WO2017108744A1 - Nouveaux indazoles substitués, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments - Google Patents

Nouveaux indazoles substitués, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments Download PDF

Info

Publication number
WO2017108744A1
WO2017108744A1 PCT/EP2016/081851 EP2016081851W WO2017108744A1 WO 2017108744 A1 WO2017108744 A1 WO 2017108744A1 EP 2016081851 W EP2016081851 W EP 2016081851W WO 2017108744 A1 WO2017108744 A1 WO 2017108744A1
Authority
WO
WIPO (PCT)
Prior art keywords
indazol
hydroxy
carboxamide
trifluoromethyl
methylbutyl
Prior art date
Application number
PCT/EP2016/081851
Other languages
German (de)
English (en)
Inventor
Ulrich Bothe
Holger Siebeneicher
Nicole Schmidt
Judith GÜNTHER
Holger STEUBER
Ulf Bömer
Martin Lange
Reinhard Nubbemeyer
Sven Ring
Christian Stegmann
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2017108744A1 publication Critical patent/WO2017108744A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Novel substituted indazoles processes for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
  • the present application relates to novel substituted indazoles, processes for their preparation, intermediates for use in the preparation of the novel compounds, the use of the novel substituted indazoles for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular of proliferative diseases, of autoimmune diseases, of metabolic and of inflammatory diseases such as Rheumatoid arthritis, spondyloarthritis (especially psoriatic spondylarthritis and ankylosing spondylitis), chronic obstructive pulmonary disease (abbreviation: COPD), multiple sclerosis, systemic lupus erythematosus, gout, metabolic syndrome, fatty liver hepatitis, insulin resistance, endometriosis and inflammation-induced or chronic Pain as well as lymphoma.
  • the present invention relates to novel substituted indazoles of general formula (I) which inhibit interleukin-1 receptor-
  • I RAK.4 is expressed by a variety of cells and mediates the signal transduction of Toll-like receptors (TLR), except TLR3, as well as receptors of the interleukin (IL) - l ß family, consisting of the I L-! R (receptor), i L-! NR, IL-33R, and IL-36R (Janeway and Medzhitov, Annu., Rev. Immunol., 2002; Dinarello, Annu., Rev.
  • I RAK.4 knockout mice nor human cells from patients lacking I RAK4 respond to the stimulation of TLRs (except TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002, Davidson, Vol. Currie, et al., The Journal of Immunology, 2006; Ku, by Bemuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
  • MyD88 interacts with I RAK4, resulting in the formation of an active complex that interacts with kinases I RAK! or I RAK2 interacts and activates (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004, Precious et al., 1 Bio! Chem., 2009).
  • NF nuclear factoD- ⁇ signal pathway and the MAPK (mitogen-activated protein kinase) signal pathway
  • Activation of the F-KB pathway as well as the MAPK signal This leads, for example, to increased expression of various inflammatory signaling molecules and enzymes, such as cytokines, chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammations associated ( 'those such as COX-2, IL-6 (interleukin-6) -, IL-8 (Holtmann, Enninga, et al, Journal of Biologicai Chemistry, 2001; Datta, Novotny, et al, The..
  • these processes may be associated with the proliferation and differentiation of certain cell types, such as monocytes, macrophages, dendritic cells, T cells, and B cells (Wan, Chi, et al., Nat Immunol, 2006, McGettrick and J. O'Neiil, British Journal of Haematology, 2007).
  • I RAK.4 The central role of I RAK.4 in the pathology of various inflammatory diseases has already been demonstrated by the direct comparison of wild-type (WT) mice with genetically modified animals with a kinase-inactive form of I RAK.4 (IRAK4 KDKI). IRAK4 KDKI animals have an improved clinical picture in the animal model of multiple sclerosis.
  • Atherosclerosis myocardial infarction and Alzheimer's disease (Rekhter, Staschke, et al., Biochemical and Biophysical Research Communication, 2008; Maekawa, Mizue, et al., Circulation, 2009; Staschke, Dong, et al., The Journal of Immunology, 2009 Kim, Febbraio, et al., The Journal of Immunology, 2011, Cameron, Tse, et al., The Journal of Neuroscience, 2012).
  • I RAK.4 in the animal model protects against viral-induced myocarditis as a result of an improved anti-viral response with concomitant reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013).
  • expression of I RAK4 has been shown to correlate with the extent of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
  • I RAK4 immune-complex-mediated IFNa (interferon-alpha) production by plasmacytoid dendritic cells, a key process in the pathogenesis of systemic lupus erythematosus (SLE), has been demonstrated (Chiang et al., The Journal of Immunology , 2010). Furthermore, the signaling pathway is associated with obesity (Ahmad, R .. P. Shihab et al., Diabetology & Metabolism Syndrome, 2015).
  • I RAK4 differentiates the so-called Tbl 7 T cells. Components of adaptive immunity, influenced. In the absence of I RAK4 kinase activity, fewer IL-17 producing T cells (Th17 T cells) are generated compared to WT mice.
  • I RAK4 By the inhibition of I RAK4 is the prophylaxis and / or treatment of atherosclerosis, diabetes mellitus type 1, rheumatoid arthritis, spondyloarthritis (especially psoriatic psoriasis and ankylosing spondylitis), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, inflammatory bowel disease and Vissuserk such as HIV (human immunodeficiency virus), hepatitis virus possible (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rhem Dis.
  • HIV human immunodeficiency virus
  • I RAK4 Due to the central role of I RA 4 in the MyD 88-mediated signaling cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of I RAK4 can be used for the prophylaxis and / or treatment of disorders mediated by said receptors.
  • TLRs as well as components of the I L-1 receptor homia are in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis such as Beheet's disease, granulomatosis with polyangiitis and giant cell arteritis, pancreatitis, systemic lupus erythematosus, dermatomy and polymyositis, of the metabolic syndrome including, for example, insulin resistance, hypertension, dyslipoproteinemia and obesity, diabetes mellitus (type 1 and type 2), diabetic nephropathy, osteoarthritis, Sjogren's syndrome, and sepsis (Yang, Tuziin, et al.,.
  • Skin disorders such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway and the I L-1 R family, respectively (Schmidt, Mittnacht, et al , J Dermatol Sei, 1996; Hoffmann, J Investig Dermatol Symp Proc, 1999; Gilliet, Conrad, et al., Archives of Dermatology, 2004; Niebuhr, Langnickel, et al, Allergy, 2008; Miller, Adv Dermatol., 2008; Terhorst, Kalali et al., Am J Clin Dermatol., 2010; Viguier, Guigue, et al., Annais of Internal Medicine, 2010; Cevikbas, Steinhoff, J.
  • 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 are associated with different TLR-mediated signaling pathways.
  • COPD obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • ILD interstitial lung disease
  • sarcoidosis pulmonary hypertension
  • the pathogenesis of pulmonary diseases can be both infectiously mediated and non-infectious mediated processes (Ramire / Cruz, Maldonado Bernai, et al., Rev Alerg Mex, 2004, Jeyaseelan, (hu, 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 Nadal, Prefontaine, et al, Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 201 1; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang Freeman, Martinez, et al., Respiratory Research, 2013; Dubaniewicz, A., Human Immunology, 2013) TLRs as well as
  • R family members are also more inflammatory in the pathogenesis of others Diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Perika rditis and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, graft rejection and graft-versus-host reaction, so inhibition of I RAK.4 is a suitable prophylactic and / or therapeutic approach (Liu-Bryan, Scott et al., Arthritis & Rheumatism, 2005; Piggott, Eisenbarth, et al., J Clin Inves, 2005; Christensen, Shupe, et al., Immunity, 2006; Cario, Infiammatory Bowel Diseases, 2010; Nickerson, Christensen, et al., The Journal of Immunology, 2010; Rakoff-Nahoum, Hao, et al., Immunity, 2006; Heimesaat, Fischer, et
  • TLR and I L-1 R family-mediated gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, especially endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia
