WO2017207385A1 - 3-methylindazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments - Google Patents

3-methylindazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments Download PDF

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WO2017207385A1
WO2017207385A1 PCT/EP2017/062534 EP2017062534W WO2017207385A1 WO 2017207385 A1 WO2017207385 A1 WO 2017207385A1 EP 2017062534 W EP2017062534 W EP 2017062534W WO 2017207385 A1 WO2017207385 A1 WO 2017207385A1
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pain
diseases
methyl
indazol
compounds
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Inventor
Ulrich Bothe
Sven Ring
Reinhard Nubbemeyer
Ulf Bömer
Judith GÜNTHER
Nicole Schmidt
Dorothee ANDRES
Holger Siebeneicher
Andreas Sutter
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Bayer Pharma AG
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Bayer Pharma AG
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the present application relates to novel substituted 3-methylindazoles, processes for their preparation, intermediates for use in the preparation of the novel compounds, the use of the novel substituted 3-methylindazoles for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for treatment and / or prophylaxis of diseases, in particular proliferative diseases, autoimmune diseases, metabolic and 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 hepatitis, insulin resistance, renal disease, endometriosis, and inflammation-induced or chronic pain as well as lymphoma.
  • the present invention relates to novel substituted 3-methylindazoles of general formula (I) which inhibit interleuk
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • TLR Toll-like receptors
  • IL interleukin
  • IRAK4 knockout mice nor human cells from patients lacking IRAK4 respond to the stimulation of TLRs (except TLR3) and the IL-1 ⁇ family (Suzuki, Suzuki, et al., Nature, 2002, Davidson, Currie, et al , The Journal of Immunology, 2006; Ku, Bernuth, et al., JEM, 2007; Kim, Staschke, et al., JEM, 2007).
  • MyD88 interacts with IRAK4 to form an active complex which interacts with and activates the IRAK1 or IRAK2 kinases (Kollewe, Mackensen, et al., Journal of Biological Chemistry, 2004, Precious et al. Biol. Chem., 2009).
  • NF nuclear factor
  • MAPK mitogen-activated protein kinase
  • inflammatory signaling molecules and enzymes such as cytokines, Chemokines and COX-2 (cyclooxygenase-2), and increased mRNA stability of inflammation-associated genes such as COX-2, IL-6 (interleukin-6) -, IL-8 (Holtmann, Enninga, et al., Journal of Biological Chemistry, 2001; Datta, Novotny, et al., The Journal of Immunology, 2004).
  • 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. OTS Supplementl, British Journal of Haematology, 2007).
  • IRAK4 KDKI The central role of IRAK4 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 IRAK4 (IRAK4 KDKI).
  • IRAK4 KDKI animals have an improved disease pattern 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; 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).
  • IRAK4 has been shown that deletion of IRAK4 in the animal model protects against viral-induced myocarditis as a result of an improved anti-viral response with concomitantly reduced systemic inflammation (Valaperti, Nishii, et al., Circulation, 2013).
  • expression of IRAK4 has been shown to correlate with the extent of Vogt-Koyanagi-Harada syndrome (Sun, Yang, et al., PLoS ONE, 2014).
  • IRAK4 immune-complex-mediated IFNa (interferonpha) 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).
  • the signaling pathway is associated with obesity (Ahmad, R., P. Shihab, et al., Diabetology & Metabolism Syndrome, 2015).
  • IRAK4 affects the differentiation of the so-called Th17 T cells, components of adaptive immunity.
  • Th17 T cells fewer IL-17 producing T cells (Th17 T cells) are generated compared to WT mice.
  • IRAK4 By the inhibition of IRAK4 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 viral diseases such HIV (human immunodeficiency virus), hepatitis virus possible (Staschke, et al., The Journal of Immunology, 2009; Marquez, et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza, et al., International Journal of Inflammation, Vol.
  • IRAK4 Due to the central role of IRAK4 in the MyD88-mediated signaling cascade of TLRs (except TLR3) and the IL-1 receptor family, the inhibition of IRAK4 can be used for the prophylaxis and / or treatment of disorders mediated by said receptors.
  • TLRs as well as components of the IL-1 receptor family are involved in the pathogenesis of rheumatoid arthritis, psoriatic arthritis, myasthenia gravis, vasculitis such as Behcet's disease, granulomatosis with polyangiitis and giant cell arteritis, pancreatitis, systemic lupus erythematosus, dermatomitis and polymyositis Including 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, Tuzun, et al., J Immunol Candia, Marquez et al., The Journal of Rheumatology, 2007; Scanzello, Plaas, et al Curr Opin Rheumatol, 2008; Deng, Ma-Krupa, et al.
  • Diabetes Complications 2014; Kaplan, Yazgan, et al., Scand J Gastroenterol, 2014; Talabot-Aye, et al., Cytokines, 2014; Zong, Dorph, et al., Ann Rheum Di, 2014; Ballak, Stienstra, et al., Cytokines, 2015; Timper, Seelig, et al., J. Diabetes Complications, 2015).
  • Skin diseases such as psoriasis, atopic dermatitis, Kindler syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa and acne vulgaris are associated with the IRAK4-mediated TLR signaling pathway and the IL-1R family, respectively (Schmidt, Mittnacht, et al.
