatographic separations should be avoided, since a massive uneconomical consumption of organic solvents is usually required.

The crystallization procedure has not been described. According to common practice in research laboratories, the compound of formula (V) was evaporated to dryness. This operation is not technically possible.

The yield is unsatisfactory: for technical purposes, a yield of at least 75% must be achieved.

Surprisingly, it has been found that the compound of formula (V) can be obtained in significantly higher yields if methylmagnesium chloride and lithium chloride (2:1) in THF are used instead. The reactions proceeded with fewer side products, which, using the method described in WO 2015/091426 and WO 2016/083433, also had to be removed using laborious column chromatography. It was found that the reaction proceeds best with the use of THF as a solvent. Stir from 6 to 10 eq. methylmagnesium chloride (approximately 3M in THF) and 3 to 5 eq. lithium chloride and maintained at a temperature of from -10 to 0°C. Within 1-3 hours, preferably 2 hours, the compound according to formula (VI) is dropped into the mixture as a solution in THF. The reaction mixture is stirred for 5 to 30 minutes in the indicated temperature range (-10 to 0°C) and then quenched by pouring into water. The resulting mixture is vigorously stirred. The pH of the mixture is then adjusted to approximately 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 distillation of the solvent with toluene by 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) in a vacuum. Typically, yields at this stage ranged from 80 to 96% and purity from 95 to 99 area % (HPLC).

In order to obtain a substance of quality in accordance with modern good manufacturing practice (cGMP), it turned out to be advantageous to finally mix this product in a mixture of isopropanol/water (1:1; 2 to 10 volumes relative to the starting substance). The material is stirred for 1 to 5 hours, preferably 3 hours. It is then filtered and washed twice with small amounts of 1:1 isopropanol/water. The product is dried at elevated temperature (50-60°C) under vacuum. Typically >90% yield and >97 area % purity (HPLC) is achieved.

In the following examples in the experimental section, a variant is also described (see Example No. 2, variant No. 3), in which, after treatment with activated carbon, the solvent is replaced directly with isopropanol. The product is crystallized by adding water. In this way, a product of very high purity is obtained directly.

The preparation of a compound according to formula (VI) has also been described in patent application WO 2015/091426. Thus, 6-(trifluoromethyl)pyridine-2-carboxylic acid (VII) (CAS No. 21190-87-4) was coupled with an aniline-like compound of formula (VIII) (methyl-5-amino-1Nindazole-6-carboxylate; CAS No. 1000373-79-4) using 1-[bis-(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyrimidinium 3-oxide-hexafluorophosphate (CAS No. 148893-10- 1) as a coupling reaction agent. Amide (VI) was obtained in 84% yield.

(VI)

For process safety reasons, uronium-based coupling reagents cannot be scaled up due to their explosive potential. Therefore, it was necessary to find an alternative method of combination.

A safe and scalable method for the preparation of an amide-like compound of formula (VI) is based on the use of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4,6-trioxide; CAS No. 68957 -94-8) as a coupling agent.

The reaction proceeds smoothly and gives the amide-like compound of formula (VI) in high yields. In a one-pot process, a carboxylic acid compound of formula (VII) (best used with a slight deficit in relation to aniline (VIII), from about 0.90-0.95 eq.) is placed together with 1.5 eq. N,N-diisopropylethylamine in 16 volumes of THF. Then slowly add 2 eq. T3P (50 wt.% solution in ethyl acetate) at a temperature of from 0 to 5°C. The reaction mixture is further stirred for 2 to 4 hours, preferably 2 hours at 0 to 5°C.

The mixture is then quenched with water, its pH is adjusted using aq. sodium carbonate solution to about 7.4 and the THF/ethyl acetate mixture is largely distilled off (200 mbar, at 45-50° C. internal temperature). Water and ethanol were then added and the pH was adjusted to approximately 7.0 by adding aq. sodium carbonate solution. The mixture was stirred for 1 to 5 hours, preferably 1 to 2 hours, at 50°C, then cooled to 20-25°C and stirred for 10 to 30 minutes. The product was isolated by filtration and then washed with a mixture of ethanol and water, finally dried under vacuum at 45°C. Very high yields of 95 to 96% were generally obtained with this process. In all cases, the purity was >98 area % (HPLC).

In some cases, especially when an aniline-like compound of formula (VIII) with a low optical quality (eg dark brown color) was used as starting material, it has proven advantageous to carry out treatment with activated carbon. This procedure is described in the next section.

The crude amide (VI) was dissolved in a mixture of methanol and THF (2:1) and activated carbon was added. The mixture was heated to 60-65°C for 1 to 1.5 hours. The activated carbon was filtered off and the filtrate was concentrated (up to 2 volumes relative to the starting material).

Water was added and the product precipitated, filtered, washed and dried at 55 to 60° C. (vacuum).

The synthesis of compounds of formulas (VII) and (VIII) has been described in the literature, and both are commercially available in large quantities.

For compounds according to formula (VII): Cottet, Fabrice; Marull, Marc; Lefebvre, Olivier; Schlosser, Manfred, European Journal of Organic Chemistry, 2003, 8 pp. 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: US 2005/54627 A1, 2005; Ashimori; ono; Uchida; Ohtaki; Fukaya; Watanabe; Yokoyama Chemical and Pharmaceutical Bulletin, 1990, vol. 38, 9, p. 2446-2458.

For a compound according to formula (VIII): Nissan Chemical Industries, Ltd.; CHUGAI SEIYAKU KABUSHIKI KAISHA, EP 2045253 A1, 2009.

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Evaluation of the entire process.

Scheme 3 shows the overall synthesis of a pure product of formula (I) from an aniline-like compound of formula (VIII). The product of formula (I) is obtained with a purity of >99 area % (HPLC). When calculated with the best yields obtained for each step, an overall yield of 50% is obtained. This also includes setting up the final crystalline form.

Scheme 3

General synthesis of a pure product of formula (I) from an aniline-like compound according to formula (VIII)

When comparing this overall yield with published prior art data:

1) amide coupling (preparation of a compound according to formula (VI)): 84% yield;

2) Grignard reaction followed by chromatographic purification: 45% yield;

3) alkylation with 2-bromoethyl-methyl-sulfone similarly to methods known from the literature, followed by chromatographic purification: yield 9.68%;

the advantages of the new method become very obvious.

Thanks to the method known from the prior art and described above, a total yield of only 3.7% can be achieved, not to mention the setting of the final crystalline form.

In conclusion, the novel process according to the invention provides a compound according to formula (I) in a total yield 13 times greater than prior art. In addition, it includes the targeted and reproducible production of a target polymorph for the preparation of a pharmaceutical composition such as a tablet.

It should be emphasized that the reaction of substituted vinyl sulfone for the directed highly selective preparation of N2-functionalized indazoles is new, without precedence in the literature, and therefore a very significant invention for the preparation of such substitution patterns.

Therefore, in a first aspect, the present invention relates to a process for preparing a compound of formula (I) using the following steps shown in Reaction Scheme IA.

Scheme IA

Preparation of a compound of formula (I) from a compound of formula (VIII) as starting material

where R is an alkyl group, such as a methyl, ethyl, or n-propyl group, for example, or an aryl group, such as, for example, a phenyl group, and an aromatic hydrocarbon solvent is a solvent, such as, for example, toluene or xylene.

In an embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (I) using the following steps shown in Reaction Scheme I.

Scheme I

Preparation of a compound of formula (I) from a compound of formula (VIII) as starting material

In an embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (I)

which includes the next stage (A), where the compound of formula (V)

reacted with a vinyl sulfone compound of formula (IX')

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

In an embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (I) as described above, wherein said aromatic hydrocarbon solvent is toluene.