  • I RAK.4 inhibitors Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Sikora, Mieiczarek-Paiacz, et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima, et al., Journal of Obstetrics and Gynecology Research, 2013; Santulli,
  • I RAK4 inhibitors may also positively affect atherosclerosis (Seneviratne, Sivagurunathan, et al., Ciinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Sedimbi , Hagglof, et al., Cell Mol Life Sei, 2013).
  • IRAK4-mediated TLR processes in the pathogenesis of ocular diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis are described (Kaarniranta and Salminen, J Mol Med (Berl), 2009, Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 201 1; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012 Guo, Gao, et al., Immunol Cell Bio! 2012; Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zliao et al., Investigative Ophthalmology & Visual Science, 2014).
  • Inhibition of IRAK4 is also a suitable therapeutic approach for fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zliao et al., Scand J Gastroenterol, 2011, Benias, ( iopal., Et al. Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Biochim Biophys Acta., 2015).
  • fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zliao et al., Scand J Gastroenterol, 2011, Benias, ( iopal., Et al. Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu
  • IR K.4 has in TLR and I L-1 R family-mediated diseases
  • I RAK.4 Due to the central role of I RAK.4 in TLR-mediated processes, the inhibition of I RAK4 also leads to the treatment / and / or prevention of cardiovascular and neurological diseases such as myocardial reperfusion, myocardial infarction, hypertension, hypertension (Oyama , Blais, et al., Circulation, 2004; Timmers, Siuijter, et al., Circulation Research, 2008; Fang and Hu, Med Sei Monit, 2011; Bijani International Reviews of Immunology, 2012; Bomfim, Dos Santos, et al Clin Sei (Lond), 2012, Christia and Frangogiannis, European Journal of Clinical Investigation, 2013, Thompson and Webb, Clin Sei (London), 2013; Hernan / Martinez-Revelles, et al., British Journal of Pharmacology, 2015; Frangogiannis, Opin Cardiol, 2015; Bomfim, Echem, et al., Life Sciences, 2015) as well as Alzheimer'
  • TLR-mediated signals and I L-1 receptor family-mediated signals via I RAK 4 Due to the invivoization of TLR-mediated signals and I L-1 receptor family-mediated signals via I RAK 4 for itching and pain, including acute, chronic, inflammatory and neuropathic pain, a therapeutic effect in the indicated indications due to the inhibition of IRAK4 can be assumed.
  • pain examples include hyperalgesia, allodynia, premenstrual pain, endometriosis-associated pain, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, H IV treatment-induced neuropathy, burn-induced pain, and chronic pain
  • CRPS complex regional pain syndrome
  • trigeminal neuralgia prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, H IV treatment-induced neuropathy, burn-induced pain, and chronic pain
  • Wilf Livshits, et al., Brain, Behavior, and Immunity, 2008
  • Kim Lee, et al., Toii-like Receptors: Roles in Infection and Neuropathology, 2009; Roy, Apkarian, et al., Annais of the New York Academy of Sciences, 2012; Guerrero, Cunha
  • lymphomas such as ABC-DLBCL (activated B cell diffuse large B-cell lymphoma), mantle cell lymphoma and Waldenström's disease, as well as chronic lymphocytic leukemia, melanoma, pantral tumor and hepatocellular carcinoma are characterized by mutations in MyD88 or changes in MyD88 activity , which can be treated by an IRAK4 inhibitor (Ngo, Young, et al., Nature, 2011; Puente, Pinyol, et al., Nature, 2011; Ochi, Nguyen, et al., J Exp Med, 2012; Srivastava, Geng, et al., Cancer Research, 2012; Treon, Xu, et al., New England Journal of Medicine, 2012; Choi, Kim, et al., Human Pathology, 2013; (Liang, Chen, et al.
  • MyD88 plays an important role in Ras-dependent tumors, so that I RAK.4 inhibitors are also suitable for their treatment (Kfoury, A., KL Corf, et al., Journal of the National Cancer Institute, 2013) It is also of therapeutic benefit in breast cancer, Ova rialkar / inom. Colorectal carcinoma, head and neck carcinoma, lung cancer, prostate cancer due to the inhibition of I RAK 4, as the indicated indications are associated with the signaling pathway (Szczepanski, Czystowska, et al., Cancer Res, 2009, Zhang, He, et al, Mol Bio! Rep.
  • Inflammatory diseases such as CAPS (cryopyrin-associated periodic syndromes), including FCAS (familial cold urticaria), MWS (Mückle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular) syndrome; FMF (familial Mediterranean fever), HIDS (hyper-IgD syndrome), TRA S (tumor necrosis factor receptor 1 -associated periodic syndrome), juvenile idiopathic arthritis, adult Still's disease.
  • CAPS cystopyrin-associated periodic syndromes
  • FCAS familial cold urticaria
  • MWS Mückle-Wells syndrome
  • NOMID nonatal-onset multisystem inflammatory disease
  • CONCA chronic infantile, neurological, cutaneous, and articular
  • FMF familial Mediterranean fever
  • HIDS hyper-IgD syndrome
  • TRA S tumor necrosis factor receptor 1 -associated periodic syndrome
  • juvenile idiopathic arthritis adult Still's disease.
  • Adrenal gland disease, Adamantiades-Behcet's disease, rheumatoid arthritis, osteoarthritis, kerato conjunctivitis sicca, PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne), Schnitzler syndrome and Sjögren syndrome are treated by blocking the IL-i signaling pathway, so here as well an IRAK4 inhibitor is useful in the treatment of said diseases (Narayanan, Corrales, et al., Cornea, 2008; Brenner, Ruzicka, et al., British Journal of Dermatology, 2009; Henderson and Goldbach-Mansky, Clinical Immunology, 2010; Dinarello , European Journal of Immunology, 2011; Gul, Tu-al-Tutkun, et al., Ann R cum Dis, 2012; Pettersson, Annais of Medicine Petterson, 2012; Ruperto, Brunner, et al., New England Journal of Medicine, 2012; Nordström, Knight, et al.,
  • the ligand of IL-33R, i L -33 is particularly involved in the pathogenesis of acute renal failure, so that inhibition of IRAK4 for prophylaxis and / or treatment is a suitable therapeutic approach (Akcay, Nguyen, et al., Journal of the American Society of Nephrology, 2011). Components of the I L-!
  • Receptor family are associated with myocardial infarction, various pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS), so that a prophylactic and / or therapeutic effect in the indications mentioned by the inhibition of I RAK .4 (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; Pauweis, Bracke, et al., European Respiratory Journal, 201 1; Haenuki, Matsushita, et al., Journal of Allergy and Clinical Immunology, 2012; Yin, Li, et al., Clinical
  • I RA K 4 inhibitors are known from the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 117-133). substituted indazole structure. 2-substituted indazoles are not described.
  • WO2013106254 and WO2011153588 2,3-disubstituted indazole derivatives are disclosed.
  • WO2007091107 describes 2-substituted indazole derivatives for the treatment of Duchenne muscular dystrophy. Explicitly described are only Indazolderivate with a phenyl group at the 2-position.
  • WO2015091426 describes indazoles, such as example WO2015091426-64, which are substituted at position 2 by a carboxamide side chain.
  • Example 117 describes an indazole derivative having a hydroxyethyl substituent at the 1-position. However, no indazole derivatives having a 3-hydroxy-3-methylbutyl substituent at the 1-position or 2-position are described.
  • Indazoles having a hydroxy-substituted alkyl group at position 2 are included generically with the general formula but are not explicitly disclosed in WO2015104662.
  • WO2015104662 describes indazoles with a substitution at position 6 for which Ri has the following meaning: alkyl, cyano, -NR a R b or optionally substituted groups from cycloalkyl, aryl or heterocyclyl, where the substituents independently of one another are alkyl, Alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy.
  • WO2015104662 describes for Ri cyclopropyl, cyclohexyl, cyano, 3-fluorophenyl [and saturated heterocyclic substituents.
  • the object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (I RA .4).
  • the present invention relates to compounds of the general formula (I)
  • Tetrahydrofuranyl, pyranyl, an oxo group or a C ⁇ -G - alkoxy group may be substituted
  • R 5 is hydrogen, C3-C6-cycloalkyl or CVCV alkyl, wherein G -CV alkyl optionally substituted one to three times with cyclopropyl, cyano and hydroxy, each substituent can occur only once or one to five times with fluorine atoms;
