WO2013041119A1 - N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques - Google Patents

N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques Download PDF

Info

Publication number
WO2013041119A1
WO2013041119A1 PCT/EP2011/066220 EP2011066220W WO2013041119A1 WO 2013041119 A1 WO2013041119 A1 WO 2013041119A1 EP 2011066220 W EP2011066220 W EP 2011066220W WO 2013041119 A1 WO2013041119 A1 WO 2013041119A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
alkyl
series consisting
pyrazin
pyrazolo
Prior art date
Application number
PCT/EP2011/066220
Other languages
English (en)
Inventor
Marc Nazaré
Nis Halland
Friedemann Schmidt
Tilo Weiss
Uwe Dietz
Armin Hofmeister
Original Assignee
Sanofi
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 Sanofi filed Critical Sanofi
Priority to SG11201400551UA priority Critical patent/SG11201400551UA/en
Priority to AU2011377409A priority patent/AU2011377409B2/en
Priority to CA2846369A priority patent/CA2846369C/fr
Priority to KR1020147010212A priority patent/KR20140064975A/ko
Priority to PCT/EP2011/066220 priority patent/WO2013041119A1/fr
Publication of WO2013041119A1 publication Critical patent/WO2013041119A1/fr
Priority to IL231097A priority patent/IL231097A0/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to N-[4-(1 H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]- sulfonamides of the formula I,
  • the compounds of the formula I are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1 , SGK1 ), and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism.
  • the invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.
  • Protein kinases Due to their physiologic importance, variety, and ubiquity, protein kinases have become one of the most important and widely-studied family of enzymes in biochemical and medical research. Currently, there are about 500 different known protein kinases. However, because three to four percent of the human genome is a code for the formation of protein kinases, there may be many thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the gamma-phosphate of the ATP-Mg 2+ complex to said amino acid side chain.
  • the protein kinase family of enzymes is typically classified into two main subfamilies, protein tyrosine kinases, which phosphorylate tyrosine residues, and protein serine/threonine kinases (PSTK), which phosphorylate serine and threonine residues.
  • PSTK subfamily includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium- and phospholipid-dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins.
  • serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and their associated signal transduction pathways are important targets for drug design.
  • Serum and glucocorticoid regulated kinases also designated as serum/glucocorticoid regulated kinase, serum and glucocorticoid induced kinase, serum and glucocorticoid inducible kinase or serum and glucocorticoid dependent kinase, form a family of serine/threonine kinases.
  • serum/glucocorticoid regulated kinase serum and glucocorticoid induced kinase
  • serum and glucocorticoid inducible kinase or serum and glucocorticoid dependent kinase form a family of serine/threonine kinases.
  • SGK-1 serum and glucocorticoid induced kinase
  • SGK-1 was described in 1993 for the first time as an "immediate early genes" in a rat mammary cancer cell line (Webster et al., 1993a; Webster et al., 1993b). At the protein level the three isoforms show a homology of at least 80% in their catalytic domain.
  • SGK-1 is expressed in almost all tissues that have been tested so far, but the amounts of mRNA expressed vary greatly depending on the nature of the studied tissue type (Gonzalez-Robayna et al., 1999; Waldegger et al., 1999; Alliston et al., 2000; Klingel et al., 2000; Lang et al., 2000; Loffing et al., 2001 ; Fillon et al., 2002; Warntges et al., 2002a).
  • SGK-1 mRNA is found in several embryonic tissues.
  • the SGK-1 mRNA shows development- dynamic changes in specific tissues of the embryo (decidua, yolk sac, otic vesicle), and is detectable during the organogenesis in lung buds, brain, heart, liver, thymus, etc. (Lee et al., 2001 ).
  • SGK-2 is expressed with greatest abundance in epithelial tissues, such as in the kidney, liver, pancreas, and specific areas of the brain
  • a distinguishing feature of SGK to many other kinases is based on the stringent stimulus-dependent regulation of transcription, cellular localization and enzymatic activation (Firestone et al., 2003) of the molecule.
  • a variety of stimuli are known. These include mineralocorticoids (Brennan and Fuller, 2000; Shigaev et al., 2000; Bhargava et al., 2001 ), gonadotropins
  • SGK growth-dependent signaling pathways SGK is induced by serum (Webster et al., 1993a), insulin and IGF-1 (Kobayashi and Cohen, 1999; Park et al., 1999; Perrotti et al., 2001 ), FSH (Alliston et al., 1997), Fibroblast and Platelet-derived growth factor (Davies et al., 2000), activators of the Erk signaling cascade (Hayashi et al., 2001 ) and TPA (Mizuno and Nishida, 2001 ).