In an embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (I) as described above, wherein said compound of formula (V)

is obtained by means of the next step (B) wherein the compound of formula (VI)

- 15 042116

is reacted with a reductive methylating agent such as a methyl metal agent such as methyl magnesium halide such as, for example, methyl magnesium chloride, optionally in the presence of an alkali metal halide, such as, for example, lithium chloride, thereby providing a compound of formula (V).

In an embodiment of the first aspect, the present invention relates to a process for preparing a compound of formula (I) as described above, wherein said compound of formula (VI)

is obtained by means of the next step (C), where the compound of formula (VIII)

subjected to reaction with a compound of formula (VII)

optionally in the presence of an organic base, in particular a weak organic base such as a tertiary amine such as, for example, N,N-diisopropylethylamine, optionally in the presence of a coupling agent, such as, for example, 2,4,6-tripropyl1, 3,5,2,4,6-trioxatrifosfinan-2,4,6-trioxide (T3P), thus providing a compound of formula (VI).

In another embodiment of the first aspect, the present invention relates to a process for the preparation of a compound of formula (I) as described above, wherein said compound of formula (I) is purified by crystallization, in particular from a solvent such as, for example, ethanol or isopropanol.

In a variation of said other embodiment of the first aspect, said solvent is ethanol.

In a variation of said other embodiment of the first aspect, said solvent is isopropanol.

In an embodiment of the first aspect, the present invention relates to a process for the preparation of a compound of formula (I) as described above, said compound of formula (I) being in the form of polymorph B.

According to a second aspect, the present invention relates to polymorph B of the compound of formula (I)

obtained in the manner described above.

According to a third aspect, the present invention relates to polymorph B of the compound of formula (I)

- 16 042116

In accordance with an embodiment of the third aspect, the present invention relates to the above polymorph B, as described above, having the peaks of the powder X-ray diffraction [°2θ] (copper (Cu)), as follows.

table 2

Powder x-ray diffraction of polymorph A, B and

1,7-hydrate of compound (I)

Reflections [max °2Theta peaks] Polymorph A 4.4 8.9 9.2 9.8 10.2 10.4 11.2 12.3 12.5 12.9 13.3 13.5 14.0 14.7 15.5 15.6 16.1 16.5 17.8 18.3 18.5 19.1 19.3 19.6 19.8 20.1 20.4 20.7 20.9 21.2 21.6 21.7 21.8 22.2 22.6 22.8 23.1 23.2 25.0 25.7 27.2 27.6 28.3 28.9 29.0 Polymorph B 4.4 8.9 9.3 9.7 10.1 12.4 12.9 13.3 14.1 14.7 15.4 16.1 16.4 16.7 17.3 17.9 18.3 18.4 18.5 19.2 19.4 19.7 20.2 20.6 21.2 21.4 21.9 22.3 22.6 22.8 23.6 24.5 24.9 25.2 25.5 25.8 27.2 27.5 28.8 29.6 30.2 31.2 31.5 32.5 33.5 1,7-hydrate 9.2 9.9 10.6 11.8 13.0 13.5 14.5 14.9 15.1 15.3 16.2 16.7 17.2 17.5 17.6 18.0 18.3 18.4 18.7 19.4 19.8 20.3 20.9 21.2 21.5 22.1 22.5 22.7 22.9 23.1 23.3 23.8 23.9 24.6 25.1 25.2 25.9 26.0 26.3 26.4 26.6 27.2 27.6 27.8 28.1

- 17 042116

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

to obtain a compound of formula (I) or polymorph B of a compound of formula (I), as described above, in the manner described above.

According to a fifth aspect, the present invention relates to the use of a vinyl sulfone compound of formula (IX')

in which R represents an alkyl group, such as, for example, a methyl, ethyl or n-propyl group, or an aryl group, such as, for example, a phenyl group,

- 18 042116 to obtain a compound of formula (I)

O or polymorph B of the compound of formula (I) as described above.

In one embodiment of the fifth aspect, the present invention relates to a use wherein said vinyl compound of formula (IX') is methyl vinyl sulfone.

According to a sixth aspect, the present invention relates to the use of crystalline forms of a compound of formula (I), preferably the Form B polymorph, for the manufacture of a medicament.

Method of treatment.

Crystalline forms of the compound of formula (I) according to the invention, preferably polymorph form B, may have useful pharmacological properties and may be used for the prevention and treatment of disorders in humans and animals. The forms of the compound of formula (I) according to the invention may provide a further treatment alternative and thus may enrich the pharmaceutical industry.

Crystalline forms of the compound of formula (I) according to the invention, preferably polymorph form B, may be useful in the treatment and prevention of proliferative and inflammatory diseases which are characterized by overreaction of the immune system. In this case, particular mention should be made of the use of crystalline forms of the compound of formula (I), preferably polymorph form B, according to the invention for the treatment and prevention of neoplastic diseases, dermatological diseases, gynecological disorders, cardiovascular diseases, lung diseases, ophthalmological disorders, neurological disorders, metabolic disorders, liver disease, kidney disease, inflammatory diseases, autoimmune disorders and pain. In particular, the use of crystalline forms of a compound of formula (I) according to the invention for the treatment and prevention of lymphomas, 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-associated pain and other endometriosis-associated symptoms, in this context should be specifically mentioned, such as dysmenorrhea, dyspareunia, dysuria and dyschesia.

Crystalline forms of the compound of formula (I) according to the invention, preferably polymorph form B, may be useful in the treatment and prevention of pain, including acute, chronic, inflammatory and neuropathic pain, preferably hyperalgesia, allodynia, arthritis pain (such as osteoarthritis , rheumatoid arthritis and spondyloarthritis), premenstrual pain, pain associated with endometriosis, postoperative pain, pain from interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, pain from inflammation of the prostate, pain caused by spinal cord injury caused by inflammation pain, low back pain, cancer pain, chemotherapy-related pain, HIV-associated neuropathy, burn pain, and chronic pain.

In addition, in some embodiments, the implementation of the present invention relates to a method of treating and/or preventing diseases, in particular the above diseases, by using an effective amount of at least one of the forms of the compounds of formula (I) in accordance with the invention.

In some embodiments, in addition, the present invention relates to a method for the treatment and/or prevention of proliferative and inflammatory diseases that are characterized by overreaction of the immune system, in particular neoplastic diseases, dermatological diseases, gynecological disorders, cardiovascular diseases, lung diseases, ophthalmic disorders , neurological disorders, metabolic disorders, liver diseases, inflammatory diseases, autoimmune disorders and pain, by using an effective amount of at least one of the forms of the compound of formula (I) in accordance with the invention.

The forms of the compound of formula (I) according to the invention can be used alone or, if necessary, in combination with other active substances. In addition, the present invention relates to medicaments containing at least one of the forms of the compound of formula (I) according to the invention and one or more other active substances, in particular for the treatment and/or prevention of the diseases mentioned above. As suitable

- 19 042116 mention other active substances.

Mention may be made of active ingredients such as antibacterial (eg penicillins, vancomycin, ciprofloxacin), antiviral (eg acyclovir, oseltamivir) and antifungal (eg naftifine, nystatin) substances and gamma globulins, immunomodulatory and immunosuppressive compounds such as cyclosporine, Methotrexat®, TNF antagonists (eg, Humira®, etanercept, infliximab), IL-1 inhibitors (eg, anakinra, canakinumab, rilonacept), phosphodiesterase inhibitors (eg, apremilast), Jak/STAT inhibitors (eg, tofacitinib, baricitinib, GLPG0634 ), leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids (eg, prednisone, prednisolone, methylprednisolone, hydrocortisone, betamethasone), cyclophosphamide, azathioprine, and sulfasalazine; paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, ibuprofen, naproxen, etodolac, celecoxib, colchicine).