  • 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 show an association with various 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 (Ramirez Cruz, Maldonado Bernal, et al., Rev Alerg Mex, 2004, Jeyaseelan, Chu, et al., Infection and Immunity , Seki, Tasaka, et al., Inflammation Research, 2010; Xiang, Fan, et al., Mediators of Inflammation, 2010; Margaritopoulos, Antoniou, et al., Fibrogenesis & Tissue Repair, 2010; Hilberath, Carlo, et al., The FASEB Journal, 2011; Nadigel, Prefontaine, et al., Respiratory Research, 2011; Kovach and Standiford, International Immunopharmacology, 2011; Bauer, Shapiro, et al., Mol Med, 2012; Deng, Yang, et al ., PLoS One, 2013; Freeman, Martinez, et al., Respiratory Research
  • TLRs as well as IL-1R family members are also involved in the pathogenesis of other inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
  • inflammatory diseases such as Allergy, Behcet's Disease, Gout, Lupus Erythematosus, Adult Still's Disease, Pericarditis, and Inflammatory Bowel Diseases such as Colitis Ulcerosa and Crohn's Disease, Graft Repulsion, and Grafting.
  • TLR- and IL-1R 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
  • IRAK4 inhibitors Akoum, Lawson, et al., Human Reproduction, 2007; Allhorn, Boing, et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier, et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz, et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima, et al., Journal of Obstetrics and Gynecology Research, 2013; Santulli, Borghes
  • IRAK4 inhibitors may also positively affect atherosclerosis (Seneviratne, Sivagurunathan, et al., Clinica Chimica Acta, 2012; Falck-Hansen, Kassiteridi, et al., International Journal of Molecular Sciences, 2013; Sedimbi, Hagglof, et al., Cell Mol Life 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 (Kaamiranta and Salminen, J Mol Med (Berl), 2009, Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor, et al., J Leukoc Biol, 2011; Chang, McCluskey, et al., Clinical & Experimental Ophthalmology, 2012; Guo Lee, Hattori, et al., Investigative Ophthalmology & Visual Science, 2012, Qi, Zhao, 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, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Biochim Biophys Acta., 2015).
  • fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao, et al., Scand J Gastroenterol, 2011, Benias, Gopal, et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu, et al., Bio
  • IRAK4 has in TLR and IL-1R family-mediated diseases can be chronic liver diseases such as fatty liver hepatitis and especially non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic fatty liver disease (NASH) steatohepatitis), alcoholic hepatitis (ASH - alcoholic steatohepatitis) can be preventively and / or therapeutically treated with IRAK4 inhibitors (Nozaki, Saibara, et al., Alcohol Clin Exp Res, 2004, Csak, T., A. Velayudham, et al.
  • NASH non-alcoholic fatty liver disease
  • IRAK4 inhibitors are also useful in the treatment of renal dysfunction and kidney disease, such as chronic kidney disease (CKD), chronic renal failure, glomerular disease, diabetic nephropathy, lupus nephritis, IgA nephritis (Berger's disease), nephrosclerosis.
  • CKD chronic kidney disease
  • chronic renal failure glomerular disease
  • diabetic nephropathy lupus nephritis
  • IgA nephritis (Berger's disease)
  • nephrosclerosis nephrosclerosis
  • the inhibition of IRAK4 also includes the treatment / and / or prevention of cardiovascular and neurological disorders such as myocardial reperfusion injury, myocardial infarction, hypertension, hypertension (Oyama, Blais, et al., Circulation Timmers, Sluijter, 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), Christina and Frangogiannis, European Journal of Clinical Investigation, 2013, Thompson and Webb, Clin Sei (London), 2013; Hernanz, Martinez-Revelles, et al., British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015 Bomfim, Echem, et al., Life Sciences, 2015) as well as Alzheimer's, stroke, stroke, craniocerebral
  • TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 Due to the involvement of TLR-mediated signals and IL-1 receptor family-mediated signals over IRAK4 in 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, HIV 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, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain
  • Wilf Livshits, et al., Brain, Behavior, and Immunity, 2008
  • Kim Lee, et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009; del Rey, Apkarian, et al., 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, pancreatic tumors 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., Clinical Cancer Research, 2013).
  • ABC-DLBCL activated B cell diffuse large B-cell lymphoma
  • MyD88 plays an important role in Ras-dependent tumors, so that IRAK4 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 effect in breast cancer, ovarian carcinoma, colorectal carcinoma, head and neck carcinoma, lung cancer, prostate cancer due to the inhibition of IRAK4, as the indicated indications are associated with the signaling pathway (Szczepanski, Czystowska, et al., Cancer Res, 2009; Zhang, He, et al., Mol Biol Rep, 2009; Wang, Qian, et al., Br J Cancer Kim, 2010; Jo, et al., World J Surg Oncol, 2012; Zhao, Zhang, et al .; Front Immunol, 2014; Chen, Zhao, et al., Int J Clin Exp Pathol, 2015).