  • R is hydrogen, fluorine or methyl
  • R ' is hydrogen, C 3 -C 6 -cycloalkyl, cyano, NH 2 , NH (GC 6 -alkyl), N (GC 6 -alkyl) 2, pyrrolidin-1-yl, piperidin-1-yl, morpholine 4-yl. 4-methylpiperazin-1-yl or G-Ce-Alkyi, wherein CVG alkyl may be optionally substituted one to three times with cyclopropyl, cyano and hydroxy, wherein each substituent may occur only once or one to five times with fluorine atoms;
  • R 8 , R 9 , R 10 are hydrogen, methyl or fluorine
  • R 3 stands for * where R 11 is for
  • Cs-Cö-cycloalkyl or CVCV alkyl where G-C-C-alkyl may be optionally substituted one to three times with cyclopropyl, cyano and hydroxy, where each substituent may occur only once or one to five times with fluorine atoms; and R 12 is hydrogen, fluorine or C iG -alkvl; or
  • R 3 stands for
  • R a is C 1 -C -alkyl or C 3 -C 7 -cycloalkyl
  • G-Ce-alkyl and C3-C7-cycloalkyl may be optionally mono- or polysubstituted, identically or differently, by fluorine, hydroxyl, cyano, C 1 -C -alkyl, C 1 -C 4 -alkoxy or C 3 -C 7 -cycloalkyl;
  • R b is C 1 -C 12 -alkyl or C 3 -C 7 -cycloalkyl
  • novel I RA 4 inhibitors are particularly useful for the treatment and prevention of proliferative, metabolic and inflammatory diseases characterized by an overreacting immune system. Inflammatory skin diseases, cardiovascular disease, lung diseases, eye diseases, neurological diseases, pain disorders and cancers are particularly mentioned here.
  • the new I RAK.4 inhibitors are suitable for treatment and prevention
  • autoimmune "" 1 • inflammatory diseases, especially rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Spondyloarthritides and gout,
  • Metabolic disorders especially liver diseases such as fatty liver as well
  • gynecological diseases especially endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea. Dyspareunia, dysuria and dyschez.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. But also included are salts which are not suitable for pharmaceutical applications themselves, but can be used for example for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric. Maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine in. lysine, ethylenediamine and NM ethylpip eridine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 211 (deuterium), 3H (tritium), 13C, 14C , 15N, 170, 180, 32P, 3. 33 p. 34S, 35S, 36S, 18F, 36C1, 82Br, 1 231. 1241, 1291 and 1311.
  • isotopic variants of a compound of the invention such as those in which one or more radioactive isotopes are incorporated, may be useful, for example for the investigation of the mechanism of action or the distribution of active substance in the body; Because of the comparatively easy production and detectability, compounds labeled with 311 or 14C isotopes are particularly suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred inhibitor of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the methods described below and the instructions given for the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • Another object of the present invention are all possible crystalline and polymorphic forms of the compounds of the invention, wherein the polymorphs may be present either as a single polymorph or as a mixture of several polymorphs in all mixing ratios.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs here denotes compounds which may themselves be biologically active or inactive, but during their residence time in the body to compounds of the invention are reacted (for example, metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Examples which may be mentioned are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3 Methyl-butyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyi, 1-ethylbutyl and 2-ethylbutyl.
  • Preferred are methyl, ethyl. n-propyl, n-butyl, 2-methylbutyl, 3-methylbutyl and 2,2-dimethylpropyl.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having in each case the number of carbon atoms specified.
  • cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl may be mentioned:
  • Heterocycloalkyl, heterocyclyl or heterocycle in the context of the invention is a saturated heterocycle having a total of 3 to 10 ring atoms which contains one or two ring heteroatoms from the series N, O, S, SO and / or SO.
  • Examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl. Piperazinyl, tetrahydropyranyl, morpholinyl. Thiomorpholinyl. Dioxothiomorpholinyl, dihydroindolyl and dihydroisoindolyl.
  • alkoxy represents a linear or branched alkoxy radical with the number of carbon atoms indicated in each case. From 1 to 6 carbon atoms are preferred. Examples are methoxy, ethoxy, n-propoxy. I sopropoxy. 1-methylpropoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, I-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy.
  • Particularly preferred is a linear or branched alkoxy radical having 1 to 4 carbon atoms.
  • a linear or branched alkoxy radical having 1 to 4 carbon atoms.
  • methoxy, ethoxy, n-propoxy. 1-methylpropoxy, n-butoxy and iso-butoxy called.
  • Halouen is in the context of the invention for fluorine, chlorine and bromine. Preference is given to fluorine.
  • Hvdroxy is OH within the scope of the invention.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
  • R 1 is chlorine
  • R ! is OR 4 .
  • R is C; -G, alkyl which is substituted with a hydroxy group.
  • R " is particularly preferably a compound in which R is 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl or 3-hydroxy-3-methylbutyl. 3-methylbutyl radical is preferred.
  • R 2 is a C 2 -C 6 alkyl radical which is substituted with two hydroxy groups.
  • R particularly preferably represents 2,3-dihydroxypropyl, 2,3-dihydroxy-3-methylbutyl or 2,3-dihydroxybutyl. Most preferably, R 2 is 2,3-dihydroxypropyl.
  • R 2 is G-Cs-alkyl which is substituted with an oxetanyl group or tetrahydrofuranyl group.
  • R tr is oxetan-3-ylmethyl, oxetan-2-ylmethyl, tetrahydrofuran-3-ylmethyl or tetrahydrofuran-2-ylmethyl.
  • R 2 is oxetan-3-ylmethyl or tetrahydrofuran-3-ylmethyl.
  • R 2 is C ' -C, alkyl which is substituted with a C 1 -C 3 alkoxy group. More preferably, R 2 is CVCV alkyl which is substituted with a methoxy group. Very particular preference is given to compounds in which R 2 is 3-methoxy-3-methylbutyl, 3-methoxypropyl or 2-methoxyethyl.
  • R is C; -%, -alkyl which is substituted with a 2-hydroxyethoxy group.
  • Particularly preferred are compounds in which R 2 is 2- (2-hydroxyethoxy) ethyl or 3- (2-hydroxyethoxy) propyl. Very particular preference is given to 2- (2-hydroxy oxy) ethyl.
  • R 2 represents
  • R is 3-oxobutyl.
  • R 4,4,4-trifluorobutyl, 3.3.3-trifluoropropyl. 2,2,2-trifluoroethyl or 3,3-difluorobutyl.
  • R is 4,4,4-trifluorobutyl or 3.3.3-trifluoropropyl 1.
  • Very particular preference is given to 4,4,4-trifluorobutyl.
  • R ' is 2- (C 1 -C 6 -alkyl) -1,3-thiazol-4-yl, where the (C 1 -C 6 -alkyl) substituent is optionally simply cyclopropyl, one to five times fluorine atoms and optionally simply substituted with a hydroxy group.
  • R 3 particularly preferably represents 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-methyl-1,3-thiazol-4-yl, 2-ethyl-1 .3-ihia / ol-4 yl. 2-propyl! , 3-thia / ol-4-yl. 2-Isopropyl-l, 3-thiazol-4yl or 2-ien-butyl-! 3-thiazole-4-yl.
  • R 3 is 2-cyclopropyl-1,3-hia / ol-4-yl.
  • R 3 is 4- ⁇ C 1 -C 4 -alkyl) -1,3-thiazol-2-yl, where the (C 1 -C 6 -alkyl) substituent is optionally simply substituted by cyclopropyl, up to five times with
  • Fluorine atoms and optionally substituted with a simple hydroxy group are optionally substituted with a simple hydroxy group.
  • R ' particularly preferably represents 4- (trifluoromethyl) -1,3-thiazol-2-yl, 4-methyl-1,3-thiazol-2-yl,
  • R 3 is 4- (trifluoromethyl) -1,3-thiazol-2-yl.
  • R 3 is 4-cyclopropyl-1, 3-thia / ol-2-yl.
  • R ' represents 2- (Ci-C 6 -ASkyl) -l, 3-oxazol-4-yl, wherein said (C i -C ⁇ - alkyl) - sub stituent which is optionally monosubstituted with cyclopropyl, a - Can be substituted by five times with fluorine atoms and optionally simply with a hydroxy group.
  • R 3 is 2 - M et hy 1 - 1 .3 -oxa / o I -4 -y 1.
  • R 3 is 2- (trifluoromethyl) -1,3-oxazol-4-yl, 2-ethyl-1, 3 -oxazol-4-yl, 2- (1,1-difluoroethyl) -1,3-oxazol-4-yl, 2- (2,2,2-trifluoroethyl) -1,3-oxa / ol-4-vi, 2-isopropyl-1,3-oxa / ol-4-yl, 2-tert-butyl-1,3-oxazol-4-yl or 2- (cyclopropylmethyl) -1,3-oxazol-4-yl.
  • R 3 is 2- (trifluoromethyl) -1,3-oxazol-4-yl.
  • R 3 is 2-cyclopropyl-1