For the treatment of tumors, the following should be mentioned: immunotherapeutics (e.g., aldesleukin, alemtuzumab, basiliximab, catumaxomab, cellmoleukin, denileukin diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab tiuxetan, imiquimod, interferon-alpha, interferon beta, interferon-gamma, ipilimumab, lenalidomide, lenograstim, mifamurtide, otatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tazonermine, teceleukin, tocilizumab), antiproliferative agents, e.g. but not exclusively amsacrine, arglabin, arsenic trioxide, asparaginase, bleomycin, busulfan, dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, obinutuzumab, ofatumumab, tositumomab, aromatase inhibitors (eg, exemestane, fadrozole, formatestan, letrozole, anastrozole, vorozol), antiestrogen (eg, chlormadinone, fulvestrant, mepitiostane, tamoxifen, toremifene) , estrogens (eg, estradiol, polyestradiol phosphate, raloxifene), progestogens (eg, m edroxyprogesterone, megestrol), topoisomerase I inhibitors (eg, irinotecan, topotecan), topoisomerase II inhibitors (eg, amrubicin, daunorubicin, elliptinium acetate, etoposide, idarubicin, mitoxantrone, teniposide), microtubule-containing active substances (eg, cabazitaxel, eribulin, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine), telomerase inhibitors (eg, imetelstat), alkylating agents, and histone deacetylase inhibitors (eg, bendamustine, carmustine, chlormethine, dacarbazine, estramustine, ifosfamide, lomustine, mitobronitol, mitolactol, nimustine, prednimustine, procarbazine , ranimustine, streptozotocin, temozolomide, thiotepa, treosulfan, trofosfamide, vorinostat, romidepsin, panobinostat); substances that affect cell differentiation processes such as abarelix, aminoglutethimide, bexarotene, MMP inhibitors (peptide mimetics, non-peptide mimetics and tetracyclines, e.g. marimastat, BAY 12-9566, BMS-275291, clodronate, prinomastat, doxycycline), mTOR inhibitors (eg sirolimus, everolimus, temsirolimus, zotarolimus), antimetabolites (eg clofarabine, doxyfluridine, methotrexate, 5-fluorouracil, cladribine, cytarabine, fludarabine, mercaptopurine, methotrexate, pemetrexed, raltitrex, tegafur, thioguanine), platinum compounds (eg, carboplatin, cisplatin, cisplatin, eptaplatin, lobaplatin, myriplatin, nedaplatin, oxaliplatin); anti-angiogenic compounds (eg, bevacizumab), anti-androgen compounds (eg, bevacizumab, enzalutamide, flutamide, nilutamide, bicalutamide, cyproterone, cyproterone acetate), proteasome inhibitors (eg, bortezomib, carfilzomib, oprosomib, ONYX0914), GnRH agonists and antagonists (eg, abarelix, buserelin, deslorelin, ganirelix, goserelin, gistrelin, triptorelin, degarelix, leuprorelin), methionine aminopeptidase inhibitors (eg benhamide derivatives, TNP-470, PPI-2458), heparanase inhibitors (eg SST0001, PI-88); inhibitors against genetically modified Ras protein (eg farnesyl transferase inhibitors such as lonafarnib, tipifarnib), HSP90 inhibitors (eg geldamycin derivatives such as 17-allylaminogeldanamycin, 17-demethoxygeldanamycin (17AAG), 17-DMAG, retaspimycin hydrochloride, IPI-493 , AUY922, BIIB028, STA-9090, KW-2478), spindle kinesin inhibitors (eg, SB715992, SB743921, pentamidine/chlorpromazine), MEK (mitogen-activated protein kinase) inhibitors (eg, trametinib, BAY 86-9766 (refametinib) , AZD6244), kinase inhibitors (eg: sorafenib, regorafenib, lapatinib, Sutent®, dasatinib, cetuximab,

BMS-908662, GSK2118436, AMG 706, erlotinib, gefitinib, imatinib, nilotinib, pazopanib, roniciclib, sunitinib, vandetanib, vemurafenib), hedgehog signaling inhibitors (eg, cyclopamine, vismodegib), BTK inhibitor (Bruton's tyrosine kinase) (eg, ibrutinib) , JAK/pan-JAK (Janus kinase) inhibitor (e.g. SB-1578, baricitinib, tofacitinib, pacritinib, momelotinib, ruxilitinib, 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 ) (eg, fostamatinib, Excellair, PRT-062607), p53 gene therapy, bisphosphonates (eg, etidronate, clodronate, tiludronate, pamidronate, alendronic acid, ibandronate, risedronate, zoledronate).

For the combination, the following active substances may also be listed as examples and not exclusively: rituximab, cyclophosphamide, doxorubicin, doxorubicin in combination with es

- 20 042116 tronome, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 1311-chTNT, abiraterone, aclarubicin, alitretinoin, bisantrine, calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, crisantaspase alfa, darbepoetabine , denosumab, dibrospidium chloride, eltrombopag, endostatin, epitiostanol, epoetin alfa, filgrastim, fememustine, gallium nitrate, gemcitabine, glutoxim, histamine dihydrochloride, hydroxycarbamide, improsulfan, ixabepilone, lanreotide, lentinan, levamisole, lisuride, lonidamine, mazoprocol, methoxzalene, methoxzalene , methyl-aminolevulinate, miltefosine, mitoguazone, mitomycin, mitotane, nelarabine, nimotuzumab, nitracrine, omeprazole, palifermin, panitumumab, peraspargasa, epoetin beta PEG (methoxyPEG epoetin beta), pegfilgrastim, peg interferon alfa-2b, pentazocine, pentostatin, perfosfamide , pyrarubicin, plicamycin, polyglumam, sodium porfimer, pralatrexate, quinagolide, razoxane, sisofiran, sobuxane, glycidi sodium dazole, tamibarotene, tegafur and gimeracil and oteracil combination, testosterone, tetrofosmin, thalidomide, thymalfasin, trabectedin, tretinoin, trilostane, tryptophan, ubenimex, vapreotide, yttrium-90 glass beads, cynostatin, cynostatin stimalamer.

A combination of non-drug therapies such as chemotherapy (e.g., azacitidine, belotecan, enocytabin, melphalan, valrubicin, vinflunine, zorubicin), radiotherapy (e.g., grains I-125, grain palladium-103, radium-223 chloride) are also suitable for the treatment of tumors. or phototherapy (e.g. temoporfin, thalaporfin) which is accompanied by treatment with IRAK4 inhibitor drugs according to the invention or which, after anticancer therapy such as chemotherapy, radiation therapy or phototherapy has ended, is supplemented by treatment with IRAK4 inhibitor drugs according to the invention with invention.

In addition to those mentioned above, the IRAK4 inhibitors according to the invention can also be combined with the following active substances:

active substances for the treatment of Alzheimer's disease, eg acetylcholinesterase inhibitors (eg donepezil, rivastigmine, galantamine, tacrine), NMDA receptor antagonists (N-methyl-Daspartate) (eg memantine); L-DOPA/carbidopa (L-3,4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors (eg, entacapone), dopamine agonists (eg, ropinirole, pramipexole, bromocriptine), MAO-B (monoamine oxidase-B) inhibitors ) (eg selegiline), anticholinergics (eg trihexyphenidyl) and NMDA antagonists (eg amantadine) for the treatment of Parkinson's disease; interferon-beta (IFN-beta) (eg, IFN beta-1b, IFN beta-1a Avonex® and Betaferon®), glatiramer acetate, immunoglobulins, natalizumab, fingolimod, and immunosuppressants such as mitoxantrone, azathioprine, and cyclophosphamide for the treatment of multiple sclerosis;

agents for the treatment of lung disorders, eg beta-2 sympathomimetics (eg salbutamol), anticholinergics (eg glycopyrronium), methylxanthines (eg theophylline), leukotriene receptor antagonists (eg montelukast), PDE-4 inhibitors (phosphodiesterase type 4) (for example, roflumilast), methotrexate, IgE antibodies, azathioprine and cyclophosphamide, drugs containing cortisol;

substances for the treatment of osteoarthritis, such as non-steroidal anti-inflammatory drugs (NSAIDs).