  • Inflammatory diseases such as CAPS (cryopyrin-associated periodic syndromes), including FCAS (familial cold urticaria), MWS (Mückle-Wells syndrome), NOMID (neonatal-onset multisystem mflammatory disease) and CONCA (chronic infantile, neurological, cutaneous, and articular) syndrome; FMF (Familial Mediterranean Fever), HIDS (Hyper-IgD Syndrome), TRAPS (Tumor Necrosis Factor Receptor 1 -associated Periodic Syndrome), Juvenile Idiopathic Arthritis, Adult Still's Disease, Adamantiades-Hepet's Disease, Rheumatoid Arthritis, Osteoarthritis, Keratoconjunctivitis sicca, PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne), Schnitzler syndrome and Sjögren syndrome are treated by blocking the IL-1 signaling pathway, so here too an IRAK4 inhibitor is suitable for the treatment of these diseases (
  • the ligand of IL-33R, IL-33 is particularly involved in the pathogenesis of acute renal failure, so 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 IL-1 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), thus providing a prophylactic and / or therapeutic action in said indications by the inhibition of IRAK4 is expected
  • pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia, allergic rhinitis, pulmonary fibrosis and acute respiratory distress syndrome (ARDS)
  • ARDS acute respiratory distress syndrome
  • IRAK4 inhibitors are known from the prior art (see, for example, Annual Reports in Medicinal Chemistry (2014), 49, 177-133).
  • WO 201/153588 describes 2,3-disubstituted indazole derivatives of the general formula:
  • R is an optionally substituted cycloalkyl, heterocyclyl, aryl or heteroaryl radical and R 3 is an optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl radical stand.
  • An alkyl radical for R 2 is not described.
  • the compounds are described as viral polymerase inhibitors.
  • indazole skeleton is substituted with an amino group.
  • the compounds are described as effective pesticides.
  • WO2015091426 describes indazoles substituted at position 2 with a carboxamide side chain and inhibiting IRAK-4:
  • WO2015104662 discloses substituted indazoles of the following general formula:
  • R 2 is an alkyl or cycloalkyl group.
  • R2 is methyl at the same time as well as 1,3-disubstituted indazoles, in which R2 can represent different substituents.
  • Ri may be an alkyl, cyano, a group -NR a Rb or an optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl, wherein the substituents independently of one another alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, Haloalkyl, haloalkoxy, -OCOCH 2 -O-alkyl, -OP (O) (O-alkyl) 2 or -CH 2 -OP (O) (O-alkyl) 2 .
  • An alkoxy group is not disclosed for Ri.
  • the object of the present invention is to provide novel compounds which act as inhibitors of Interleukin-1 Receptor Associated Kinase-4 (IRAK4).
  • IRAK4 Interleukin-1 Receptor Associated Kinase-4
  • the present invention relates to compounds of the general formula (I)
  • R is OH or C0 2 H; represents an optionally mono- to trisubstituted fluorine-substituted C 1 -C 6 -alkyl radical or a cyclopropylmethyl group;
  • R is an optionally mono- to quintuply fluorine-substituted C 1 -C 6 -alkyl radical or a C 3 -C 6 -cycloalkyl radical;
  • R is hydrogen, fluorine or an optionally mono- to trisubstituted fluorine-substituted Ci-Ce-alkyl radical; and their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • the new IRAK4 inhibitors are particularly useful in the treatment and prevention of proliferative, metabolic and inflammatory diseases characterized by an overreacting immune system. Especially mentioned here are inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, neurological diseases, pain disorders and cancers.
  • the new IRAK4 inhibitors are suitable for treatment and prevention
  • Metabolic disorders especially liver diseases such as fatty liver as well
  • kidney diseases in particular chronic renal disease, nephropathies and gynecological diseases, in particular endometriosis as well as
  • Endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia.
  • 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 and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • 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 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methyl-piperidine.
  • 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 am
  • 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 in the case of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or Diastereomers can be the stereoisomerically uniform components in a known manner to isolate; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, 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 2H (deuterium), 3H (tritium), 13C, 14C , 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36C1, 82Br, 1231, 1241, 1291 and 1311.
  • isotopic variants of a compound of the invention such as those in which one or more radioactive Isotopes may be useful, for example, to study the mechanism of action or drug distribution in the body; because of the comparatively easy production and detectability, compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose.
  • 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;
  • modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment 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 can be present either as a single polymorph or as a mixture of several polymorphs in all concentration ranges.
  • the present invention also encompasses prodrugs of the compounds according to the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive but are converted during their residence time in the body to compounds according to the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl, 1-ethyl-propyl, 1-methylbutyl, 2-methylbutyl , 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 2-ethylbutyl.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having in each case the number of carbon atoms specified. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Hydroxy is OH in the context 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, for all radicals that occur repeatedly, their meaning is independent of -ehrander. Substitution with one, two or three equal or different sub-substituents is preferred.
  • R 1 is OH. In a preferred embodiment, R 1 is C0 2 H.
  • R 2 is preferably a C 1 -C 4 -alkyl radical.
  • R 2 is particularly preferably an isopropyl, ethyl or methyl radical.
  • R 2 is a cyclopropylmethyl radical.
  • R 2 is 2,2,2-trifluoroethyl or 2,2-difluoroethyl.
  • R 3 is an optionally mono- to trisubstituted with fluorine-substituted Ci-C i-alkyl radical.
  • R 3 is particularly preferably a 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1,1-difluoroethyl, trifluoromethyl, difluoromethyl radical.
  • R 3 is a 1, 1 -difluoroethyl or trifluoromethyl radical.
  • R 3 is C 1 -C 4 -alkyl.
  • R 3 is methyl.
  • R 3 is cyclopropyl
  • R 4 is hydrogen, fluorine or methyl. More preferably R 4 is hydrogen.