  • R 3 is 2- (C 1 -C 4 -alkyl) -1,3-oxazol-5-yl. wherein the (GC 6 alkyl) substituent may optionally be substituted with cyclopropyl, one to five times with fluorine atoms and optionally simply with a hydroxy group.
  • R 3 is 2-methyl-1, 3-oxazol-5-yl, 2-ethyl-l, 3-oxazoi-5-yl, 2-isopropyl-1, 3-oxazol-5-yi.
  • R 3 is 2-methyl-1, 3-oxa / ol-5-yl.
  • R 3 is 1 - (C ⁇ -C, alkyl) -1-l-pyrazol-3-yl. wherein the (Ci-C6-alkyl) substituent may optionally be substituted with cyclopropyl, one to five times with fluorine atoms and optionally simply with a hydroxy group.
  • R 3 particularly preferably represents I - (difunctionalethyl) -1H-pyra / ol-3-yl, 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1 - (2,2,2-Tri-fluoroethyl) -!
  • R 3 is 1 - (di-lluoromethyl) -1 H-pyra / ol-3-yl.
  • R is 6- (Ci-C 6 alkyl) pyridin-2-yl, wherein said (C i -C ⁇ - alky 1) - sub stituent which is optionally monosubstituted with cyclopropyl, one- to five-fold with fluorine atoms and optionally simply substituted with a hydroxy group.
  • R 3 is particularly preferably 6-methylpyridin-2-yl, 6- (difluoromethyl) pyridin-2-yl, 6- (trifluoromethyl) pyridin-2-yl, 6-ethylpyridin-2-yl, 6- (1, 1 -Difluoroethyl) pyridin-2-yl, 6- (pentafluoroethyl) pyridin-2-yl, 6- (2,2,2-trifluoroethyl) pyridin-2-yl, 6-propylpyridin-2-yl, 6-isopropylpyridine-2 -yl, 6- (2-hydroxypropan-2-yl) pyridin-2-yl, 6-tert-butylpyridin-2-yl.
  • R 3 is 6- (1, 1 -difluoroethyl) pyridin-2-yl, 6- (2-hydroxypropan-2-yl) pyridin-2-yl, 6- (difluoromethyl) pyridin-2-yl, 6- (pentafluoroethyl) pyridin-2-yl or 6- (trifluoromethyl) pyridin-2-yl.
  • R 3 is 6- (1,1-difluoroethyl) pyridin-2-yl or 6- (trifluoromethyl) pyridin-2-yl.
  • R 3 is 6-aminopyridin-2-yl, 6 - ((C 1 -C 4 -alkyl) amino) pyridin-2-yl, 6- (di- (C 1 -C 4 -alkyl) ) amino) pyridin-2-yl, 6- (pyrrolidin-1-yl) pyridin-2-yl,
  • R 3 particularly preferably represents 6-aminopyridin-2-yl, 6- (methylamino) pyridin-2-yl, 6- (ethylamino) pyridin-2-yl or 6- (dimethylamino) pyridin-2-yl. Most preferably, R 3 is 6-aminopyridin-2-y 1.
  • R 3 is 6-cyclopropyipyridin-2-yl.
  • R 3 is 6,7-dihydro-4H-pyrazolo [5, 1-c] [1,4-oxazin-2-yl, 5-methyl-4,5,6,7-tetrahydropyra / olo [! , 5-ajpyrazin-2-yl or 4,5,6,7-tetrahydropyrazolo [l, 5-a] pyrazine-2-yl, pyrazolo [l, 5-a] pyrimidin-3-yl, pyrrolo [2, 1 -f] [1, 2,4] triazine
  • R 3 is 6,7-dihydyl-4H-pyrazolo [5,1- c] [1,4] oxazin-2-yl, pyrazolo [1,5-a] pyrimidin-3-yl.
  • R 4 are cyclopropyl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, azetidin-3-yl, 1-methylazetidin-3-yl, Oxetan-3-yl, tetrahydrofuran-3-yl or tetrahydro-2H-pyran-4-yl.
  • R 4 particularly preferably represents oxetan-3-yl, tert-butyl-3-yl or tetrahydro-2H-pyran-4-yl. Most preferably, R 4 is oxetan-3-yl or tetrahydrofilan-3-yl.
  • Another preferred embodiment for R 4 is CVC-alkyl.
  • R4 is particularly preferably methyl, ethyl or isopropyl. Most preferably, R 4 is methyl or ethyl.
  • R 4 is a C: -C ( -alkyl radical which is substituted with a
  • R 4 is a C 2 -C 4 alkyl radical substituted with a hydroxy group. Most preferably, R 4 is 2-hydroxyethyl, 2-hydroxypropyl or Most preferably, R "is 2-hydroxyethyl
  • R 4 is trifluoromethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl. More preferably R 4 is trifluoromethyl.
  • R 6 is preferably hydrogen or fluorine. Most preferably, R 'is hydrogen.
  • R 8 is hydrogen or fluorine. More preferably, R 8 is hydrogen.
  • R 9 is hydrogen or fluorine. More preferably, R 9 is hydrogen.
  • R 10 is hydrogen or fluorine. More preferably R 10 is hydrogen.
  • R i2 is hydrogen or fluorine. More preferably, R 12 is hydrogen.
  • R a is methyl, ethyl or cyclopopyl.
  • R b is methyl, ethyl or cyclopropyl.
  • R is Ci-Cs-alkyl
  • R 1 is chlorine or OR 4 ,
  • R 2 is C 1 -C 6 -alkyl
  • R 2 is 3-oxobutyi
  • R 5 is hydrogen, cyclopropyl or CVG alkyl, wherein CV, - alkyl may be optionally substituted one to three times with cyclopropyl, cyano and hydroxy, each substituent may occur only once or one to five times with fluorine atoms; and R "is hydrogen; or R * stands for a group
  • R 7 is hydrogen, cyclopropyl, cyano, NH 2 , NH (C 1 -C 6 -alkyl), N (C 1 -C 6 -alkyl) 2 , pyrrolidin-1-yl, piperidin-1-yl, morpholin-4 yl, 4-methyl-piperazine-1-yl
  • (VC alkyl may optionally be substituted one to three times with cyclopropyl, cyano and hydroxy, where each substituent may occur only once or one to five times with fluorine atoms and R 8 , R 9 , R 10 are hydrogen or
  • R * stands for a group
  • R 3 stands for
  • R 1 is chlorine or ⁇ - ⁇ ;
  • R : represents CyCVlkyl which is substituted
  • R is 3.3.3 trifluoropropyl 1.,4,4,4-trifluorobutyl or 3-oxobutyl; is 1 - ((iC, -alkyl) -1H-pyrazol-3-yl, wherein the (Ci-C6-alkyl) substituent optionally with cyclopropyl, one to five times with fluorine atoms and optionally simply with a hydroxy group may be substituted
  • 6-aminopyridin-2-yl 6 - ((C 1 -C 4 -acyl) amino) pyridin-2-yl, 6- (di (C 1 -C 4 -alkyl) amino) pyridin-2-yl, 6 (Pyrrolidin-1-yl) pyridin-2-yl, 6- (piperidin-1-yl) pyridin-2-yl, 6- (morpholin-4-yl) pyridin-2-yl, 6- (4-methylpiperazine - 1 -yl) pyridin-2-yl, or
  • R 5 is hydrogen or fluorine; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • R is 3-hydroxypropyl, 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 4-hydroxybutyl, 4-hydroxypentyl, 2,3-dihydroxypropyl, 2,3-dihydroxy-2-methylpropyl, 2-hydroxypropyl,
  • R for 1 - (di-methylhexyl) -1 H-pyrazol-3-yl 1-methyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-3-yl, 1- (2,2,2-trifluoroethyl) -1H-pyrazol-3-yl, 1-isopropyl-1 H-pyra / ol-3-yl.
  • R 4 is methyl, ethyl, isopropyl, propyl. Cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl, tetrahydrofuran-3-yl, 2-hydroxyethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2- (methylsulfonyl) ethyl, 3 (Methylsulfonyl) propyl, 2- (methylsulfanyl) ethyl,
  • R 5 is hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • R 2 for 3-1 hydroxypropyl. 3-hydroxybutyl, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 2,3-dihydroxypropyl,
  • R 3 is 1 - (di-fluoromethyl) -1 H -pyra-ol-3-yl. I-ethyl-1H-pyrazo! -3-yl, 1-isopropyl-1H-pyra-ol-3-yl, 2- (tri-fluoromethyl) -1,3-oxazol-4-yl, 2- (trifluoromethyl ) - 1, 3-thiazol-4-yl, 2-cyclopropyl-1, 3-oxa / ol-4-yl, 2-methyl-1,3-oxazol-5-yl, 2-methyl-1, 3 thiazol-4-yl.
  • R 3 is hydroxy-3-methylbutyl
  • R 3 is 1 - (ditluoromethyl) -1 H -pyra-ol-3-yl. I-ethyl-1H-pyrazol-3-yl. 2- (trifluoromethyl) -1,3-oxazol-4-yl, 2- (trifluoromethyl) -1,3-thiazol-4-yl, 2-cyclopropyl-1,3-oxazol-4-yl, 2-methyl - 1, 3-oxazol-5-yl, 2-methyl-1, 3-thia / ol-4-yl, 4- (trifluoromethyl) -1,3-thiazol-2-yl, 6- (I, Difluoroethyl) pyridin-2-yl, 6- (2-hydroxypropan-2-yl) pyridin-2-yl, 6- (difluoromethyl) pyridin-2-yl, 6- (trifluoromethyl) pyridin-2-yl, 6-aminopyridine -2-yl, pyra
  • R 4 is methyl, ethyl, isopropyl. Cyclopropylmethyl, oxetan-3-yl, oxetan-3-ylmethyl,
  • the present invention particularly relates to the following compounds:
  • the compounds of the invention act as inhibitors of the I RAK.4 kinase, and show a surprising, valuable spectrum of pharmacological activity. Therefore, in addition to the above-mentioned another object of the present invention, the use of the compounds of the invention for the treatment and / or prophylaxis of diseases in humans and animals.
  • gynecological diseases inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, autoimmune diseases, pain disorders, metabolic diseases, gout, liver diseases, the metabolic syndrome, insulin resistance and cancer diseases with the IRAK4 inhibitors according to the invention is particularly preferred.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular of TLR (except TLR3) and / or IL-1 receptor family-mediated diseases or diseases whose pathology is mediated directly by IRAK4 is.
  • IRAK4-associated diseases are multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Vogt- Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondyloarthritis and arthritis.
  • the compounds of the invention may also be used for the prophylaxis and / or treatment of MyD88 and TLR (except TLR3) -mediated diseases.
  • This includes multiple sclerosis, rheumatoid arthritis, spondyloarthritis (especially spondylarthritis psoriatica and ankylosing spondylitis), metabolic syndrome including insulin resistance, diabetes mellitus, osteoarthritis, Sjögren's syndrome, giant cell arteritis, sepsis, poly- and dermatomyositis, dermatitis like psoriasis, atopic dermatitis, alopecia areata, acne inversa and acne vulgaris, pulmonary diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS). acute lung injury (ALI), interstitial lung disease (ILD), sarcoidosis and pulmonary hypertension.