In addition to the two therapies given for rheumatoid disorders, such as rheumatoid arthritis, spondyloarthritis, and juvenile idiopathic arthritis, methotrexate and biologics for B-cell and T-cell therapy (eg, rituximab, abatacept) may be mentioned. Neurotrophic agents such as acetylcholinesterase inhibitors (eg donepezil), MAO (monoamine oxidase) inhibitors (eg selegiline), interferons and anticonvulsants (eg gabapentin); active substances for the treatment of cardiovascular diseases, such as beta-blockers (eg metoprolol), ACE inhibitors (eg benazepril), angiotensin receptor blockers (eg losartan, valsartan), diuretics (eg hydrochlorothiazide), calcium channel blockers (eg nifedipine), statins (eg simvastatin, fluvastatin); antidiabetic drugs, eg metformin, glinides (eg nateglinide), DPP-4 (dipeptidyl peptidase-4) inhibitors (eg linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT2 (sodium/glucose cotransporter 2) inhibitors, glyflozin (eg dapagliflozin) , empagliflozin), incretin mimetics (glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) analogs/agonists) (eg, exenatide, liraglutide, lixisanatide), α-glucosidase inhibitors (eg, acarbose, miglitol, voglibiosa ) and sulfonylureas (eg glibenclamide, tolbutamide), insulin sensitizers (eg pioglitazone) and insulin therapy (eg insulin NPH, insulin lispro), substances for the treatment of hypoglycemia, for the treatment of diabetes and metabolic syndrome. Lipid-lowering drugs, eg fibrates (eg, bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (eg, nicotinic acid/laropyrant), ezetimibe, statins (eg, simvastatin, fluvastatin), anion exchangers (eg, cholestyramine, colestipol , kolesevelam). Active substances such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL No. 3®, Lactobacillus GG, Lactobacillus plantarum, L. acidophilus, L. casei,

- 21 042116

Bifidobacterium infantis 35624, Enterococcus fecium SF68, Bifidobacterium longum, Escherichia coli Nissle

1917), antibiotics such as ciprofloxacin and metronidazole, antidiarrheal drugs such as loperamide, or laxatives (bisacodyl) for the treatment of chronic inflammatory bowel disorders.

Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus. By way of example, but not exclusively, calcineurin inhibitors (eg, tacrolimus and cyclosporine), cell division inhibitors (eg, azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus, or sirolimus), rapamycin, basiliximab, daclizumab, anti-CD3 antibodies, anti- T-lymphocyte globulin/anti-lymphocyte globulin for organ transplantation. Vitamin D3 analogs, eg calcipotriol, tacalcitol or calcitriol, salicylic acid, urea, cyclosporine, methotrexate, efalizumab for dermatological disorders.

pharmaceutical compositions.

Crystalline forms of the compound of formula (I) may have systemic and/or local activity. For this purpose, they may be administered by a suitable route, for example, by oral, parenteral, intrapulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

Crystalline forms of the compound of formula (I) may be administered in dosage forms suitable for these routes of administration.

For oral administration, crystalline forms of the compound of formula (I) can be prepared in dosage forms known in the art which deliver the compounds according to the invention quickly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example, having gastro-resistant coatings or coatings that dissolve with delay, or insoluble coatings that control release), tablets that quickly disintegrate in the mouth, films/wafers, films/lyophilisates, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. The compounds according to the invention can be included in said dosage forms in crystalline and/or amorphous and/or dissolved form.

Parenteral administration may be by omitting an absorption step (eg, by intravenous, intraarterial, intracardiac, intraspinal, or intralumbar route) or by including an absorption step (eg, by intramuscular, subcutaneous, intradermal, subcutaneous, or intraperitoneal route). Application forms suitable for parenteral administration are in particular injection and infusion formulations in the form of suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for other routes of administration are, for example, pharmaceutical forms for inhalation [among other 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 solutions, ocular inserts, ear drops, ear sprays, ear powders, ear piercings, ear swabs, ear rinsing liquids, ear swabs; vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milks, pastes, foams, powders, implants or stents.

Crystalline forms of the compound of formula (I) may be included in the claimed administration forms. This can be done in a manner known per se by mixing with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, among others: fillers and carriers (eg, cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®));

ointment bases (eg petrolatum, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols);

suppository bases (eg polyethylene glycols, cocoa butter, tallow);

solvents (eg water, ethanol, isopropanol, glycerol, propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycols, paraffins);

surfactants, emulsifiers, dispersants or wetting agents (eg sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitol fatty acid esters (such as, for example, Span®) , polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters , poloxamers

- 22 042116 (such as, for example, Pluronic®);

buffers, acids and bases (eg phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine);

isotonicity agents (eg glucose, sodium chloride);

adsorbent substances (for example, highly dispersed silicates);

viscosifying agents, gelling agents, thickeners and/or binders (eg polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatin);

disintegrants (eg modified starch, sodium carboxymethylcellulose, sodium starch glycolate (such as, for example, Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (such as, for example, AcDiSol®));

flow regulators, lubricants, glidants and mold removers (eg magnesium stearate, stearic acid, talc, fine silicates (such as eg Aerosil®);

coating materials (e.g. sugar, shellac) and film formers or diffusion membranes that dissolve rapidly or in a modified manner (e.g. polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®);

capsule materials (eg gelatin, hydroxypropyl methylcellulose);

synthetic polymers (eg polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols, and copolymers and block copolymers thereof);

plasticizers (eg, polyethylene glycols, propylene glycol, glycerin, triacetin, triacetyl citrate, dibutyl phthalate);

penetration enhancers;

stabilizers (eg antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propylgallate);

preservatives (eg parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate);

dyes (eg inorganic pigments such as, for example, iron oxides, titanium dioxide);

flavoring agents, sweeteners, masking the taste and / or smell of the product.

In addition, the present invention relates to a pharmaceutical composition containing at least one crystalline form of the compound of formula (I), usually together with one or more pharmaceutically acceptable carriers, and their use in accordance with the present invention.

The dosage of pharmaceutical compositions in accordance with the present invention.

Based on laboratory methods known to evaluate compounds useful in the treatment of disorders, by pharmacological assays to determine the treatment of the above conditions in mammals, and by comparing these results with the results of known drugs that are used to treat these conditions, the effective dose of compounds in accordance with the present invention can be easily determined for the treatment of each necessary indication. The amount of active substance to be administered in the treatment of one of these conditions may vary over a wide range, based on such considerations as the particular compound used and dosage form, route of administration, period of treatment, age and sex of the patient to be treated, and also the nature and extent of the condition to be treated.

The total amount of active substance to be administered will generally be in the range of about 5 to 2000 mg per day, preferably 15 to 750 mg per day, more preferably 15 to 200 mg per day. The dosage unit may contain from about 15 to 750 mg, preferably from 15 to 120 mg of the active substance and may be administered one or more times a day.

Of course, the specific initial and ongoing dosage regimen for each patient will vary depending on the nature and severity of the condition as determined by the treating physician, the potency of the particular compound used, the age and general condition of the patient, the time of administration, route of administration, rate of drug release, combination of drugs. and so on. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof may be

- 23 042116 established by experts in this field using conventional tests during treatment.