  • Another object of the present invention are compounds of formula (I) wherein R 1 is OH or C0 2 H;
  • R 2 is a C 1 -C 4 -alkyl radical, cyclopropylmethyl, 2,2,2-trifluoroethyl or 2,2-difluoroethyl;
  • R 3 is an optionally mono- to trisubstituted fluorine-substituted C 1 -C 4 -alkyl radical or
  • R 4 is hydrogen, fluorine or methyl; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • Another object of the present invention are compounds of formula (I), wherein
  • R 1 is OH or C0 2 H
  • R 2 is a Ci-C 4 alkyl radical
  • R 3 is an optionally monosubstituted to trisubstituted by fluorine Ci-C2-alkyl radical
  • R 4 is hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • Another object of the present invention are compounds of formula (I) in which R 1 is OH or C0 2 H;
  • R 2 is methyl, ethyl or isopropyl
  • R 3 is 1,1-difluoroethyl or trifluoromethyl
  • R 4 is hydrogen; as well as their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • the present invention particularly relates to the following compounds:
  • the invention further provides a process for the preparation of the compounds according to the invention of the general formula (I) from compounds of the formula (II)
  • R, R, R and R have the same meaning as in the above formula (I).
  • R 1 has the meaning CO 2 H
  • CAS 3709-08-8 3,3-dimethyldihydrofuran-2 (3H) -one
  • potassium carbonate is used as the base.
  • compounds of the formula (II) are converted into the compounds of the formula (II) by reaction with 4-bromo-2-methylbutan-2-ol or 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate in the presence of a base. I) transferred.
  • 4-bromo-2-methylbutanol is used as the base in the presence of potassium carbonate.
  • Another object of the invention are compounds of general formula (II),
  • R 2 , R 3 and R 4 have the same meaning as in the above formula (I) and their diastereomers, enantiomers, their metabolites, their salts, their solvates or the solvates of their salts.
  • the compounds of general formula (II) are suitable for the preparation of a subset of the compounds of general formula (I).
  • the compounds of the invention act as inhibitors of IRAK4 kinase, and show a surprising, valuable pharmacological Wirk's spectrum.
  • the substances weakly or not at all inhibit the kinase Trk (tropomyosin-related kinase) -A, a kinase whose inhibition can be associated with possible side effects (see section Moreover, the compounds according to the invention show no evidence of mutagenic potential (compare the section "in vitro micronucleus test").
  • gynecological diseases inflammatory skin diseases, cardiovascular diseases, lung diseases, eye diseases, autoimmune diseases, pain disorders, metabolic diseases, gout, liver diseases, metabolic syndrome, insulin resistance, kidney diseases and cancers with the IRAK4 inhibitors according to the invention 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.
  • IRAK4-associated diseases include multiple sclerosis, atherosclerosis, myocardial infarction, Alzheimer's disease, viral-induced myocarditis, gout, Vogt-Koyanagi-Harada syndrome, lupus erythematosus, psoriasis, spondyloarthritis and arthritis.
  • the compounds of the 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 psoriatic spondylarthritis and ankylosing spondylitis), metabolic syndrome including insulin resistance, diabetes mellitus, osteoarthritis, Sjögren's syndrome, giant cell arteritis, sepsis, poly- and dermatomyositis, skin diseases such as 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
  • the compounds of the invention are useful in the prophylaxis and / or treatment of TLR-mediated diseases of Behcet's disease, gout, endometriosis, endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschez. Furthermore, the compounds of the invention are useful for the prophylaxis and / or treatment of graft rejection, lupus erythematosus, Adult Still's disease 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 of 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 cirrhosis.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of TLR and IL-1 receptor family-mediated kidney diseases, in particular chronic kidney disease and nephropathies.
  • 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. Due to the mechanism of action of the compounds of the invention they are suitable for the prophylaxis and / or treatment of oncological diseases such as lymphoma, chronic lymphocytic leukemia, melanoma and hepatocellular carcinoma, breast cancer, prostate cancer and Ras-dependent tumors. In addition, the compounds of the present invention are useful for the treatment and / or prevention of Erkran '' ''' '-ins, which are mediated via the IL-1 receptor family.
  • CAPS cryopyrin-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 Milal Mediterranean Fever
  • HIDS 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, lupus erythematosus, alopecia areata, diabetes mellitus type 1, diabetes mellitus type 2 and the
  • Pulmonary diseases such as asthma, COPD, idiopathic interstitial pneumonia and ARDS, gynecological diseases such as endometriosis and endometriosis-associated pain and other endometriosis-associated symptoms such as dysmenorrhoea, dyspareunia, dysuria and dyschezia, chronic inflammatory bowel diseases such as Crohn's disease and colitis ulcerosa are associated with Dysregulation of the IL-1 receptor family associated and suitable for the therapeutic and / or prophylactic use of the compounds of the invention.
  • the compounds according to the invention can furthermore be used for the treatment and / or prevention of IL 1 receptor family-mediated neurological disorders such as stroke, Alzheimer's, stroke, Traumatic brain injury and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis are used.
  • IL 1 receptor family-mediated neurological disorders such as stroke, Alzheimer's, stroke, Traumatic brain injury and dermatological disorders such as psoriasis, atopic dermatitis, acne inversa, alopecia areata and allergic contact dermatitis are used.
  • 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.
  • pain disorders in particular of acute, chronic, inflammatory and neuropathic pain.
  • hyperalgesia allodynia
  • pain in arthritis such as osteoarthritis, rheumatoid arthritis and spondylarthritis
  • premenstrual pain endometriosis-associated pain
  • postoperative pain pain in interstitial cystitis
  • CRPS complex regional pain syndrome
  • trigeminal neuralgia pain in prostatitis, pain caused by spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-associated pain, HIV treatment-induced neuropathy, burn-induced pain, and chronic pain.