  • SGK-1 is also known to be activated in pathological changes such as ischemic brain injury (Imaizumi et al., 1994), viral hepatitis (Fillon et al., 2002), pulmonary fibrosis (Warntges et al., 2002b) or cardiac fibrosis (Funder 2001 ).
  • pathological changes such as ischemic brain injury (Imaizumi et al., 1994), viral hepatitis (Fillon et al., 2002), pulmonary fibrosis (Warntges et al., 2002b) or cardiac fibrosis (Funder 2001 ).
  • SGK-1 requires activation by phosphorylation. This is mediated by a signaling cascade involving the
  • the activation of SGK-1 through the PI-3 kinase signaling pathway is known to be a response to insulin, IGF and growth factors.
  • the phosphorylation of two amino acid residues is necessary, threonine 256 on the T-loop and serine 422 at the hydrophobic motif of the protein.
  • Phosphorylation at threonine 256 is mediated by PDK1
  • phosphorylation at serine 422 should be catalyzed by a putative PDK2, which is not yet known (Kobayashi and Cohen, 1999; Park et al., 1999; Biondi et al., 2001 ).
  • ENaC and SGK The interaction of ENaC and SGK is not by direct phosphorylation (Lang et al., 2000), but due to the inactivation of the ubiquitin ligase Nedd4-2 (Debonneville et al., 2001 ; Snyder et al., 2002) as a result of phosphorylation by SGK. As a result, the amount and residence time of ENaC in the cell membrane is increased (Staub et al., 1997; Alvarez de la Rosa et al., 1999; Wagner et al., 2001 ). It has also been shown in a number of experiments that ROMK1 is a molecular target of SGK.
  • ROMK1 is not directly regulated by SGK, but needs the "Na + /H + exchange regulating factor 2" (NHERF2) as an intermediary molecule (Shenolikar and Weinmann, 2001 ; Yun, 2003).
  • NHERF2 Na + /H + exchange regulating factor 2
  • the same mechanism applies to another target molecule of SGK, the Na YH + transporter NHE3 (Yun et al., 2002).
  • SGK influences the Kv1.3 channel-dependent K + current (Gamper et al., 2002; Warntges et al., 2002a).
  • SGK regulates the amino acid transporter SN1 and 42F/LAT (Wagner et al., 2000; Bohmer et al., 2003a, b). SGK-1 has also been shown to play a role in cell proliferation and electrolyte homeostasis (Loffing et al., 2006; McCormick et al., 2005; Vallon et al., 2005; Vallon and Lang, 2005; Lang et al., 2003). SGK-1 is thought to regulate several cellular mechanisms that contribute to disease states. For example, SGK-1 has been shown to mediate fibronectin formation in diabetic nephropathy (Feng et al., 2005).
  • SGK1 has also been shown to mediate insulin, IGF-1 , and aldosterone-induced Na + retention in renal and cardiovascular disease (McCormick et al., 2005; Vallon et al., 2005; Lang et al., 2003).
  • SGK-1 has been shown to be involved in inducing the transcription and procoagulation activity of tissue factor (TF) (BelAiba et al., 2006), and in regulating IGF-1 -mediated cell proliferation (Henke et al., 2004).
  • TF tissue factor
  • Osteoarthritis is one of the most common degenerative joint diseases and leads in an advanced stage to a loss of joint function.
  • the healthy functioning of the adult cartilage is created by its unique biomechanical properties, providing both the resistance against high pressure as well as the necessary elasticity of the tissue.
  • the decisive factor is the special organization of the cartilage tissue. Unlike most other tissues, the cartilage cells are not in direct contact but are embedded separately from each other in an extracellular matrix (ECM).
  • ECM extracellular matrix
  • the macromolecules of this ECM guarantee the viability of the articular cartilage and joints.
  • the basic structure of the ECM consists of a network that is formed by fibrils of collagen types II, IX and XI.
  • Proteoglycans mainly aggrecan, are embedded in the ECM producing an extremely high osmotic water binding capacity. The water pressure generated in connection with the properties of the collagen backbone guarantee the specific properties of the cartilage.
  • a main feature of the pathogenesis of OA is the loss of the ECM of the cartilage and the articular cartilage tissue.
  • the function of the affected joint is restricted by or lost by this mechanism.
  • various symptomatic parameters such as pain appear during symptomatic progression of the disease.
  • Current treatments for osteoarthritis are limited mostly to the alleviation of symptomatic complaints.
  • a causal therapy based on drugs, which leads to the decrease of cartilage degeneration, is not possible to current knowledge. Therefore, there is a considerable need for novel drugs for the prevention and/or therapy of osteoarthritis.
  • SGK-1 The role of SGK-1 in this model of skeletal development and endochondral ossification shows that the natural occurrence of SGK-1 in cartilage is not associated with the synthesis and maintenance of cartilage, but exerts its function in the conversion (hypertrophy) and degradation.