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention are suitable for the prophylaxis and / or treatment of the TLR-mediated diseases Behfet's disease, gout, endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschez.
  • the compounds of the invention are for the prophylaxis and / or treatment of transplant rejection, lupus erythematosus, adult morbus Still. and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
  • the use of the compounds according to the invention is also suitable for the treatment and / or prevention of the following diseases: eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis; Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
  • eye diseases such as keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration and uveitis
  • Cardiovascular diseases such as atherosclerosis, myocardial reperfusion injury, myocardial infarction, hypertension and neurological disorders such as Alzheimer's, stroke and Parkinson's.
  • the mechanism of action of the compounds according to the invention also enables the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated liver diseases, in particular NAFLD, NASH, ASH. Liver fibrosis and liver / irrigation.
  • the prophylaxis and / or treatment of itching and pain, in particular of acute, chronic, inflammatory and neuropathic pain by the compounds of the invention is given.
  • the compounds of the invention are for the prophylaxis and / or treatment of oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and liver cell carcinoma, breast cancer. Prostate cancer and Ras-dependent tumors.
  • the compounds of the invention are useful for the treatment and / or prevention of diseases mediated via the I L-1 receptor family.
  • diseases include CAPS (cryopyrin-associated periodic syndromes) including FCAS (familial cold urticaria), MWS (Muckle-Wells syndrome), NOMID (neonatal-onset multisystem inflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular ) Syndrome, FMF (Familial Mediterranean Fever), HI DS (Hyper-IgD Syndrome), TRAPS (Tumor Necrosis Factor Receptor 1 -associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Behcet's Disease, Rheumatoid Arthritis, Psoriatic Arthritis , Ankylosing spondylitis, osteoarthritis, keratoconjunctivitis sicca and sjögren syndrome, multiple sclerosis.
  • CAPS cysto
  • Lupus erythematosus, alopecia areata, diabetes mellitus type 1, diabetes mellitus type 2 and the consequences of myocardial infarction.
  • Pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia and ARDS.
  • gynecological disorders such as endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia.
  • Dysuria and dyschezia chronic inflammatory diseases such as Crohn's disease and ulcerative colitis are associated with a dysregulation of the IL-1 receptor family and are suitable for the therapeutic and / or prophylactic use of the compounds according to the invention.
  • the compounds according to the invention can furthermore be used for the treatment and / or prevention of I L 1 receptor family-mediated neurological disorders such as stroke. Alzheimer's, stroke. Skull and neck and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of pain disorders, in particular of acute, chronic, inflammatory and neuropathic pain.
  • these are hyperalgesia, allodynia, arthritis (such as osteoarthritis, rheumatoid arthritis and spondyloarthritis), premenstrual pain, endometriosis-associated pain, postoperative pain, Schiner / interstitial cystitis, CR PS (complex regional pain syndrome), trigeminal neuralgia, pain for prostatitis, spinal cord injury, inflammation-induced pain, low back pain, cancer pain.
  • Chemotherapy-associated pain H I V treatment-induced neuropathy, burn-induced pain and chronic pain.
  • the present invention also provides a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds according to the invention.
  • treatment or “treating” includes inhibiting, delaying, arresting, alleviating, attenuating, restricting, reducing. Suppressing, repressing or curing a disease, condition, illness, injury or disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • the term “therapy” is hereby understood to be synonymous with the term "treatment”.
  • prevention means prevention, prophylaxis or “prevention” are used synonymously in the context of the present invention and designate the avoidance or reduction of the risk To get, to experience, to suffer or to have a disease, a disease, a disease, an injury or a health disorder, a development or progression of such conditions and / or the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned E diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • active substances 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 cyclosporin, methotrexate®, TNF antagonists (eg Humira® "Etanercept, Infliximab), I L-!
  • antibacterial eg penicillins, vancomycin, ciprofloxacin
  • antiviral eg acyclovir, oseltamivir
  • antifungal eg naftifine, nystatin
  • Inhibitors e.g., anakinra, canakinumab, rilonacept
  • phosphodiesterase inhibitors e.g., apremilast
  • Jak S TAT inhibitors e.g., tofacitinib, baricitinib, GLPG0634
  • LefSunomide cyclophosphamide, rituximab.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • immunotherapy eg aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab.
  • immunotherapy eg aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilim
  • Lenalidomide lenograstim, mifamurtide, ofatumumab, oprelvekin, picibane I, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermine, teceleukin, tocilizumab
  • antiproliferative substances such as but not limited to amsacrine, arglabin.
  • Arsenic trioxide asparaginase, bleomycin, busulfan, dactinomycin, docetaxel, epirubicin, peplomycin, trastuzumab, rituximab, obinutuzumab, ofatumumab, toositumomab, aromatase inhibitors (eg exemestane, fadrozole, formestan, letrozole, anastrozole, vorozole), antiestrogens (eg chlormadinone, fulvestrant, Mepitiostan, tamoxifen, raloxifene, toremifene), E estrogens (eg estradiol, polyestradiol phosphate), progestagens (eg medroxyprogesterone, megestrol), topoisomerase I inhibitors (eg irinotecan, topotecan), topoisomerases 11 inhibitors (eg amrubicin, daunorubic
  • the following active ingredients rituximab, cyclophosphamide, doxorubicin, doxorubicin in combination with estrone, vincristine, chlorambucil, fludarabine, dexamethasone, cladribine, prednisone, 1311-chTNT, abiraterone, aclarubicin, alitretinoin, bisantrene, Calcium folinate, calcium levofolinate, capecitabine, carmofur, clodronic acid, romiplostim, crisantaspase, darbepoetin-alfa, decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitropanol, epoetin-alfa, filgrastim, fotemustine, gallium nitrate, gemcitabine, glutoxime, hist
  • non-drug therapy such as chemotherapy (eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin), radiotherapy (eg I-125 seeds, palladium-103-seed, radium-223 chloride) or phototherapy (eg temoporfin, talaporfin), which are accompanied by a drug treatment with the I RAK.4 inhibitors according to the invention or which after the end of the non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy by a drug treatment with the IRAK4 invention Inhibitors are supplemented.
  • the I RA 4 inhibitors according to the invention can, in addition to those already mentioned, also be combined with the following active substances:
  • Active ingredients for Alzheimer's therapy such as acetylcholinesterase inhibitors (eg donepezil, rivastigmine, galantamine, tacrine), NM DA (N-methyl-D-aspartate) receptor antagonists (eg memantine); L-DOPA / carbidopa (L-3, 4-dihydroxyphenylalanine), COMT (catechol-O-methyltransferase) inhibitors (eg entacapone), dopamine agonists (eg, ropinrol, pramipexole, bromocriptine), MAO-B (monoamine oxidase B) inhibitors (eg selegiline), anticholinergics (eg trihexyphenidyl) and NMDA antagonists (eg amantadine) for the treatment of Parkinson's; Beta-interferon (IFN-beta) (eg IFN beta-lb, IFN beta-la Avonex® and Betaferon®), glatiram
  • rheumatoid diseases such as rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis include methotrexate and biologics for B-cell and T-cell therapy (eg rituximab, abatacept).
  • Neurotrophic substances such as acetylcholinesterase inhibitors (eg donepezil), MAO (monoamine oxidase) inhibitors (eg selegiline), interferons and anticonvulsants (eg gabapentin); Active ingredients 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); Anti-diabetics such as metformin, glinides (eg nateglinide), DPP-4 (dipeptidyl peptidase-4) inhibitors (eg linagliptin, saxagiiptin, sitagiiptin, vildagiiptin), SGLT2 (