The weight data in the tests and examples below, unless otherwise indicated, are percentages by weight; parts are parts by weight. Solvent ratios, dilution factors and liquid concentration data/liquid solutions are in each case based on volume.

Demo examples

The following examples demonstrate the present invention.

Methods.

DSC thermograms were recorded using differential scanning calorimeters (model DSC7, Pyris-1 or Diamond) from Perkin-Elmer. Measurements were made at a heating rate of 20 K/min using non-sealed aluminum cups. The feed gas was nitrogen. No samples were taken.

TGA thermograms were recorded using a thermobalance (model TGA7 and Pyris 1) from Perkin-Elmer. Measurements were made at a heating rate of 10 K/min using open platinum cups. The feed gas was nitrogen. No samples were taken.

X-ray diffraction patterns were recorded at room temperature using X'Pert PRO (PANalytical) and STOE STADI-P X-ray diffractometers (radiation copper K alpha 1, wavelength 1.5406 A). No samples were taken. All X-ray reflections are given as °2Theta values with a resolution of ± 0.2°.

Raman spectra were recorded at room temperature using Bruker Fourier transform FP spectrophotometers (Model RFS 100 and MultiRam). The resolution is 2 cm ^-1 . The measurements were carried out in glass vials or aluminum disks. No samples were taken.

ATR IR spectra were recorded at room temperature using a Perkin-Elmer Universal Diamond ATR FT-IR spectrophotometer. The resolution is 4 cm ^-1 . No samples were taken.

HPLC.

Method A.

Device: Agilent Technologie 1260 Infinity with 1290 Infinity Sampler & Agilent 1100 Series.

Zorbax SB-AQ, 50x4.6 mm, 1.5 µm.

Buffer: ammonium dihydrophosphate pH: 2.4.

Acetonitrile:

min 5% buffer,

8.3 min 80% buffer, min 80% buffer,

210 nm/4 nm,

1.2 ml/min.

- 24 042116

Method B.

device 1. Agilent Technologies HPLC 1290 Infinity (with DAD): Ultra high performance liquid chromatograph with thermostatically controlled column oven, UV detector and data evaluation system 2. Stainless steel column Length: 5 cm Int. 2.1mm Diameter: Filling: SB-Aq Rapid Resolution HD, 1.8 µm Reagents 1. Acetonitrile, for HPLC 2. Tetrahydrofuran, for HPLC 3. water pure for analysis 3. Phosphoric acid 85% pure for analysis

test solution Dissolve a sample of the compound of formula (I) in tetrahydrofuran at a concentration of 0.5 mg/ml. (e.g. dissolve approx. 25 mg of a sample of the compound of formula (I) accurately weighed in 50 ml of acetonitrile) Calibration solution Dissolve reference standard compound * in acetonitrile at a concentration of 0.5 mg/ml (eg dissolve approx. 25 mg of reference standard accurately weighed in 50 ml acetonitrile). *reference standard compound means a compound that should be analyzed as a high purity compound, i.e. >97 area% HPLC control solution Prepare a control solution identical to the calibration solution. In addition, the control solution contains

- 25 042116

small amounts of organic impurities. Sensitivity detection solution Prepare a solution containing Solbrol P (CAS no: 94-13-3; propyl 4hydroxybenzoate) (By approx. 2.80 min.) diluted to a concentration of 0.76 µg/ml. HPLC conditions The specified conditions are guideline values. To achieve an optimal separation, if necessary, they must be adapted to the technical capabilities of the chromatograph and to the properties of the respective column. eluent A. water: tetrahydrofuran (vol : vol) 9 : 1, then add. 0.1% phosphoric acid 85% B. acetonitrile: tetrahydrofuran 9:1 Flow rate 0.8 ml/min Column oven temperature 40°C Sample chamber temperature Room temperature Detection Wavelength measurement: 220 nm Frequency range: 6 nm Injected sample volume 2.0 µl Curve drawing speed 200 µl/min Flushing the needle Wash channel solvent: tetrahydrofuran Transfer rate 10 Hz Cell size 10 mm Equilibrium Time Gradient 10 min (under starting conditions) Time [min] % A Gradient 0 95 5 1 85 15 4 80 20 6 40 60 8 20 80 12 20 80 Chromatogram run time 12 min.

Assay Calculation (Content) The assay is calculated using linear regression and taking into account sample weight, assay and reference standard weight using a validated chromatographic data system (eg Empower).

Headspace GC.

Residual solvent analysis by headspace gas chromatography (GC-HS).

Agilent 6890 split injection gas chromatograph with FID (column: Restek Rxi Sil MC; length: 20 m; inner diameter: 0.18 mm; d _f : 1 µm). Injector temperature 160°C, flow 1.2 ml/min (H ₂ ). split ratio 18, thermostat temperature 40°C (4.5 min) - 14°C/min - 70°C 90°C/min - 220°C (1.69 min). Detector: temp. 300°C, 400 ml/min (synth air), 40 ml/min (H ₂ ), 30 ml/min (N2), speed 20 Hz.

- 26 042116

Perkin Elmer Turbomatrix 40 Headspace Sampler: 80°C thermostat setting, 150°C needle, 160°C transfer line, 140 kPa system pressure, 32 min equilibration time, 4.0 min pump, 0.04 min injection time (Sampler) 0.05 min (GC).

Sample concentration: 20 mg of substance in 2 ml of DMF.

Preparation of Na{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide (I).

Example #1.

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

2000 g (10.46 mol) methyl 5-amino-1H-indazole-6-carboxylate, 1899 g (9.94 mol) 6-(trifluoromethyl)pyridine-2-carboxylic acid and 2028 g (15.69 mol) N,N -diisopropylethylamine is mixed in 14.2 kg of THF. At 0-5° C., 13.3 kg of a solution of T3P in ethyl acetate (50 wt%) are added dropwise over 30 minutes. Stirring is continued for 2 hours at the same temperature.

Treatment.

The reaction mixture is heated to ambient temperature (20°C). 3000 g of water is added while maintaining the temperature between 20 and 25°C. Stirring is continued for 10 minutes. The pH value is adjusted to approximately 7.4 (7-8) using 4N. aq. sodium carbonate solution. Stirring is continued for 10 minutes. If necessary, the pH value is again adjusted to 7.4 using 4N. aq. sodium carbonate solution.

The solvents (THF/ethyl acetate) are evaporated off under reduced pressure (ca. 200 mbar, at 45-50° C. internal temperature) until the stirring limit is reached. Add a mixture of 4.7 kg of ethanol and 14.0 kg of water and the pH is again adjusted to pH 7.4 (7-8) using 4N. aq. sodium carbonate solution.

The mixture is stirred for 1 hour at 50°C, then cooled to 20-25°C. Stirring is continued for 10 minutes 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 an oven (45°C, N2 flow, at least 12 h).

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

Outputs:

batch #1: 3476 g (95%);

batch #2: 3449 g (95%);

batch #3: 3476 g (95%);

lot 4: 3494 g (96%).

The purity of all batches was determined as being >98 area % (HPLC).

HPLC (Method A): By = 6.5 min.

MS (ESI pos): m/z = 365 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 3.98 (s, 3H), 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).

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

Example #2.

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

The following section describes various options for the reaction procedure and workup. Under given conditions, these procedures are geared towards the respective technical equipment.

The following experiments were carried out, except for water and air, using an inert gas (N2 or Ar).

Option number 1.

g (137.255 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6carboxylate (VI) was dissolved in 800 ml THF. At normal pressure (1 atm), approximately 300 ml of THF was distilled off at 70°C. Then the solution was cooled to 0-3°C.