  • the expression of SGK-1 in osteoarthritic cartilage is thus a process that causes or promotes the pathology of OA. Due to its regulatory properties SGK-1 could be a key molecule for the induction of early pathological changes in cartilage as well as for the later degradative activities. Therefore, SGK-1 is a very relevant target for the pharmacological intervention in osteoarthritis.
  • SGK-1 represents a highly relevant target molecule for the development of novel drugs for the treatment of degenerative cartilage changes, especially osteoarthritis.
  • inhibitors of SGK-1 such as the compounds of the present invention can be used in the treatment, including therapy and prophylaxis, of various disease states in which SGK-1 activity plays a role or which are associated with an inappropriate SGK-1 activity, or in which an inhibition, regulation or modulation of signal transduction by SGK-1 is desired by the physician, for example degenerative joint disorders and degenerative cartilage changes including osteoarthritis, osteoarthrosis, rheumatoid arthritis, spondylosis, chondrolysis following joint trauma and prolonged joint immobilization after meniscus or patella injuries or ligament tears, connective tissue disorders such as collagenoses, periodontal disorders, wound-healing disturbances, diabetes including diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy, obesity, metabolic syndrome
  • dislipidaemia systemic and pulmonary hypertension
  • cerebral infarctions cardiovascular diseases including cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriosclerosis, renal diseases including
  • glomerulosclerosis glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte excretion disorder, and any type of fibrosis and inflammatory processes including liver cirrhosis, lung fibrosis, fibrosing pancreatitis, rheumatism, arthritis, gout, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scar formation and Alzheimer's disease.
  • Inhibitors of SGK-1 such as the compounds of the present invention can also be used in the treatment of pain including acute pain like pain following injuries, post-operative pain, pain in association with an acute attack of gout and acute pain following jaw-bone surgery interventions, and chronic pain like pain associated with chronic musculoskeletal diseases, back pain, pain associated with osteoarthritis or rheumatoid arthritis, pain associated with
  • Inhibitors of SGK-1 such as the compounds of the present invention can also be used in tumor therapy for inhibiting the growth of tumor cells and tumor metastases.
  • Inhibitors of SGK-1 such as the compounds of the present invention can also be used for the treatment of chronic disorders of the locomotor system such as inflammatory, immunologically or metabolically related acute and chronic arthritides, arthropathies, myalgias and disturbances of bone metabolism.
  • inhibitors of SGK-1 such as the compounds of the present invention can be used in the treatment of peptic ulcers, especially in forms that are triggered by stress, in the treatment of tinnitus, in the treatment of bacterial infections and in anti-infective therapy, for increasing the learning ability and attention, for counteracting cellular aging and stress and thus increasing life expectancy and fitness in the elderly, in states of neuronal excitability including epilepsy, in the treatment of glaucoma or cataracts, and in the treatment of coagulopathies including dysfibrinogenaemia,
  • hypoproconvertinaemia haemophilia B, Stuart-Prower defect, prothrombin complex deficiency, consumption coagulopathy, fibrinolysis, immunokoagulopathy or complex coagulopathies.
  • the PIF- binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J, 20, 4380-4390.
  • glucocorticoidregulated kinase sgk gene expression by corticosteroids in vivo.
  • Mol Cell Endocrinol 166, 129-136.
  • the serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithlial Na(+) Channel alpha, beta, gamma-EnaC. Pflugers Arch, 445(6), 693-696.
  • IGF-1 up-regulates K+ Channels via PI3-kinase, PDK1 and SGK1 .
  • FSH Follicle-Stimulating hormone
  • BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J Biol Chem 276(12), 8631 - 8634.
  • Sgk a putative serine/threonine kinase, is differentially expressed in the kidney of diabetic mice and humans. J Am Soc Nephral, 10, 2488-2494.
  • SGK1 a rapid aldosterone- induced regulator of renal sodium reabsorption. Physiology (Bethesda), 20, 134-9. Mizuno,H. and Nishida,E. (2001 ).
  • the ERK MAP kinase pathway mediates induction of SGK (serumand glucocorticoid-inducible kinase) by growth factors. Genes Cells, 6, 261 -268.
  • Serum and glucocorticoid-inducible kinase is a target of the PI 3- kinasestimulated signaling pathway. EMBO J, 18, 3024-3033.
  • Ovarian cell differentiation a cascade of multiple hormones, cellular Signals, and regulated genes. Recent Prag Horm Res, 50, 223-254.
  • glucocorticoidregulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ Channel. J Biol Chem, 277, 5-8.
  • glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure. Curr Opin Nephrol Hypertens, 14(1 ), 59-66.