  • Lipid-lowering agents such as fibrates (eg bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (eg nicotinic acid / laropiprant), ezetimibe, statins (eg simvastatin, fluvastatin), anion replacements (eg colestyramine, colestipol, colesevelam).
  • Agents such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL # 3®, Lactobacillus GG, Lactobacillus plantarum, L.
  • Immunosuppressants such as glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), cortisone, chloroquine, cyclosporine, azathioprine, belimumab, rituximab, cyclophosphamide for the treatment of lupus erythematosus.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • calcineurin inhibitors eg tacrolimus and ciclosporin
  • cell division inhibitors eg azathioprine, mycophenolate mofetil, mycophenolic acid, everolimus or sirolimus
  • rapamycin basiiiximab, daclizumab, An!
  • Vitamin D3 analogs such as calcipotriol, tacalcitol or calcitriol; Salicylic acid, urea, ciclosporin, methotrexate, efalizumab in dermatological diseases.
  • drugs which contain at least one of the compounds according to the invention and one or more further active compounds, in particular EP4 inhibitors (prostaglandin E2 receptor 4 inhibitors), P2X3 inhibitors (P2X purinoceptor 3), PTGES inhibitors (prostaglandin E synthase inhibitors) or AKR1C3 inhibitors (Aldo-keto reduetase family 1 member C3 inhibitors) for the treatment and / or prevention of the aforementioned diseases.
  • EP4 inhibitors prostaglandin E2 receptor 4 inhibitors
  • P2X3 inhibitors P2X purinoceptor 3
  • PTGES inhibitors prostaglandin E synthase inhibitors
  • AKR1C3 inhibitors Aldo-keto reduetase family 1 member C3 inhibitors
  • the compounds according to the invention can act systemically and / or locally. To this
  • Purpose they can be applied in a suitable manner, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, via the ear or as an implant or stent.
  • a suitable manner such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, via the ear or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • working forms which release the compounds according to the invention rapidly and / or modified and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form such as e.g. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • suitable as application forms i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures) lipophilic suspensions
  • ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • compositions containing at least one compound of the invention usually together with one or more inert, non- contain toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • parenteral application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results.
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg kg body weight.
  • 6-chloro-5-nitro-1H-indazole (CAS 101420-98-8) can be converted to intermediate 1 as part of an alkylation reaction or Mitsunobu reaction.
  • Suitable for the alkylation reaction are reactions with optionally substituted alkyl chlorides, alkyl bromides, alkyl iodides or alkyl 4-methylbenzenesulfonates.
  • the AI ky Dialogen ide or Alky 1-4-methyl enyl sulfonates used are commercially available or can be prepared analogously to literaturb known ways (for the preparation of alkyl-4-methylbenzenesulfonates is, for example, the reaction of a corresponding Aikoholes with 4-methylbenzenesulfonyl chloride in the presence of triethylamine or pyridine, see, for example, Bioorganic and Medicinal Chemistry, 2006, 14, 12, 4277-4244).
  • an alkali metal iodide such as potassium iodide or sodium iodide may be added.
  • Alkyl halides may also be used in some cases, N-cyclohexyl-N-methylcyclohexanamin.
  • Suitable solvents are, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF.
  • the alkyl halides or alkyl 4-methylbenzenesulfonates used may have functional groups previously optionally protected with a protecting group (see also PGM Wuts, TW Greene, Greene's Protective Croups in Organic Synthesis, Fourth Edition, ISBN: 9780471697541).
  • alkyl halides or alkyl-4-methylbenzenesulfonates which have one or more hydroxyl groups
  • these hydroxy groups may optionally be protected by a terf-butyl (dimethyl) sily 1 group or a similar silicon-containing protective group familiar to the person skilled in the art
  • the hydroxy groups can also be present protected with the Tetrahyil ro-2 H -pyran (THP) group or with the acetyl or benzoyl group.
  • THP Tetrahyil ro-2 H -pyran
  • the protecting groups used can then be cleaved subsequently to the synthesis of Intermediate 1 or Intermediate 2, but also after the synthesis of (I) -a.
  • a tert-butyl (dimethylsilyl) group is used as protective group, this can be cleaved off using tetrabutylammonium fluoride in a solvent such as THF.
  • a THP protecting group can be cleaved using 4-methylbenzenesulfonic acid (optionally as a monohydrate).
  • Acetyl groups or benzoyl groups can be cleaved off by treatment with aqueous sodium hydroxide solution.
  • alkyl halides or alkyl 4-methylbenzenesulfonates used may contain functional groups which may be converted to alternative functional groups by reactions known to those skilled in the art. Examples are oxidation or reduction reactions or saponification reactions of alkyl carboxylic esters called (compare, for example, Science of Synthesis, Georg Thieme Verlag).
  • 6-chloro-n-nitro-1H-inda / oi can be converted to intermediate 1 in a Mitsunobu reaction (see, for example, KCK Swamy et al., Chem. Rev. 2009, 109, 2551-2651) with optionally substituted alkyl alcohols be implemented.
  • Various phosphines such as triphenylphosphine, tributylphosphine or 1,2-diphenylphosphinoethane in combination with diisopropyl azodicarboxylate (CAS 2446-83-5) or other diazene derivatives mentioned in the literature (KCK Swamy et al., Chem. Rev. 2009, 109, 2551-2651) can be used.
  • Intermediate 1 can be converted by a reduction of the nitro group to intermediate 2.
  • iron and ammonium chloride in water and ethanol (see, for example, also Journal of the Chemical Society, 1955, 241-22419).
  • an amide synthesis can be used.
  • Various coupling reagents known in the literature can be used (Amino Acids, Peptides and Proteins in Organic Chemistry, Vol.3 - Building Blocks, Catalysis and Coupling Chemistry, Andrew B. Hughes, Wiiey, Chapter 12 - Peptide-Coupling Reagents, 407- 442; Chem. Soc. Rev., 2009, 38, 606).
  • H -imidazole-1-yl-methanone can be used as coupling reagents, wherein in each case to the reaction mixture, a base such as triethylamine or N-ethyl-N-isopropylpropan-2-amine is added. Preference is given to the use of HATU and -E thy 1- -i-propyl-1-propan-2-amine in DM.
  • a further subset (I) -b of the compounds of the formula (I) according to the invention can be obtained as indicated in synthesis scheme 2.
  • 6-chloro-1 I-indazole-5-amine (CAS 221681 -75-0) is reacted with a carboxylic acid.
  • the methods described in Synthesis Scheme 1 for amide synthesis into consideration. Preference is given to the use of 1-hydroxy-1H-benzotriazole hydrate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and triethylamine in THF.
  • Intermediate 3 is obtained, which is then reacted analogously to Synthetic Scheme 1 with an alkyl halide to give (I) -b.
  • the Mitsunobu reaction is preferred for the preparation of the intermediates 4 from 5-nitro-1H-indazol-6-ol (cf. synthesis scheme 1). Particularly preferred is the use of triphenylphosphine and diisopropyl azodicarboxylate in THF.
  • a further subset (I) -d of the compounds of the formula (I) according to the invention can be obtained as indicated in synthesis scheme 4.
  • Intermediate 4 is converted into intermediate 7 as described in Synthetic Scheme 1 as part of an alkylation reaction.
  • the reduction of the nitro group (see synthesis scheme 4) leads to intermediate 8, which is then replaced by a
  • Intermediate 8 can be prepared starting from Intermediate 5 by alternative means.
  • Intermediate 5 is first protected with the tert-butoxycarbonyl group (cf. WO2015091426), then the alkylation is carried out as described in Synthetic Scheme 1 and the deprotection in the presence of trifluoroacetic acid in dichloromethane.
  • R and R 4 have the definitions given in the general formula (I).
  • the substituent R 4 can also be introduced according to synthesis scheme 6 starting from the intermediates 1 1, 12 and 13 by an alkylation reaction with alkyl halides or alkyl 4-methylbenzenesulfonates, whereby intermediate 6, a subset (I) -e of the compounds of the formula ( I) and Intermediate 10 can be obtained.