The solution was kept at this temperature and added dropwise over 120 min to a cooled mixture of 457.5 ml (1372.6 mmol) of methylmagnesium chloride 3 M in THF and 29.1 g of lithium chloride (686.3 mmol) at a temperature of 0 to 3°C. After completion of the addition, the sample was removed from the mixture and subjected to HPLC analysis showing that the conversion was complete. The mixture was carefully poured over 25 minutes at 0 to 3°C into 500 ml of 1/2-sat. aq. sodium chloride solution (caution: exothermic! During the first 50 ml, a strong temperature rise up to 29°C was observed!). Was obtained suspension, which was dissolved by adding 358 ml of 20 wt.% aq. citric acid (pH was lowered from 8.08 to 4.28). Stirring was continued for 10 min at 20-25°C. 500 ml of ethyl acetate was added and stirring was continued for 10 minutes. The phases were separated. Interfacial material was added to the organic phase. 5 g of activated carbon was added to the organic phase. The mixture was heated to 78°C (internal temperature), stirred for 30 min at this temperature and

- 27 042116 then cooled to 50°C (internal temperature). The warm solution was filtered through Celite and washed twice with 125 ml of ethyl acetate. The mixture was concentrated to approximately 150 ml at atmospheric pressure (1 atm) and 110°C. 350 ml of toluene was added and 200 ml was distilled off at atmospheric pressure (1 atm) and 110°C. The product fell out. At 60°C (internal temperature), 200 ml of n-heptane were added over 45 minutes. The mixture was cooled to 0-3°C and stirred for 2 hours at this 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 an oven at 40°C and 20 mbar for >48 h.

Yield: 39.42 g (78.83%, purity 97.84 area % HPLC).

HPLC (Method A): By = 5.8 min.

MS (ESI pos): m/z = 365 (M+H)+.

1H-NMR (400 MHz, DMSO-H6): δ [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).

13 batches were made, following the procedure of option No. 1. In table. 3 collected the corresponding outputs. Reactions were carried out on a 1 kg scale, taking into account the use of methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6-carboxylate (VI) as starting material. In most cases, two of the batches were combined after treatment with activated carbon.

Table 3

Yields obtained for batches 1-13 of the synthesis of (V) from (VI)

Lot No. Yield [kg] [%] 1 1.60 kg 79.9% 2 3 1.88 kg 94.0% 4 5 1.82 kg 90.8% 6 7 1.66 kg 83.0% 8 9 1.75 kg 87.6% 10 AND 1.85 kg 92.7% 12 13* 0.92 kg 96.4%

* Single batch.

Option number 2.

g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6carboxylate (VI) was dissolved in 480 ml THF. At normal pressure (1 atm), approximately 180 ml of THF was distilled off at 70°C. The mixture (light suspension) was then cooled to 0-3°C.

The solution was kept at this temperature and added dropwise over 120 min to a chilled mixture of 274.5 ml (823.5 mmol) of methylmagnesium chloride 3 M in THF and 17.5 g of lithium chloride (411.8 mmol) at a temperature of 0 up to 3°C. After 15 minutes the addition was complete, the sample was removed from the mixture and subjected to HPLC analysis showing that (VI) was completely converted. The mixture was carefully poured over 15 minutes at 0 to 3°C into 300 ml of water (caution: exothermic! During the first 50 ml a strong temperature increase was observed!). Added 310 ml of 20 wt.% aq. citric acid (pH was lowered to 4.05). Stirring was continued for 60 minutes at 20 to 25°C. 300 ml of ethyl acetate was added and stirring was continued for 30 minutes. The phases were separated. Interfacial material was added to the organic phase. The organic phase was washed twice with 450 ml of water. The organic phase was concentrated to 350 ml at 65°C (internal temperature) and atmospheric pressure (1 atm). 250 ml of ethyl acetate was added. 6 g of activated carbon was added to the organic phase. The mixture was heated to 65°C (internal temperature), stirred for 120 min at this temperature and then cooled to 50°C (internal temperature). The warm solution was filtered through Celite and washed twice with 125 ml of ethyl acetate. The mixture was concentrated to approximately 150 ml at atmospheric pressure (1 atm) and 110°C. 300 ml of toluene was added and 200 ml was distilled off at atmospheric pressure (1 atm) and 110°C. The product fell out. At 60° C. internal temperature, 200 ml n-heptane was added over 45 minutes. The mixture was cooled to 0-3°C and stirred at this temperature for 2 hours. 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 an oven at 40°C and 20 mbar for >48 h.

- 28 042116

Yield: 24.0 g (80%, purity: 95.8 area % HPLC).

HPLC (Method A): By = 5.8 min.

MS (ESI pos): m/z = 365 (M+H)+.

1H-NMR (400 MHz, DMSO-d6): δ [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).

Option number 3.

g (82.4 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6carboxylate (VI) was dissolved in 600 ml of THF. At normal pressure (1 atm), approximately 150 ml of THF was distilled off at 70°C. The mixture (light suspension) was then cooled to 0-3°C.

The solution was kept at this temperature and added dropwise over 120 min to a cooled mixture of 274.5 ml (823.5 mmol) of methylmagnesium chloride 3 M in THF and 17.5 g (411.8 mmol) of lithium chloride at a temperature of 0 to 3°C. The addition funnel was washed twice with 10 ml of THF. After 15 minutes the addition was complete, the sample was removed from the mixture and subjected to HPLC analysis showing that (VI) was completely converted. The mixture was carefully poured over 10 min at 0 to 3°C into 300 ml of water (caution: exothermic! During the first 50 ml, a strong temperature rise to 25°C was observed!). Added 250 ml of 20 wt.% aq. citric acid (pH lowered from 8 to 4). Stirring was continued for 30 min at 20-25°C. 300 ml of ethyl acetate was added and stirring was continued for 10 minutes. The phases were separated. Interfacial material was added to the organic phase.

The organic phase was washed twice with 200 ml of 1 wt.% aq. sodium chloride solution. 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 this temperature and then cooled to 50°C (internal temperature). The warm solution was filtered through Celite and washed twice with 50 ml of ethyl acetate. The mixture was concentrated to approximately 100 ml at atmospheric pressure (1 atm) and 110°C. 300 ml of isopropanol was added. 300 ml was distilled off at atmospheric pressure (1 atm) and 110°C. Again 300 ml of isopropanol was added and distilled off (approximately 355 ml) at 110°C. The resulting suspension was cooled to 20-25°C. 45 ml water was added over 45 minutes. The mixture was stirred for 1 hour. The precipitated product was filtered and washed with 50 ml of water/isopropanol (1:1). The precipitated product was dried in an oven at 50°C and 20 mbar for >48 h.

Yield: 24.9 g (83%, purity: 97.84 area % HPLC).

HPLC (Method A): By = 5.8 min.

MS (ESI pos): m/z = 365 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [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).

Option number 4.

This variant was used for the production of technical batches in the kilogram scale (>10 kg) (see Table 4).

g (164.7 mmol) methyl 5-({[6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-1H-indazole-6carboxylate (VI) was dissolved in 1500 ml THF. At normal pressure (1 atm), approximately 600 ml of THF was distilled off at 70°C. The mixture (yellow solution) was then cooled to 0-3°C.