  • the heterodimeric amino acid transporter 4F2hc/LAT1 is associated in Xenopus oocytes with a non-selective cation Channel that is regulated by the serine/threonine kinase sgk-1 . J Physiol, 526(Pt1 ), 35-46.
  • serinethreonine protein kinas[theta] as transcriptional target of p38/MAP kinase pathway in HepG2 human hepatoma cells. Cell Physiol Biochem, 10, 203-208. Waldegger,S., Klingel.K., Barth.P., Sauter,M., Rfer.M.L., Kandolf.R., and Lang,F. (1999). h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine. Gastroenterology, 1 16, 1081 - 1088.
  • SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport. Am J Physiol Renal Physiol, 280, F303- F313.
  • sgk a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol, 13, 2031 -2040.
  • SGK inhibitors which effectively inhibit an aberrant activity of SGK in a pathological context and which have further advantageous properties, for example high bioavailability, stability in plasma and liver, and selectivity versus other kinases and receptors which are not intended to be influenced in an agonistic or antagonistic manner.
  • This object is achieved by providing the novel compounds of the formula I which exhibit excellent SGK-1 inhibitory activity and are favorable agents with high bioavailability and stability in plasma and liver.
  • a subject of the present invention are the compounds of the formula I, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salts thereof,
  • Ar is selected from the series consisting of phenyl and a 5-membered or 6- membered monocyclic aromatic heterocycle comprising 1 , 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10; n is selected from the series consisting of 0, 1 and 2; R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14, -C(0)-N(R16)-R17, -CN, (Ci-C )- alkyl and -(Ci-C 4 )-alkyl-0-R18;
  • R2 is selected from the series consisting of halogen, -(Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl and -CN;
  • R10 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl, (C3-C7)- cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, -0-(Ci-C )-alkyl, -0-(C 3 -C 7 )-cycloalkyl, -0-(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl-, -N(R19)-R20, -N(R21 )-N(R19)-R20, -N(R21 )- C(0)-R22, -NO2, -C(0)-N(R23)-R24 and -CN, and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 8-membered unsaturated ring which comprises 0, 1
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl, (C3-C 7 )-cycloalkyl and -(Ci-C 4 )-alkyl-(C3-C 7 )-cycloalkyl, or R1 1 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R1 1 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C 7 )- cycloalkyl;
  • R14 and R15 are independently of one another selected from the series consisting of (Ci-Ce)-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, -(Ci-C 4 )- alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R16 is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C 7 )- cycloalkyl
  • R17 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C3-C 7 )- cycloalkyl, -(Ci-C 4 )-alkyl-(C3-C 7 )-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30, or R16 and R17, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from
  • R18 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R19 is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C 7 )- cycloalkyl;
  • R20 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C3-C 7 )- cycloalkyl, -(Ci-C 4 )-alkyl-(C3-C 7 )-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30, or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of flu
  • R21 is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C7)- cycloalkyl;
  • R22 is selected from the series consisting of (Ci-C 4 )-alkyl, (C3-C7)-cycloalkyl and -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl;
  • R23 and R24 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R30 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl and -CN;
  • Het is a monocyclic, 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
  • dialkylamino group for example, the alkyl groups can be identical or different.
  • Alkyl groups i.e. saturated hydrocarbon residues, can be linear (straight-chain) or branched. This also applies if these groups are substituted or are part of another group, for example an -O-alkyl group (alkyloxy group, alkoxy group) or an HO- substituted alkyl group (-alkyl-OH, hydroxyalkyl group).
  • the number of carbon atoms in an alkyl group can be 1 , 2, 3, 4, 5, 6, 7 or 8, 1 , 2, 3, 4, 5 or 6, or 1 , 2, 3 or 4, or 1 , 2 or 3, or 1 or 2, or 1 .
  • alkyl examples include methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec- butyl, isobutyl and tert-butyl, pentyl including n-pentyl, 1 -methylbutyl, isopentyl, neopentyl and tert-pentyl, hexyl including n-hexyl, 2,2,-dimethylhexyl, 3,3- dimethylbutyl, 2-methylpentyl, 3-methylpentyl and isohexyl, heptyl including n-heptyl, and octyl including n-octyl.
  • -O-alkyl groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy.
  • a substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound.
  • An alkyl group which, independently of any other substituents, can be substituted by one or more fluorine substituents, can be unsubstituted by fluorine substituents, i.e.
  • fluorine substituents not carry fluorine substituents, or substituted, for example by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 fluorine substituents, or by 1 , 2, 3, 4 or 5 fluorine substituents, or by 1 , 2 or 3 fluorine substituents, which can be located in any positions.