  • object of the present invention also provides a method for treating and / or pre ⁇ prevention of diseases, especially of the aforementioned Er-'krankungen, using an effective amount of at least one of the OF INVENTION'dungswashen-compounds.
  • treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restricting, reducing, depressing, restraining or curing a disease, a disease, a disease, a disease Injury or a health disorder, the unfolding, the course or the progression of such conditions and / or the symptoms of such circumstances.
  • therapy is understood here as a syno-'nym with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder to be experiencing, experiencing, suffering or having a manifestation or progression of such states and / or the symptoms of such states of affairs.
  • 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.
  • the present invention furthermore relates to medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the aforementioned medicaments.
  • active ingredients may be mentioned by way of example and by preference:
  • 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), IL-1 inhibitors (eg anakinra, canakinumab, rilonacept), phosphodiesterase inhibitors (eg apremilast), Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), leflunomide, cyclophosphamide, rituximab, belimumab, tacrolimus,
  • antibacterial
  • immunotherapy eg aldesleukin, alemtuzumab, basiliximab, catumaxomab, celmoleukin, denileukin-diftitox, eculizumab, edrecolomab, gemtuzumab, ibritumomab-tiuxetan, imiquimod, interferon-alpha, interferon-beta, interferon-gamma, ipilimumab, Lenalidomide, lenograstim, mifamurtide, ofatumumab, oprelvekin, picibanil, plerixafor, polysaccharide-K, sargramostim, sipuleucel-T, tasonermine, teceleukin, tocilizumab), antiproliferative substances such as but not limited to amsacrine, arglabine, arsenic trioxide,
  • 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, darbepoetinefa, decitabine, denosumab, dibrospidium chloride, eltrombopag, endostatin, epitoxanol, epoetine alfa, filgrastim, fotemustine, gallium nitrate, gemcitabine, glutoxime, histamine dihydroch
  • 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 IRAK4 inhibitors according to the invention or which are supplemented after the non-drug tumor therapy such as chemotherapy, radiotherapy or phototherapy by a drug treatment with the IRAK4 inhibitors according to the invention.
  • chemotherapy eg azacitidine, belotecan, enocitabine, melphalan, valrubicin, vinflunine, zorubicin
  • radiotherapy eg I-125 seeds, palladium-103 seed, radium-223 chloride
  • phototherapy eg temoporfin, talaporfin
  • IRAK4 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), NMDA (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®), glatiramer
  • rheumatoid diseases such as rheumatoid arthritis, spondyloarthritis and juvenile idiopathic arthritis methotrexate, leflunomide, Jak / STAT inhibitors (eg tofacitinib, baricitinib, GLPG0634), TNF antagonists (eg adalimumab in Humira®, etanercept, infliximab), IL-1 inhibitors (eg anakinra, canakinumab, rilonacept) and biologics for B-cell and T-cell therapy (eg rituximab, abatacept).
  • Jak / STAT inhibitors eg tofacitinib, baricitinib, GLPG0634
  • TNF antagonists eg adalimumab in Humira®, etanercept, infliximab
  • IL-1 inhibitors eg anakinr
  • Neurotrophic substances such as acetylcholinesterase inhibitors (eg donepezil), MAO (monoamine oxidase) inhibitors (eg selegiline), interferons and anticonvulsants (eg gabapentin); Active substances for the treatment of cardiovascular diseases such as beta-blockers (eg metoprolol), ACE inhibitors (eg benazepril), angiotensin receptor blockers (eg losartan, valsartan), diuretics (eg hydrochlorothiazide), calcium channel blockers (eg nifedipine), statins (eg simvastatin , Fluvastatin); Anti-diabetics such as metformin, glinides (eg nateglinide), DPP-4 (dipeptidyl-peptidase-4) inhibitors (eg, linagliptin, saxagliptin, sitagliptin, vildagliptin), SGLT
  • Lipid lowering agents such as fibrates (eg bezafibrate, etofibrate, fenofibrate, gemfibrozil), nicotinic acid derivatives (eg nicotinic acid / laropiprant), ezetimibe, statins (eg simvastatin, fluvastatin), anion exchangers (eg colestyramine, colestipol, colesevelam).
  • Agents such as mesalazine, sulfasalazine, azathioprine, 6-mercaptopurine or methotrexate, probiotic bacteria (Mutaflor, VSL # 3®, Lactobacillus GG, Lactobacillus plantarem, 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 basiliximab, daclizumab
  • anti-CD3 antibodies anti-T lymphocyte globulin / anti-lymphocyte globulin on organ transplantation
  • Vitamin D3 analogs such as calcipotriol, tacalcitol or calcitriol
  • Salicylic acid urea
  • ciclosporin methotrexate
  • efalizumab in dermatological diseases.
  • Glucocorticoids eg, prednisone
  • immunosuppressants such as azathioprines, cyclophosphamide, mycophenolate mofetil; Hydroxychloroquine, ACE inhibitors (eg, captopril, benazepril, enalapril, fosinopril), angiotensin receptor blockers (eg, losartan, valsartan), beta-blockers (eg, metoprolol), calcium channel blockers (eg, nifedipine), and immunosuppressants such as ciclosporin for the treatment of kidney disease , Nephropathies and glomerular diseases.