The solution was kept at this temperature and added dropwise over 120 min to a chilled mixture of 550 ml (1647.1 mmol) of methylmagnesium chloride 3 M in THF and 35 g (823.5 mmol) of lithium chloride at a temperature of 0 to 3°C . After 15 minutes the addition was complete, the 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 600 ml of water (attention: exothermic! During the first 50 ml a strong temperature increase was observed!). Added 600 ml of 20 wt.% aq. citric acid (pH lowered to 4). Stirring was continued for 30 min at 20-25°C. The phases were separated. The organic phase was washed twice with 400 ml of 1 wt.% aq. sodium chloride solution. Interfacial material was added to the organic phase. The phases were separated. The organic phase was concentrated to 700 ml at 65° C. (internal temperature) and atmospheric pressure (1 atm). 500 ml of ethyl acetate and 12 g of activated charcoal were added to the organic phase. The mixture was heated to 65°C (internal temperature), stirred for 120 min at this temperature and then cooled to 50°C (internal temperature). The warm solution was filtered through Celite and washed twice with 200 ml of ethyl acetate. The concentration was continued under reduced pressure (200 mbar). The solvent was exchanged for toluene (remaining volume approx. 850 ml). The resulting suspension was cooled to 0-3°C. The precipitated product was filtered and washed with 50 ml of toluene. The precipitated product was dried in an oven at 50°C and 20 mbar for >48 h.

Yield: 51.2 g (85.3%, purity 96.51 area % HPLC).

HPLC (Method A): By = 5.8 min.

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MS (ESI pos): m/z = 365 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [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).

Option number 5.

Purification by stirring in isopropanol/water.

Depending on the purity of the crude product, an additional purification step can be carried out by stirring in mixtures of isopropanol and water, preferably 1:1. Depending on the purity of the crude product, mixing is carried out in the range of 2-10 volumes in relation to the crude starting material. The following example describes mixing in 3 volumes of isopropanol/water.

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

Yield: 6.8 g (90.7%, purity > 98 area % HPLC).

HPLC (Method A): By = 5.8 min.

MS (ESI pos): m/z = 365 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-4): δ [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).

The combination of options No. 4 and 5 was carried out on a scale of 44 kg (see Table 4).

Table 4

Obtaining a compound according to formula (V) following the protocols of options No. 4 and 5

Lot No. Exit Content (Analysis for application) 1 38.4 kg 79% 95.9% 2 33.6 kg 76% 96.0%

Example #3

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

Option number 1.

This variant was used to make technical batches in the kilogram scale and followed the protocol described in WO 2016/083433.

2.5 kg (6.86 mol) N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2carboxamide (V) was suspended in 33 L ( 28.6 kg) toluene. The mixture was heated to reflux and approximately 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 another 15 min at 90° C. before 1.17 kg (10.98 mmol) of methyl vinyl sulfone was added. The reaction mixture was held at 112°C (toluene at reflux) and stirred for at least 72 hours. The mixture was cooled to 20°C. The mixture was then heated to reflux and 8 L of toluene was distilled off from the mixture. The mixture was then cooled to 70°C and 12.6 kg of methyl tert-butyl ether (MTBE) was added over 30 min. The mixture was cooled to 20°C over 2 h and stirred at 20°C overnight. It was then cooled to 0° C. and stirred for 1 hour. The precipitate was filtered off and washed twice with 3 L of cold MTBE. The crystalline product was dried in an oven at 50°C under vacuum.

Yield: 2.39 kg (73.9%, purity: 97.8 area % HPLC).

HPLC (Method B): By = 3.07 min.

MS (ESI pos): m/z = 471 (M+H) ⁺ .

*H NMR (400 MHz, DMSO-d6): δ [ppm] = 1.63 (s, 6H), 2.90 (s, 3H), 3.85 (t, 2H), 4.86 (t, 2H), 5.97 (s, 1Н), 7.59 (s, 1Н), 8.13-8.19 (m, 1H), 8.37 (s, 1Н), 8.41-8.48 (m, 2Н), 8.74 (s, 1H), 12.37 (s, 1H ).

Table 5

Yields and purity (in % after HPLC) obtained for three lots (I) from (V)

Starting material (V) Quantity [kg] Product (I) Yield [kg], [%] Product (I) Purity [area %] (HPLC)* 2.50 2.47, 76.5 97.4 2.50 2.32, 71.4 97.2 2.50 2.39, 73.9 (described) 97.8 (described)

* Method B.

In order to obtain a substance with very high purity and with a specific crystalline form (polymorph B), an additional purification step was introduced.

- 30 042116

1.85 kg crude N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide (I) dissolved in 36.6 kg (46.3 L) of acetone at ambient temperature. The resulting solution was dosed into refluxing ethanol for 2.5 hours. During the dosing process, 54 liters of the solvent were distilled off and an internal temperature of 63°C was reached. An additional 20.8 L of ethanol was added and 27 L of solvents were distilled off from the mixture. In addition, another 10.2 L of ethanol was added and 9.3 L was distilled off from the mixture. Finally, another 10.2 L of ethanol was added and 10.2 L of solvents were distilled off from the mixture. The mixture was cooled to 20° C. over 3 hours and stirred overnight. The mixture was cooled to 0-2°C over 1.5 h and stirred at this temperature for another 3 h. The suspension was filtered and the precipitate was washed with 2x0.93 L of cold ethanol. The product was dried in an oven at 50° C. under vacuum.

Yield: 1.59 kg (85.7%, purity: 99.0 area % HPLC).

HPLC (Method B): By = 3.07 min.

MS (ESI pos): m/z = 471 (M+H)+.

1H NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.63 (s, 6 H), 2.90 (s, 3 H), 3.85 (t, 2H), 4.86 (t, 2H), 5.97 (s, 1H), 7.59 (s, 1H), 8.16 (d, 1H), 8.37 (t, 1H), 8.41-8.48 (m, 2H), 8.74 (s, 1H), 12.37 (s, 1H) .

Table 6

Yield and purity obtained after synthesis, as well as purity (%) after HPLC for (I) synthesized from (V)

Starting material: crude (I) Quantity [kg], Purity [area %] (HPLC) Product (I) Yield [kg], [%] Product (I) Purity [area %] (HPLC)* 1.85, 97.4 1.56, 84.2 98.9 1.85, 97.2 1.59, 86.1 99.1 1.85, 97.8 1.59, 85.7 (described) 99.0 (described)

Option number 2.

This option was used for the production of technical batches in kg scale.

g (27.448 mmol) of N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2carboxamide (V) was suspended in 100 ml of toluene. 3.496 g (32.937 mmol) of methyl vinyl sulfone was added. The reaction mixture was heated to 110°C (refluxing 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 reverse refrigerator. 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 starting material (V) was still present in the reaction mixture. The N1/N2 selectivity was up to 1:8. 30 ml of toluene was distilled off. The mixture was cooled to 70°C. At this temperature, 70 ml of MTBE was added dropwise over 5 minutes to the mixture obtained in suspension. The mixture was cooled to 20°C during the night. It was then cooled to 0° C. and stirred for 2 hours. The precipitate was filtered off and washed twice with 10 ml of cold MTBE. The crystalline product is dried in an oven for at least 48 hours at 50° C. and <100 mbar.

Yield: 8.6 g (66.6%, purity: 94.7 area % HPLC).

HPLC (Method B): By = 3.07 min.

MS (ESI pos): m/z = 471 (M+H)+.

¹ H NMR (400 MHz, DMSO-de): δ [ppm] = 1.63 (s, 6H), 2.90 (s, 3H), 3.85 (t, 2H), 4.86 (t, 2H), 5.97 (s, 1H), 7.59 (s, 1H), 8.16 (d, 1H), 8.37 (t, 1H), 8.41-8.48 (m, 2H), 8.74 (s, 1H), 12.37 (s, 1H).

Parties on a technical scale.

In accordance with the procedure described under Option No. 2, batches were obtained in the scales of 3.396 kg and 1.699 kg in relation to the starting substance (V):

Table 7

Yield for compound (I) synthesized from compound (V)

Starting material (V) Quantity Product (I) Yield 3.40 kg 2.81 kg, 64.1% 1.70 kg 1.28 kg, 58.2%

Preparation of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2Nindazol-5-yl}-6-(trifluoromethyl)pyridine-2-carboxamide polymorphs (I).