  • fluorine substituents for example, in a fluoro- substituted alkyl group one or more methyl groups can carry three fluorine
  • substituents each and be present as trifluoromethyl groups, and/or one or more methylene groups (CH 2 ) can carry two fluorine substituents each and be present as difluoromethylene groups.
  • the explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group, for example of an -O-alkyl group.
  • fluoro- substituted alkyl groups are -CF 3 (trifluoromethyl), -CHF 2 , -CH 2 F, -CHF-CF 3 , -CHF- CHF 2 , -CHF-CH2F, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CF2-CF3, -CF2-CHF2, -CF 2 - CH 2 F, -CH2-CHF-CF3, -CH2-CHF-CHF2, -CH2-CHF-CH2F, -CH2-CH2-CF3, -CH2-CH2- CHF 2 , -CH2-CH2-CH2F, -CH2-CF2-CF3, -CH2-CF2-CHF2, -CH2-CF2-CH2F, -CHF-CHF-CF 3 , -CHF-CHF-CHF2, -CHF-CHF-CH2F, -CHF-CH2F, -CHF-CH2-CF3, -CHF-CH2-CH
  • fluoro-substituted -O-alkyl groups are trifluoromethoxy (-OCF3), 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.
  • groups or substituents in the compounds of the formula I which can be an alkyl group which can generally contain one or more fluorine substituents as an example of groups or substituents containing fluorine- substituted alkyl which may be included in the definition of the group or substituent, the group CF 3 (trifluoromethyl), or a respective group such as CF3-O-, may be mentioned.
  • alkyl groups which in the definition of a group in the compounds of the formula I are bonded to two adjacent groups, or linked to two groups, and may be regarded as divalent alkyl groups (alkanediyl groups), like in the case of the alkyl part of a substituted alkyl group.
  • alkyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be unsubstituted or substituted by fluorine substituents independently of any other substituents.
  • divalent alkyl groups are -CH 2 -, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2- CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -C(CH 3 ) 2 -CH 2 -, -CH2-C(CH 3 )2-.
  • fluoro-substituted alkanediyl groups which can contain 1 , 2, 3, 4, 5 or 6 fluorine substituents, or 1 , 2, 3 or 4 fluorine substituents, or 1 or 2 fluorine substituents, for example, are -CF 2 -, -CHF-, -CHF-CHF 2 -, -CHF-CHF-, -CH 2 - CF 2 -, -CH2-CHF-, -CF2-CF2-, -CF2-CHF-, -CH2-CHF-CF2-, -CH2-CHF-CHF-, -CH2- CH2-CF2-, -CH2-CH2-CHF, -CH2-CF2-CF2-, -CH2-CF2-CHF-, -CHF-CHF-CF2-, -CHF- CHF-CHF-, -CHF-CH2-CF2-, -CHF-CH2-CH2-, -CHF-CH2-CH2-, -CHF-CHF-CH
  • the number of ring carbon atoms in a (C3-C7)-cycloalkyl group can be 3, 4, 5, 6 or 7.
  • Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkyl which, independently of any other substituents, can be substituted by one or more (Ci-C 4 )-alkyl substituents, can be unsubstituted by alkyl substituents, i.e.
  • alkyl substituents not carry alkyl substituents, or substituted, for example by 1 , 2, 3 or 4 identical or different (Ci-C 4 )-alkyl substituents, for example by methyl groups, which substituents can be located in any positions.
  • alkyl-substituted cycloalkyl groups are 1 -methylcyclopropyl, 2,2-dimethylcyclopropyl, 1 - methylcyclopentyl, 2,3-dimethylcyclopentyl, 1 -methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl.
  • Cycloalkyl groups which, independently of any other substituents, can be substituted by one or more fluorine substituents, can be unsubstituted by fluorine substituents, i.e. not carry fluorine substituents, or substituted, for example by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 fluorine substituents, or by 1 , 2, 3, 4, 5 or 6 fluorine substituents, or by 1 , 2 or 3 fluorine substituents.
  • the fluorine substituents can be located in any positions of the cycloalkyl group and can also be located in an alkyl substituent.
  • fluoro-substituted cycloalkyl groups are 1 -fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-difluorocyclobutyl, 1 -fluorocyclohexyl, 4,4-difluorocyclohexyl, 3,3,4,4,5,5- hexafluorocyclohexyl. Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl.
  • Examples of the group -(Ci-C 4 )-alkyl-(C3-C7)-cycloalkyl are cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1 -cyclopropylethyl-, 2-cyclopropylethyl-, 1 -cyclobutylethyl-, 2- cyclobutylethyl-, 1 -cyclopentylethyl- 2-cyclopentylethyl-, 1 -cyclohexylethyl-, 2- cyclohexylethyl-, 1 -cycloheptylethyl-, 2-cycloheptylethyl-.