  • ACE inhibitors eg, captopril, benazepril, enalapril, fosinopril
  • angiotensin receptor blockers eg, losartan, valsartan
  • beta-blockers eg, metoprolol
  • calcium channel blockers eg,
  • 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 AKRIC3 inhibitors (Aldo-keto reductase 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
  • AKRIC3 inhibitors Aldo-keto reductase family 1 member C3 inhibitors
  • the compounds according to the invention can act systemically and / or locally.
  • they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, via the ear or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as 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 in the oral cavity. Lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be done bypassing a resorption step (eg mtra-'venous, intraarterial, intracardiac, intraspinal or intralumbar) or with the involvement of a resorption (eg intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • a resorption step eg mtra-'venous, intraarterial, intracardiac, intraspinal or intralumbar
  • suitable application forms include injectables 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 to be applied films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules , aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds of the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries.
  • excipients include, but are not limited to, excipients (for example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid poly-ethylene glycols), emulsifiers, and dispersing or wetting agents (for example, sodium dodecyl sulfate, polyoxy-sorbitan).
  • compositions which contain at least one erfin'orthungs ⁇ proper Ver-'bin-tion, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as their use to those mentioned above -ten purposes.
  • 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 of body weight.
  • carboxylic acids (intermediate V3) which are commercially available or are known from the literature or analogous to the literature (see, for example, European Journal of Organic Chemistry 2003, 8, 1559-1568, Chemical and Pharmaceutical Bulletin, 1990 , 38, 9, 2446-2458, Synthetic Communications 2012, 42, 658-666, Tetrahedron, 2004, 60, 51, 11869-11874) (see, for example, Synthetic Scheme 1).
  • carboxylic acids V3 can be prepared from carboxylic esters (intermediate V2) by saponification (compare, for example, the reaction of ethyl 6- (hydroxymethyl) pyridine-2-carboxylate with aqueous sodium hydroxide solution in methanol, WO2004113281) or, in the case of tert-butyl ester - by reaction with an acid such as hydrogen chloride or trifluoroacetic acid (see, for example, Dalton Transactions, 2014, 43, 19, 7176-7190).
  • the carboxylic acids V3 can also be used in the form of their alkali metal salts.
  • the preparation of the intermediates V2 may optionally take place from the intermediates VI, which as substituent X 1 carry a chlorine, bromine or iodine, by reaction in a carbon monoxide atmosphere, optionally under excess pressure in the presence of a phosphine ligands such as l, 3-bis (diphenylphoshino ) propane, a palladium compound such as palladium (II) acetate and a base such as triethylamine with the addition of ethanol or methanol in a solvent such as dimethyl sulfoxide (for manufacturing methods cf.
  • a phosphine ligands such as l, 3-bis (diphenylphoshino ) propane
  • a palladium compound such as palladium (II) acetate
  • a base such as triethylamine
  • solvent such as dimethyl sulfoxide
  • X 1 is chlorine, bromine or iodine.
  • R d is methyl, ethyl, benzyl or tert-butyl.
  • R 3 , R 4 have the definitions described in the general formula (I).
  • Intermediates 3 are prepared from intermediate 2 by reaction with alkyl chlorides, alkyl bromides, alkyl iodides or alkyl sulfonates (see, for example, WO2015091426, Preparation of intermediates 8; as suitable alkyl halides, iodomethane, iodoethane, 2-iodopropane, (bromomethyl) cyclopropane and 1,1,1 are suitable examples 1-trifluoro-2-iodoethane). Preference is given to the use of alkyl iodides in the presence of Potassium carbonate in DMF.
  • Intermediates 4 are obtained from intermediates 3 by reduction of the nitro group in a hydrogen atmosphere in the presence of palladium on carbon.
  • Suitable solvents are a mixture of methanol and THF.
  • UPLC-MS method A Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50x2.1mm; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow 0.8 mL / min; Temperature: 60 ° C; Injection: 2 ⁇ ; DAD scan: 210-400 nm.
  • UPLC-MS Method F Instrument Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.2% ammonia (32%), eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6- 2.0 minutes 99% B; Flow 0.8 mL / min; Temperature: 60 ° C; Injection: 1 ⁇ L; DAD scan: 210-400 nm; ELSD.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • Recombinant fusion protein from N-terminal GST (glutathione-S-transferase) and human IRAK4 amino acid sequence of the fusion protein see Figure 1; IRAK4 accession number NP 057207.2 (Uniport No Q9NWZ3)) expressed in baculovirus-infected insect cells (Hi5, BTI-TN) 5B1-4, cell line purchased from Invitrogen, catalog # B855-02) and purified via affinity chromatography was used as the enzyme.
  • the biotinylated peptide biotin-Ahx-KKARFSRFAGSSPSQASFAEPG C-terminus in amide form
  • concentration of Iraq4 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range.
  • Typical concentrations were on the order of about 0.2 nM.
  • the reaction was stopped by addition of 5 ⁇ M of a solution of TR-FRET detection reagents [0.1 ⁇ L streptavidin-XL665 (Cisbio Bioassays, France, catalog No. 610SAXLG) and 1.5 nM anti-phosho-serine antibodies [Merck Millipore, "STK Antibody", Catalog No. 35-002] and 0.6 nM LANCE EU-W1024-labeled anti-mouse IgG antibody (Perkin-Elmer, Product No.
  • AD0077 alternatively, a terbium cryptate labeled anti-mouse IgG antibody from Cisbio Bioassays) in aqueous EDTA solution (100 mM EDTA, 0.4% [w / v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5].