  • the use of the alkylation reaction with alkyl bromides and potassium carbonate in DMF is preferred.
  • the alkyl halides used may optionally have functional groups which, after the alkylation reaction, can be converted into other functional groups by transformations known to those skilled in the art.
  • saturated saline means a saturated aqueous sodium chloride solution
  • ACD / LABS batch version 12.01.
  • the compounds according to the invention and their precursors and / or intermediates were purified by the following exemplary preparative HPLC methods:
  • Method PI System: Waters autopurification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, E LSD 2424. SQD; Column: XBrigde C18 5 ⁇ 100x30 mm; Eluent: A: water + 0.1% Vol. Formic acid, eluent B: acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow: 50 mL / min; Temperature: room temperature; Solution: Max. 250 mg / max. 2.5 ml. DM SO or DMF; Injection: 1 x 2.5 mL; Detection: DAD scan range 210-400 nm; MS ESI +, ESI-, scan ranges 160 - 1000 m / z.
  • Method P2 System: Waters autopurification system: Pump 254, Sample Manager 2767, CFO, DAD 2996, EL SD 2424, SQD 3100; Column: XBrigde C18 5 ⁇ 100x30 mm; Eluent: A: water +
  • Method P3 System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2. IS; Column: XBrigde C18 5 ⁇ 100x30 mm; Eluent A: water + 0.2% vol. Ammonia (25%), eluent B: acetonitrile; Gradient: 0-1 min 15% B, 1-6.3 min 15-55% B, 6.3-6.4 min 55-100%) B, 6.4-7.4 min 100% o B; Flow: 60 mL / min; Temperature: room temperature; Solution: Max. 250 mg / 2 ml. DM SO; Injection: 2 x 2mL; Detection: UV 218 nm; Software: SC PA PrepConS.
  • Method P4 System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2.1 S; Column: Chromatorex RP C18 ⁇ 125x30 mm, eluent: A: water + 0.1% by volume of formic acid, eluent B: acetonitrile; Gradient: 0 - 15 min 65 - 100% B; Flow: 60 mL / min; Temperature: room temperature; Solution: Max. 250 mg / 2ml. DMSO; Injection: 2 x 2mL; Detection: UV 254 nm; Software: SC PA PrepConS.
  • Method P5 System: Sepiatec: Prep SFC100, Column: Chiralpak IA 5 ⁇ 250x20 mm; Eluent A: carbon dioxide, eluent B: ethanol; Gradient: isocratic 20% o B; Flow: 80 mL / min; Temperature: 40 ° C; Solution: Max. 250 mg / 2m L DMSO; Injection: 5 x 0.4 ml. Detection: UV 254 nm.
  • Method P6 System: Agilent: Prep 1200, 2x Prep Pump, DI A, MWD, Gilson: Liquid Handler 215; Column: Chiralcel OJ-H 5 ⁇ 250x20 mm; Eluent A: hexane, eluent B: ethanol; Gradient: isocratic 30% B; Flow: 25 mL / min; Temperature: 25 ° C; Solution: 187 mg / 8 mL ethanol / methanol; Injection: 8 x 1.0 mL Detection: UV 280 nm.
  • Method P7 System: Labomatic, Pump: HD-5000, Fraction Collector: LABOCOL Vario-4000, UV detector: Knauer UVD 2. IS; Column: XBrigde C18 5 ⁇ 100x30 mm; Eluent A: water + 0.1% by volume of formic acid, eluent B: acetonitrile; Gradient: 0-3min: 65%> B isocratic, 3-13min: 65-100% o B; Flow: 60ml / min; Temperature: room temperature; Solution: Max. 250 mg / 2ml. DMSO: Injection: 2 x 2mL; Detection: UV 254 nm.
  • Method P8 System: Agilenl: Prep 1200, 2x Prep Pump, DLA, MWD, Gilson: Liquid Handler 215; Column: Chiralpak IF ⁇ 250x20 mm; Eluent A: ethanol, eluent B: methanol; Gradient: isocratic 50% B; Flow: 25 mL / min; Temperature: 25 ° C; Solution: 600 mg / 7 l. N, N-dimethylformamide; Injection: 10 x 0.7 mL Detection: UV 254 nm.
  • the reaction mixture was stirred for 16 h at 25 ° C.
  • the reaction mixture was concentrated and the residue partitioned between water and ethyl acetate. It was extracted twice with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, filtered through a water-repellent filter and concentrated.
  • the residue was purified by flash chromatography (Biotage SNAP cartridge (340 g, KP-Sil), eluent: H exan-ethyl lac etate).
  • the combined product fractions were concentrated, slurried with water and stirred vigorously for 20 minutes. It was sucked off and washed with water and diethyl ether. 8.56 g of the title compound were obtained.
  • the combined organic phases were washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, filtered (water-repellent filter) and concentrated.
  • the aqueous solution was added again with saturated sodium bicarbonate solution (pH ⁇ 9) and extracted three times with ethyl acetate.
  • the combined organic phases were washed with saturated sodium chloride solution, filtered (water-repellent filter) and concentrated.
  • the aqueous phase was added with sodium chloride and ethyl acetate and allowed to stir for 30 minutes. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate.
  • the combined organic phases were filtered (water-repellent filter) and concentrated. 199 mg of the title compound were obtained.
  • the reaction mixture was diluted with water and extracted three times with ethyl acetate.
  • the combined organic phases were washed with saturated sodium chloride solution, filtered through a filter which stood out, and concentrated.
  • the residue was purified by flash chromatography (Biotage Interchim 15 ⁇ cartridge (80 g, KP-Sil), eluent: hexane-ethyl acetate).
  • the combined product fractions were concentrated and dried. 610 mg of the title compound were obtained.
  • reaction mixture was diluted with water and extracted with ethyl acetate.
  • the combined organic phases were washed with saturated sodium chloride solution, the phases were separated and filtered through a water-repellent filter.
  • the residue was taken up in dichloromethane and adsorbed on Isolute under concentration.
  • the residue was purified by flash chromatography (Biotage SNAP cartridge (100 g, KP-Sil), eluent: hexane-ethyl acetate).
  • the combined product fractions were concentrated and dried. 790 mg of the title compound were obtained.
  • Reaction mixture was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed twice with saturated sodium chloride solution, filtered through a washable filter and concentrated. The residue was purified by preparative HPLC. The product fractions were lyophilized. 50 mg of the title compound were obtained.
  • the organic phase was washed twice with saturated sodium chloride solution, filtered through a water-repellent filter and concentrated.
  • the residue was purified by p reparative H LC by the method P4.
  • the product fractions were lyophilized.
  • the lyophilizate was again purified by preparative H PLC by method P2 (column: YMC Triart C18 5 ⁇ 100x30 mm, gradient: 0-0.5 min 25 mL / min to 70 mL / min 52% B; 0.5-5.5 min 52-61% B Flow: 70 mL / min).
  • the product fractions were lyophilized. 14 mg of the title compound were obtained.
  • the reaction mixture was partitioned between ethyl acetate and water. The phases were separated. The organic phase was washed twice with saturated sodium chloride solution, filtered through a water-repellent filter and concentrated. The residue was purified by preparative HPLC. The product fractions were lyophilized. 45 mg of the title compound were obtained.
  • the aqueous phase was extracted three times with ethyl acetate and the combined organic phases were filtered through a water-repellent filter and concentrated.
  • the residue was treated with diethyl ether, allowed to stir for 10 minutes, filtered again, washed with diethyl ether and dried in vacuo.
  • the residue was purified by preparative H lC cleaned. The product-containing fractions were freeze-dried. 49 mg of the title compound were obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux indazoles substitués, leurs procédés de préparation, leur utilisation seuls ou en combinaison pour le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments destinés au traitement et/ou à la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie de l'endométriose, ainsi que des douleurs associées à l'endométriose et d'autres symptômes associés à l'endométriose tels que la dysménorrhée, la dyspareunie, la dysurie et la dyschésie, de lymphomes, de la polyarthrite rhumatoïde, des spondylarthrites (en particulier de la spondylarthrite psoriasique et de la spondylarthrite ankylosante), du lupus érythémateux, de la sclérose en plaques, de la dégénérescence maculaire, de la BPCO, de la goutte, des maladies de la stéatose du foie, de la résistance à l'insuline, des maladies tumorales et du psoriasis.
PCT/EP2016/081851 2015-12-22 2016-12-20 Nouveaux indazoles substitués, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments WO2017108744A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15202240 2015-12-22
EP15202240.6 2015-12-22