  • a -(Ci-C 4 )-alkyl-(C3-C7)-cycloalkyl group in any one or more occurrences of such a group, independently of any other occurrences, is a -(Ci-C2)-alkyl-(C3-C7)- cycloalkyl group, in another embodiment a -CH 2 -(C3-C7)-cycloalkyl group.
  • the terminal hyphen denotes the free bond via which the group is bonded, and thus indicates via which subgroup a group composed of subgroups is bonded.
  • substituted phenyl groups including phenyl groups representing Ar, the
  • substituents can be located in any positions. In monosubstituted phenyl groups, the substituent can be located in position 2, in position 3 or in position 4. In disubstituted phenyl groups, the substituents can be located in positions 2 and 3, in positions 2 and 4, in positions 2 and 5, in positions 2 and 6, in positions 3 and 4, or in positions 3 and 5. In trisubstituted phenyl groups, the substituents can be located in positions 2, 3 and 4, in positions 2, 3 and 5, in positions 2, 3 and 6, in positions 2, 4 and 5, in positions 2, 4 and 6, or in positions 3, 4 and 5.
  • a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in positions 2, 3, 4 and 5, in positions 2, 3, 4 and 6, or in positions 2, 3, 5 and 6.
  • substituents can be located in any suitable position, and the present invention comprises all positional isomers.
  • the number of substituents in a substituted phenyl group can be 1 , 2, 3, 4 or 5.
  • the number of substituents in a substituted phenyl group like the number of substituents in any other substituted group which can carry one or more substituents, for example the group Het, is 1 , 2, 3 or 4, in another embodiment 1 , 2 or 3, in another embodiment 1 or 2, in another embodiment 1 , where the number of substituents in any occurrence of such a substituted group is independent of the number of substituents in other occurrences.
  • heterocyclic groups including the group Het, heterocycles representing Ar and other heterocyclic rings which can be present in the compounds of the formula I, such as rings formed by two group together with the atom or atoms carrying them
  • the hetero ring members can be present in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are suitable and sufficiently stable as a pharmaceutical active compound.
  • two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be present in adjacent ring positions.
  • two hetero ring members selected from the series consisting of oxygen atoms and sulfur atoms cannot be present in adjacent ring positions in any heterocyclic ring in the compounds of the formula I.
  • two hetero ring members selected from the series consisting of nitrogen atoms carrying an exocyclic group like a hydrogen atom or a substituent, sulfur atoms and oxygen atoms cannot be present in adjacent ring positions in any heterocyclic ring in the compounds of the formula I.
  • the choice of hetero ring members in an aromatic heterocyclic ring is limited by the prerequisite that the ring is aromatic, i.e. it comprises a cyclic system of six delocalized pi electrons.
  • Monocyclic aromatic heterocycles are 5-membered or 6-membered rings and, in the case of a 5-membered ring, comprise one ring heteroatom selected from the series consisting of oxygen, sulfur and nitrogen, wherein this ring nitrogen carries an exocyclic group like a hydrogen atom or a substituent, and optionally one or more further ring nitrogen atoms, and, in the case of a 6-membered ring, comprise one or more nitrogen atoms as ring heteroatoms, but no oxygen atoms and sulfur atoms as ring heteroatoms.
  • Heterocyclic groups in the compounds of the formula I are bonded via a ring carbon atom or a ring nitrogen atom, as specified in the definition of the respective group, where a heterocyclic group can be bonded via any suitable carbon atom or nitrogen atom, respectively, in the ring.
  • the substituents can be located in any positions.
  • heterocyclic ring systems from which heterocyclic groups in the compounds of the formula I including the bicyclic heterocyclic ring system which can result in case two groups R10 bonded to adjacent ring carbon atoms in Ar together with the carbon atoms carrying them form a ring, can be derived, and from any one or more of which any of the heterocyclic groups in the compounds of the formula I is selected in one embodiment of the invention, provided that the ring system is comprised by the definition of the group, oxetane, thietane, azetidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, pyrrole, pyrroline, pyrrolidine, 1 ,3- dioxole, 1 ,3-dioxolane, isoxazole ([1 ,2]oxazole), isoxazoline, isoxazolidine, oxazole ([1 ,3]oxazo
  • heterocyclic groups can be bonded via any suitable ring atom as specified in the definition of the respective group in the compound of the formula I.
  • an oxetane and a thietane ring be bonded via positions 2 and 3, an azetidine ring via positions 1 , 2 and 3, a furan ring, a
  • Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention, halogen is in any of its occurrences fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine, in another embodiment chlorine, where all occurrences of halogen are independent of each other.
  • the present invention comprises all stereoisomeric forms of the compounds of the formula I, for example all enantiomers and diastereomers including cis/trans isomers.