Preparation of polymorph form B N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2Н- 31 042116 indazol-5-yl} -6-(trifluoromethyl)pyridine-2- carboxamide (I).

When the term room temperature is used in the following synthesis protocols, a temperature of approximately 20 to 25°C is meant.

Example 0.

An additional purification step was introduced to produce a cGMP grade substance and to control the crystal form for tablet production.

1500 kg crude N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide (I) dissolved in 45 kg of acetone and purified by filtration (filter cartridge: 3.0 µm ^ GMP filtration). The filtrate was concentrated and the solvent was replaced with ethanol. Thus, ethanol was added during simultaneous distillation until an internal temperature of 77°C was reached. The solution was concentrated to 6-7 volumes of ethanol in relation to the initial volume. The mixture was cooled to 20°C and stirred for 12 hours at this temperature. It was then cooled to 0° C. and stirred for another 3 hours. The product was filtered off and washed twice with 1 kg of cold ethanol. The product was dried in an oven at 60° C. under vacuum (<100 mbar).

Yield: 1370 g (91.33%). Similarly to the procedure described, three batches were obtained at the technical scale, see table. 7.

Table 8

Yield of pure compound (I) obtained by the purification described above from crude (I)

Starting material (crude I) [kg] Product (pure I) Yield [kg], [%] 1.50 1.37 (91.3%) 2.04 1.78 (87.5%) 2.03 1.86 (91.4%)

Table 9

Analytical data of the combined three parties, as shown in table. 8

Purity (HPLC)* > 99% (area) Content (analysis for application) > 97.7% (May) ethanol < 0.25% (May)** Pd < 1 ppm

* Method B;

** GC-HS.

Example 1

Preparation of polymorph A of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2Nindazol-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 was dissolved in 40 ml THF at reflux. The solution was filtered. Evaporation of the clear solution to dryness was carried out by storage at room temperature or in a refrigerator or freezer.

B) 400 mg of N-{6-(2-hydrokCypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide was dissolved in 40 ml of acetone at reflux. The solution is filtered. The clear solution was evaporated to dryness while stored at room temperature or in a refrigerator.

C) 400 mg of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide was dissolved in 40 ml of acetone at reflux. 20 ml of water was added to the solution. The clear solution was evaporated to dryness while stored at room temperature.

Example 2

Preparation of polymorph form B of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2Nindazol-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 was dissolved in 40 ml of acetonitrile at reflux. The solution was filtered and the clear solution was evaporated to dryness while being stored at room temperature.

B) 400 mg of N-{6-(2-hydrokCypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide was dissolved in 40 ml of acetone at reflux. The solution was filtered and the clear solution was evaporated to dryness while stored in a freezer.

- 32 042116

C) 400 mg of N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6(trifluoromethyl)pyridine-2-carboxamide was dissolved in 40 ml tetrahydrofuran at reflux. 20 ml of n-heptane was added to the solution and then it was evaporated to dryness while keeping at room temperature.

Example 3

Preparation of pseudopolymorphic form (1,7-hydrate) K-{6-(2-hydroxypropan-2-yl)-2-[2(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-(trifluoromethyl)pyridine -2-carboxamide.

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

Powder X-ray diffraction data of polymorph A, B and 1,7-hydrate of compound (I) are given in table. 2 and in FIG. 1-3.

Powder x-ray diffraction; measurement conditions:

Anode material Cu

K-alpha1 [A] 1.54060

Generator settings 40 mA, 40 kV

Primary beam monochromator focusing x-ray mirror

Sample rotation yes

Scan axis Gonio

Start position [°2Theta] 2.0066

End position [°2Theta] 37.9906

Example 4.

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

The granulation liquid is obtained by mixing the micronized form of the compound of formula (I), sodium lauryl sulfate, hypromellose 3 cP and purified angro water. Mannitol, microcrystalline cellulose and croscarmellose sodium are mixed. This mixture is granulated with granulation liquid in a fluid bed granulator. The granules are dried and sieved.

The granules are mixed with the sieved magnesium stearate in a mixer, resulting in a mixture ready for compression. The mixture ready for compression is compressed into tablets. Uncoated tablets are tested for uniformity, thickness, resistance to crushing, disintegration and friability. Hypromellose 5 cP, macrogol 3350, talc, titanium dioxide and ferric oxide are combined with purified angro water to form a homogeneous coating suspension which is sprayed onto the tablets in a suitable coating device, such as a perforated drum coater.

- 33 042116

Table 10

The composition of the tablets

Compound Quantity [mg] medicinal substance polymorphic form B of the compound 15.00 formula (I) Fillers Mannitol 25.30 Microcrystalline cellulose 41.00 Croscarmellose sodium 4.50 Hypromelose 3 cP 3.00 Sodium lauryl sulfate 0.50 magnesium stearate 0.70 Weight (uncoated tablet) 90.00

Film coating Hypromelose 5 cP 1.75 (See: Hydroxypropyl Methylcellulose 2910) Macrogol 3350 0.35 (See: Polyethylene glycol (3350)) Talc 0.35 titanium dioxide ^a 0.98 Iron oxide III ^a 0.07 Weight (film coating) 3.50 Weight (coated tablet) 93.50

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

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

Coated tablets containing 15 or 120 mg polymorph Form B N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6-( trifluoromethyl)pyridine-2-carboxamide (drug) is packaged in HDPE (high-density polyethylene) bottles with white polypropylene/polyethylene child-resistant screw caps. This packaging configuration provides sufficient protection from light and humidity.

Stability studies are performed with stability checks indicating appearance parameters, dissolution, degradation products, and drug content at regular intervals to confirm the stability of a coated tablet containing 15 or 120 mg of drug substance over the proposed study duration.

Coated tablet samples (15 or 120 mg) packaged in HDPE vials are stored at 25°C/60% RH, 30°C/75% RH and 40°C/75% RH, and at 2 -8°C. Stability experiments are carried out regularly.

Coated tablets containing either 15 or 120 mg of polymorph Form B N-{6-(2-hydroxypropan-2-yl)-2-[2-(methylsulfonyl)ethyl]-2H-indazol-5-yl}-6 -(trifluoromethyl)pyridine-2-carboxamide (drug) are stable under all conditions tested. During this storage period, no increase in degradation products and no decrease in drug content was observed.

Claims (3)

1. Crystal form of the compound of formula (I) (I) representing polymorph B, characterized by an X-ray powder diffraction pattern at 25°C and with copper K alpha 1 as the radiation source, which displays at least the following reflections, indicated as a 2Theta value ± 0.2°: 4.4; 8.9; 9.7; 10.1; 12.4; 12.9; 13.3; 14.1; 14.7; 15.4; 16.1; 16.4; 17.3; 17.9; 18.3; 18.4; 18.5; 19.2; 19.4; 19.7; 20.2; 20.6; 21.2; 21.4; 21.9; 22.3; 22.6; 22.8; 23.6; 24.5; 24.9; 25.2; 25.5; 25.8; 27.2; 27.5; 28.8; 29.6; 30.2; 31.2; 31.5; 32.5; 33.5; 33.9; 35.1; 36.2; 37.6. 2. The use of a crystalline form of a compound according to claim 1 for the treatment and prevention of proliferative and inflammatory diseases characterized by an over-reaction of the immune system. 3. The use of a crystalline form of a compound according to claim 1 for the treatment and prevention of inflammatory skin lesions, cardiovascular diseases, lung diseases, eye diseases, autoimmune disorders, gynecological disorders, especially endometriosis, and cancer.