Publications (1)

Publication Number Publication Date
WO2017108744A1 true WO2017108744A1 (fr) 2017-06-29

Family

ID=55068837

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/081851 WO2017108744A1 (fr) 2015-12-22 2016-12-20 Nouveaux indazoles substitués, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments

Country Status (4)

Country Link
AR (1) AR107127A1 (fr)
TW (1) TW201725202A (fr)
UY (1) UY37048A (fr)
WO (1) WO2017108744A1 (fr)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018060174A1 (fr) * 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft Benzimidazoles substitués, préparations pharmaceutiques les contenant et leur utilisation pour la production de médicaments
CN108663441A (zh) * 2017-12-30 2018-10-16 南京海融制药有限公司 一种他卡西醇软膏剂有关物质检查方法
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US10336762B2 (en) 2017-02-16 2019-07-02 Gilead Sciences, Inc. Pyrrolo[1,2-b]pyridazine derivatives
US10435405B2 (en) 2016-09-09 2019-10-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2020035019A1 (fr) * 2018-08-17 2020-02-20 浙江海正药业股份有限公司 Dérivé d'indazole amine, son procédé de préparation et son utilisation médicale
WO2020135513A1 (fr) * 2018-12-25 2020-07-02 上海美悦生物科技发展有限公司 Composé servant d'inhibiteur d'irak
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
CN111499612A (zh) * 2019-01-30 2020-08-07 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物及其制备方法和用途
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
CN111560012A (zh) * 2019-02-14 2020-08-21 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
CN111821297A (zh) * 2019-04-16 2020-10-27 天津合美医药科技有限公司 异吲哚啉衍生物用于治疗免疫球蛋白E（IgE）介导的疾病的应用
US10875866B2 (en) 2018-07-13 2020-12-29 Gilead Sciences, Inc. Pyrrolo[1,2-B]pyridazine derivatives
WO2020259626A1 (fr) * 2019-06-26 2020-12-30 南京明德新药研发有限公司 Composé imidazopyridine utilisé en tant qu'inhibiteur d'irak4
WO2020264499A1 (fr) 2019-06-28 2020-12-30 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
WO2021057785A1 (fr) * 2019-09-24 2021-04-01 上海美悦生物科技发展有限公司 Inhibiteur d'irak, son procédé de préparation et son utilisation
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
CN113278017A (zh) * 2021-05-27 2021-08-20 上海应用技术大学 取代吲唑类化合物、制备方法、应用和包含其的组合物
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2022267673A1 (fr) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 Indazole substitué par sulfoximide inhibiteur de la kinase irak4, son procédé de préparation et son utilisation
CN113227079B (zh) * 2018-12-25 2024-06-04 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3082178A1 (fr) * 2017-11-28 2019-06-06 Eiger Biopharmaceuticals, Inc. Methodes et compositions pharmaceutiques pour le traitement de la steatohepatite non alcoolique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015091426A1 (fr) * 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Nouveaux indazolcarboxamides, leur procédé de fabrication, préparations pharmaceutiques qui les contiennent et leur utilisation pour la préparation de médicaments
WO2015104662A1 (fr) * 2014-01-10 2015-07-16 Aurigene Discovery Technologies Limited Composés d'imidazole utilisables en tant qu'inhibiteurs de l'irak4

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015091426A1 (fr) * 2013-12-19 2015-06-25 Bayer Pharma Aktiengesellschaft Nouveaux indazolcarboxamides, leur procédé de fabrication, préparations pharmaceutiques qui les contiennent et leur utilisation pour la préparation de médicaments
WO2015104662A1 (fr) * 2014-01-10 2015-07-16 Aurigene Discovery Technologies Limited Composés d'imidazole utilisables en tant qu'inhibiteurs de l'irak4

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11795166B2 (en) 2016-09-09 2023-10-24 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
US10435405B2 (en) 2016-09-09 2019-10-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11542265B2 (en) 2016-09-09 2023-01-03 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US10934288B2 (en) 2016-09-09 2021-03-02 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11891388B2 (en) 2016-09-09 2024-02-06 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2018060174A1 (fr) * 2016-09-29 2018-04-05 Bayer Pharma Aktiengesellschaft Benzimidazoles substitués, préparations pharmaceutiques les contenant et leur utilisation pour la production de médicaments
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10336762B2 (en) 2017-02-16 2019-07-02 Gilead Sciences, Inc. Pyrrolo[1,2-b]pyridazine derivatives
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
CN108663441A (zh) * 2017-12-30 2018-10-16 南京海融制药有限公司 一种他卡西醇软膏剂有关物质检查方法
US11492354B2 (en) 2018-02-20 2022-11-08 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US11731958B2 (en) 2018-02-20 2023-08-22 Incyte Corporation Carboxamide compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11535622B2 (en) 2018-07-13 2022-12-27 Gilead Sciences, Inc. Pyrrolo[1,2-b] pyridazine derivatives
US10875866B2 (en) 2018-07-13 2020-12-29 Gilead Sciences, Inc. Pyrrolo[1,2-B]pyridazine derivatives
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11866426B2 (en) 2018-08-08 2024-01-09 Incyte Corporation Benzothiazole compounds and uses thereof
CN112513027A (zh) * 2018-08-17 2021-03-16 浙江海正药业股份有限公司 吲唑胺类衍生物及其制备方法和其在医药上的用途
CN112513027B (zh) * 2018-08-17 2024-03-29 浙江海正药业股份有限公司 吲唑胺类衍生物及其制备方法和其在医药上的用途
US11897863B2 (en) 2018-08-17 2024-02-13 Zhejiang Hisun Pharmaceutical Co., Ltd. Indazole amine derivative, preparation method therefor and medical use thereof
WO2020035019A1 (fr) * 2018-08-17 2020-02-20 浙江海正药业股份有限公司 Dérivé d'indazole amine, son procédé de préparation et son utilisation médicale
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
CN113227079A (zh) * 2018-12-25 2021-08-06 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
CN113227079B (zh) * 2018-12-25 2024-06-04 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
WO2020135513A1 (fr) * 2018-12-25 2020-07-02 上海美悦生物科技发展有限公司 Composé servant d'inhibiteur d'irak
CN111499612A (zh) * 2019-01-30 2020-08-07 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物及其制备方法和用途
CN111499612B (zh) * 2019-01-30 2022-12-30 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物及其制备方法和用途
CN111560012A (zh) * 2019-02-14 2020-08-21 上海美悦生物科技发展有限公司 一种作为irak抑制剂的化合物
CN111821297A (zh) * 2019-04-16 2020-10-27 天津合美医药科技有限公司 异吲哚啉衍生物用于治疗免疫球蛋白E（IgE）介导的疾病的应用
CN113825755B (zh) * 2019-06-26 2023-04-25 南京明德新药研发有限公司 作为irak4抑制剂的咪唑并吡啶类化合物
CN113825755A (zh) * 2019-06-26 2021-12-21 南京明德新药研发有限公司 作为irak4抑制剂的咪唑并吡啶类化合物
WO2020259626A1 (fr) * 2019-06-26 2020-12-30 南京明德新药研发有限公司 Composé imidazopyridine utilisé en tant qu'inhibiteur d'irak4
WO2020264499A1 (fr) 2019-06-28 2020-12-30 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
US11787784B2 (en) 2019-08-06 2023-10-17 Incyte Corporation Solid forms of an HPK1 inhibitor
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
CN114391013A (zh) * 2019-09-24 2022-04-22 上海美悦生物科技发展有限公司 一种irak抑制剂及其制备方法和用途
JP7353474B2 (ja) 2019-09-24 2023-09-29 上海美悦生物科技発展有限公司 Ｉｒａｋ阻害剤、その製造方法及び用途
AU2020352311B2 (en) * 2019-09-24 2023-11-09 Shanghai Meiyue Biotech Development Co., Ltd. IRAK inhibitor and preparation method therefor and use thereof
WO2021057785A1 (fr) * 2019-09-24 2021-04-01 上海美悦生物科技发展有限公司 Inhibiteur d'irak, son procédé de préparation et son utilisation
CN114391013B (zh) * 2019-09-24 2024-01-26 上海美悦生物科技发展有限公司 一种irak抑制剂及其制备方法和用途
JP2022549870A (ja) * 2019-09-24 2022-11-29 上海美悦生物科技発展有限公司 Ｉｒａｋ阻害剤、その製造方法及び用途
CN113278017B (zh) * 2021-05-27 2023-03-28 上海应用技术大学 取代吲唑类化合物、制备方法、应用和包含其的组合物
CN113278017A (zh) * 2021-05-27 2021-08-20 上海应用技术大学 取代吲唑类化合物、制备方法、应用和包含其的组合物
WO2022267673A1 (fr) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 Indazole substitué par sulfoximide inhibiteur de la kinase irak4, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
TW201725202A (zh) 2017-07-16
AR107127A1 (es) 2018-03-21
UY37048A (es) 2017-07-31

Similar Documents

Publication Publication Date Title
WO2017108744A1 (fr) Nouveaux indazoles substitués, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments
US20210053941A1 (en) Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs
EP3423446B1 (fr) Nouveaux indazoles substitués en 2, leurs procédés de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour produire des médicaments
EP3083586B1 (fr) Nouveaux indazolcarboxamides, leur procédé de fabrication, préparations pharmaceutiques qui les contiennent et leur utilisation pour la préparation de médicaments
IL283979A (en) Transformed benzamides 3,1 – thiazole – 2 – il
WO2017207385A1 (fr) 3-methylindazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments
HUE032987T2 (en) Dihydropyrazolopyrimidinone derivative
WO2018060174A1 (fr) Benzimidazoles substitués, préparations pharmaceutiques les contenant et leur utilisation pour la production de médicaments
WO2017207340A1 (fr) Nouveaux benzimidazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments
US12006304B2 (en) Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said substituted indazoles, and use of said substituted indazoles to produce drugs
US12006303B2 (en) Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said substituted indazoles, and use of said substituted indazoles to produce drugs
WO2018060072A1 (fr) Nouveaux benzimidazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16819898

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16819898

Country of ref document: EP

Kind code of ref document: A1