  • aqueous EDTA solution 100 mM EDTA, 0.4% [w / v] bovine serum albumin [BSA] in 25 mM HEPES pH 7.5].
  • the resulting mixture was incubated for 1 h at 22 ° C to allow the formation of a complex of the biotinylated phosphorylated substrate and the detection reagents. Subsequently, the amount of the phosphorylated substrate was evaluated by measuring the resonance energy transfer from europium chelate-labeled anti-mouse IgG antibody to streptavidin-XL665. For this purpose, in a TR-FRET meter, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer), which measured fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm.
  • a TR-FRET meter e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer), which measured fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm.
  • the ratio of emissions at 665 nm and 622 nm was taken as a measure of the amount of phosphorylated substrate.
  • the test substances were tested on the same microtiter plates at 11 different concentrations ranging from 20 ⁇ to 0.073 nM (20 ⁇ , 5.7 ⁇ , 1.6 ⁇ , 0.47 ⁇ , 0.13 ⁇ , 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 nM and 0.073 nM).
  • Serial dilutions were made prior to assay (2 mM to 7.3 nM in 100% DMSO) by serial dilutions.
  • the IC50 values were calculated with a 4-parameter fit.
  • the example compounds show inhibition of IRAK4 kinase activity (see Table 1).
  • Trk-A is important for the development of sympathetic nerves.
  • Patients with a loss-of-function mutation in TrkA develop hereditary sensory and autonomic neuropathy type IV (CIPA, congenital insensitivity to pain and anhidrosis), which is associated with a significant disturbance in the sense of pain and temperature (Indo, Clinical Genetics, 2012).
  • CIPA hereditary sensory and autonomic neuropathy type IV
  • TrkA appears to play a role in the maturation of cholinergic neurons, in thymic development, early ovarian development, and in the development of certain immune cells (Tessarollo, L., Cytokine & Growth Factor Reviews, 1998, Garcia-Suarez, Germana , et al., Journal of Neuroimmunology, 2000; Coppola, Barrick, et al., Development, 2004; Dissen, Garcia-Rudaz, et al., Seminars in Reproductive Medicine, 2009). Due to the mentioned potential functions, the selectivity for TrkA was determined.
  • a recombinant fusion protein consisting of N-terminal His6-tagged GST and a C-terminal fragment of human TrkA (amino acids 443-796 of TrkA Accession Number ⁇ 002520.2) expressed in baculovirus-infected insect cells (Sf9) and purified by affinity chromatography , purchased from ProQinase GmbH, Freiburg (Product No .: 0311-0000-2).
  • As a substrate for the kinase reaction biotinylated poly-Glu, Tyr (4: 1) copolymer from CisBio Bioassays (# 61GT0BLA) was used.
  • the concentration of TrkA was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range (typical final TrkA concentrations in the 5 ⁇ L assay volume were on the order of about 20 pg / ⁇ ).
  • the reaction was stopped by Add 5 ⁇ of a solution of HTRF detection reagents (30 nM streptavidin XL665 (Cisbio Bioassays, France) and 1.4 nM PT66 Eu chelate, a europium chelate-labeled anti-phospho tyrosine antibody from Perkin Elmer (instead of PT66 Eu-chelate also PT66-Tb cryptate from Cisbio Bioassays can be used) in aqueous EDTA solution (100 mM EDTA, 0.2% (w / v) bovine serum albumin (BSA) in 50 mM HEPES / HCl pH 7.0) The resulting mixture was incubated for 1 hour at 22 ° C.
  • HTRF detection reagents 30 nM streptavidin XL665 (Cisbio Bioassays, France) and 1.4 nM PT66 Eu chelate, a europium chelate-labeled anti-
  • the amount of the phosphorylated substrate was evaluated by measuring the resonance energy transfer from PT66-Eu chelate to streptavidin
  • the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in an HTRF measuring device, eg a pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • the ratio of emissions at 665 nm and at 622 nm was taken as a measure of the amount of phosphorylated substrate.
  • test substances were incubated on the same microtiter plates at 11 different concentrations ranging from 20 ⁇ to 0.072 nM (20 ⁇ , 5.7 ⁇ , 1.6 ⁇ , 0.47 ⁇ , 0.13 ⁇ , 38 nM, 11 nM, 3 , 1 nM, 0.89 nM, 0.25 nM and 0.072 nM), the serial dilutions were prepared prior to the assay at the level of 100X concentrated solution [ie 2 mM to 7.2 nM in 100% DMSO] by serial dilutions , the exact concentrations may vary depending on the particular pipettors used) were tested in duplicate for each concentration and IC50 values were calculated with a 4-parameter fit.
  • the example compounds show a high selectivity towards TrkA (see Table 1).
  • Table 1 IC50 values of the example compounds in the IRAK4 and TrkA kinase assay
  • IRAK4 (amino acid 1-460 of IRAK4 accession number NP 057207.2 (Uniport No Q9NWZ3)) was used, available from Carna Biosciences, Japan (product number: 09- 445-20N) was purchased.
  • the biotinylated IRAK4 protein was immobilized using the streptavidin-biotin interaction on an SA Biacore chip (GE Healthcare, product number 29104992).
  • the biotinylated IRAK4 protein in lx HBS-EP + (prepared from 10x HBS-EP + buffer (GE Healthcare, product number BR100669)) was diluted to 5 ⁇ g / ml and then captured on the streptavidin surface of the SA-Biacore chip in the same buffer. This resulted in a signal of about 1000 response units.