  • the invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in all ratios.
  • Asymmetric centers contained in the compounds of the formula I can all independently of each other have S configuration or R configuration.
  • the invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in enantiomerically pure form and essentially enantiomerically pure form, and in the form of their racemate, i.e.
  • the invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in all ratios.
  • the invention also comprises all cis/trans isomers of the compounds of the formula I in pure form and essentially pure form, and in the form of mixtures of the cis isomer and the trans isomer in all ratios. Cis/trans isomerism can occur in substituted rings.
  • preparation of individual stereoisomers can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemical ⁇ uniform starting compounds in the synthesis, or by stereoselective reactions.
  • a derivatization can be carried out before a separation of stereoisomers .
  • the separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course of the synthesis.
  • the individual enantiomers can be prepared by preparing the racemate of the compound of the formula I and resolving it into the enantiomers by high pressure liquid
  • the invention also comprises all tautomeric forms of the compounds of the formula I. Besides the free compounds of the formula I, i.e.
  • the present invention comprises also the physiologically or toxicologically acceptable salts of the compounds of the formula I, especially their pharmaceutically acceptable salts, which can be formed on one or more acidic or basic groups in the compounds of the formula I, for example on basic heterocyclic moieties.
  • the compounds of the formula I may thus be
  • salts can in general be prepared from acidic and basic compounds of the formula I by reaction with an acid or base in a solvent or diluent according to customary procedures.
  • the invention also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned.
  • the present invention also comprises all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.
  • an aromatic heterocycle representing the group Ar comprises 1 or 2 identical or different ring heteroatoms, in another embodiment 1 or 2 identical or different ring heteroatoms which are selected from the series consisting of nitrogen and sulfur.
  • an aromatic heterocycle representing Ar is a 5-membered heterocycle which comprises 1 or 2 identical or different ring heteroatoms which are selected from the series consisting of nitrogen and sulfur, or it is a 6-membered heterocycle which comprises 1 or 2 ring heteroatoms which are nitrogen atoms, in another embodiment it is a 5-membered heterocycle which comprises 1 or 2 identical or different ring heteroatoms which are selected from the series consisting of nitrogen and sulfur.
  • an aromatic heterocycle representing Ar is selected from the series consisting of thiophene, thiazole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine and pyrazine, in another embodiment from the series consisting of thiophene, thiazole, pyrazole, imidazole and pyridine, in another embodiment from the series consisting of thiophene, thiazole, pyrazole and imidazole, in another embodiment from the series consisting of thiophene and pyrazole, in another embodiment it is thiophene, and in another embodiment it is pyrazole, which heterocycles are all unsubstituted or substituted by one or more substituents R10.
  • Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R10, in another embodiment Ar is phenyl which is substituted by one or more identical or different substituents R10, in another embodiment Ar is a 5- membered or 6-membered aromatic heterocycle which is unsubstituted or substituted by one or more identical or different substituents R10, and in another embodiment Ar is a 5-membered or 6-membered aromatic heterocycle which is substituted by one or more identical or different substituents R10.
  • the number of identical or different substituents R10 which can be present in the group Ar is 1 , 2, 3 or 4, in another embodiment it is 1 , 2 or 3, in another embodiment it is 1 or 2, in another embodiment it is 1 , in another embodiment it 2, 3 or 4, in another embodiment it is 2 or 3, in another embodiment it is 3, in another embodiment it is 2.
  • Ar is substituted by one or more identical or different
  • the number n is selected from the series consisting of 0 and 1 , in another embodiment from the series consisting of 1 and 2, in another embodiment it is 1 , in another embodiment it is 0.
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)-R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH- R14, (Ci-C 4 )-alkyl and -(Ci-C 4 )-alkyl-0-R18, in another embodiment from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)-R14, -N(R13)-S(0) 2 - R15, -N(R13)-C(0)-NH-R14, -C(0)-N(R16)-R17, -CN and (Ci-C )-alkyl, in another embodiment from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -
  • R2 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl and -CN, in another embodiment from the series consisting of halogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of halogen and -CN, in another embodiment from the series consisting of halogen.
  • a (Ci-C 4 )-alkyl group present in R2 is a methyl group.
  • halogen representing R2 is selected from the series consisting of fluorine and chlorine, in another embodiment it is fluorine. Ring carbon atoms in the divalent phenyl group depicted in formula I which have a free binding site, i.e. are not bonded to adjacent groups in formula I, and which do not carry a group R2, carry hydrogen atoms, as does likewise the carbon atom in position 5 of the
  • n 2 and hence two groups R2 are present, two of the four carbon atoms in the ring positions of the divalent phenyl group depicted in formula I which in formula ⁇ are designated as positions 2', 3', 5' and 6', carry the groups R2 and the other two said carbon atoms carry hydrogen atoms.