  • the reference cell consisted of unsatisfied streptavidin.
  • test substances were diluted to 10 mM in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich, Germany) and then further diluted in running buffer (lx HBS-EP + pH 7.4 [prepared from HBS-EP + buffer 10x (GE Healthcare): 0.1 M HEPES, 1.5 M NaCl, 30mM EDTA and 0.5% v / v detergent P20], 1%> v / v DMSO).
  • running buffer lx HBS-EP + pH 7.4
  • 0.1 M HEPES 1.5 M NaCl
  • 30mM EDTA 0.5% v / v detergent P20
  • 1%> v / v DMSO 1%> v / v DMSO
  • test substances are injected for 80s and then taken up for 1000s dissociation.
  • the resulting grids are referenced twice against a blank and the reference surface and fitted with the Biacore T200 Evaluation Software with the formula stored in the software according to a 1: 1 binding model.
  • the example compounds show a long residence time on IRAK4 (see Table 2).
  • Table 2 Binding kinetics of the example compounds
  • Example Compound 1 showed no evidence of mutagenicity in in vitro MNT, with the substance tested to solubility limit (precipitation).
  • TNF-a tumor necrosis factor-alpha
  • THP-1 cells human monocytic acute leukemia cell line
  • TNF- ⁇ is a cytokine involved in inflammatory processes.
  • the TNF- ⁇ release is triggered in this assay by incubation with bacterial lipopolysaccharide (LPS).
  • LPS bacterial lipopolysaccharide
  • THP-1 cells are supplemented in continuous suspension cell culture [RPMI 1460 medium without L-glutamax (GE Healthcare, cat # E15-039) supplemented with fetal calf serum (FCS) 10% (Invitrogen, Cat # 10082-147 ), 1% L-Glutamine (Sigma, cat # G7513), 1% Penicillin / streptomycin (PAA, cat # PI 1-010) and 50 ⁇ M 2-mercaptoethanol (Gibco, cat # 31350-010)] and should not exceed a cell concentration of 1x106 cells / ml.
  • the assay was carried out in cell culture medium (RPMI 1460 medium supplemented with L-glutamine, penicillin, streptomycin and 2-mercaptoethanol).
  • the THP-1 cells are seeded in 96-well plates with a cell density of 2.5 ⁇ 10 5 cells / well.
  • the compounds of the invention are serially diluted in a constant volume of 100% DMSO and used in the assay at 8 different concentrations ranging from 10 ⁇ to 3 nM so that the final DMSO concentration is 0.4% DMSO.
  • the cells are thus pre-incubated for 30 min before the actual stimulation.
  • stimulation is carried out with 1 ⁇ l of LPS (Sigma, Escherichia coli 0127: B8, Cat. No. L4516) for 6 hours.
  • cells are treated with 1 ⁇ g / ml LPS and 0.04% DMSO and as inhibitor control only with 0.04% DMSO.
  • Determination of cell viability is performed using the CellTiter-Glo Luminescent Assay (Promega, Cat # G7571 (G755 / G756A)) as directed by the manufacturer.
  • the determination of the amount of secreted TNF- ⁇ in the cell culture supernatant is carried out by means of the Human Prolifflammatory 9-Plex Tissue Culture Kit (MSD, Cat. No. K15007B) according to the manufacturer's instructions.
  • the effect of the substances is expressed as the ratio between neutral and inhibitor control in percent.
  • the IC 5 0 values are calculated using a 4-parameter fit.
  • mice Female Balb / c mice (about 8 weeks, Charles River Laboratories, Germany) are injected with IL-1 ⁇ .p. applied and investigated the effect of the compounds of the invention on the IL-l ß -mediated cytokine secretion.
  • the group size is 5 animals each.
  • the control group is treated with the vehicles used to dissolve the substance and IL-1 ⁇ .
  • Each of the substance treatment groups and the positive control group is administered with 90 ⁇ g IL-1 ⁇ / kg body weight (R & D, Cat. No. 401-ML / CF) i.p.
  • the substance or its vehicle in the positive control group is administered 6 hours before IL-1 ß administration.
  • TNF- ⁇ in the plasma after the final blood withdrawal is carried out 2 hours after administration of the IL-1 ß by means of the Mouse Prolnflammatory 7-Plex Tissue Culture Kit (MSD, cat.No K15012B) according to the manufacturer.
  • Both control groups are each treated only with the vehicle of the test substance po.
  • the treatment with different doses of the test substance is carried out preventively, ie from day 0, by oral administration.
  • day 0 the starting situation of the animals with regard to the disease activity score (evaluation of the severity of the arthritis using a scoring system) is also determined.
  • the disease status of the animals is assessed until the end (day 20) from day 8 on which the animals first show signs of arthritis, and subsequently 3 times a week the disease status of the animals by means of disease activity score.
  • Statistical analysis is performed using the one-factorial analysis of variance (ANOVA) and comparison to the control group by multiple comparison analysis (Dunnett test).

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Abstract

La présente invention concerne des 3-méthylindazoles substitués de formule (I), leur procédé de préparation, leur utilisation 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/EP2017/062534 2016-05-31 2017-05-24 3-methylindazoles substitués, leur procédé de préparation, préparations pharmaceutiques les contenant, et leur utilisation pour la production de médicaments Ceased WO2017207385A1 (fr)

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