  • Groups R2 can be present in any positions of the divalent phenyl group depicted in formula I which have a free binding site. If one group R2 is present, in one
  • the group R2 is present in the position which is formula ⁇ is designated as position 2', which is equivalent to position 6', and in another embodiment it is present in the position which in formula ⁇ is designated as position 3', which is equivalent to position 5'. If two groups R2 are present, in one
  • the groups R2 are present in the positions which in formula ⁇ are designated as positions 2' and 3', in another embodiment in the positions which in formula ⁇ are designated as positions 2' and 5', in another embodiment in the positions which in formula ⁇ are designated as positions 2' and 6', in another embodiment in the positions which in formula ⁇ are designated as positions 3' and 5'.
  • this ring is at least mono-unsaturated, i.e., the resulting ring contains at least one double bond within the ring, which double bond is present between the said two adjacent ring carbon in the aromatic ring Ar which are common to the ring Ar and the ring formed by the two groups R10, and because of the rules of nomenclature for fused rings is regarded as a double bond present in both rings.
  • the ring formed by two groups R10 together with the carbon atoms carrying them can contain 1 , 2 or 3 double bonds within the ring.
  • the formed ring contains 1 or 2 double bonds, in another embodiment 1 double bond within the ring.
  • the formed ring can be aromatic and, together with the aromatic ring Ar, form a bicyclic aromatic ring system, for example a naphthalene ring system, a quinoline ring system, an isoquinoline ring system or a benzothiophene ring system.
  • the ring heteroatoms which are optionally present in a ring formed by two groups R10 bonded to adjacent ring carbon atoms in Ar together with the carbon atoms carrying them, are selected from the series consisting of nitrogen and oxygen, in another
  • the ring which can be formed by two groups R10 bonded to adjacent ring carbon atoms in Ar together with the ring carbon atoms carrying them, is a 5-membered to 7-membered, in another embodiment a 5-membered to 6-membered, in another embodiment a 6- membered to 7-membered, in another embodiment a 5-membered, in another embodiment a 6-membered ring, in another embodiment a 7-membered ring.
  • the ring which can be formed by two groups R10 bonded to adjacent carbon atoms in Ar together with the carbon atoms carrying them comprises 0 ring heteroatoms, i.e. it is a carbocyclic ring, and in another embodiment it comprises 1 or 2 identical or different ring heteroatoms.
  • the number of substituents which can be present in a ring formed by two groups R10 bonded to adjacent ring carbon atoms in Ar together with the carbon atoms carrying them is 1 , 2, 3 or 4, in another embodiment 1 , 2 or 3, in another embodiment 1 or 2, in another embodiment 1 , in another embodiment it is 0.
  • substituents which can be present in a ring formed by two groups R10 bonded to adjacent ring carbon atoms in Ar together with the carbon atoms carrying them are selected from the series consisting of halogen, (Ci-C 4 )-alkyl and -CN, in another embodiment from the series consisting of halogen and (Ci-C 4 )-alkyl, and in another embodiment are substituents in such a ring bonded to a ring nitrogen atom selected from the series consisting of (Ci-C 4 )-alkyl.
  • R10 is selected from the series consisting of halogen, (Ci-C )-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, -0-(Ci- C )-alkyl, -0-(C 3 -C 7 )-cycloalkyl, -0-(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl-, -N(R19)-R20, -N(R21 )-N(R19)-R20, -N(R21 )-C(0)-R22, -N0 2 and -CN, in another embodiment from the series consisting of halogen, (Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl, -N(R19)-R20, -N(R21 )-
  • R10 is selected from the series consisting of halogen, (Ci-C 4 )- alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, -0-(Ci-C )-alkyl, -0-(C 3 - C 7 )-cycloalkyl, -0-(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl-, -N(R19)-R20, -N(R21 )-N(R19)- R20, -N(R21 )-C(0)-R22, -N0 2 , -C(0)-N(R23)-R24 and -CN, in another embodiment from the series consisting of halogen, (Ci-C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, in another embodiment from
  • substituents R10 which are bonded to a ring nitrogen atom in Ar are selected from the series consisting of (Ci-C 4 )-alkyl, (C3-C7)-cycloalkyl, -(Ci-C 4 )-alkyl- (C3-C7)-cycloalkyl and -C(0)-N(R23)-R24, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, (C3-C7)-cycloalkyl and -(Ci-C 4 )-alkyl-(C3-C7)-cycloalkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl.
  • a (Ci-C 4 )-alkyl group which represents R10 or is present in the group -0-(Ci-C 4 )-alkyl representing R10 is a (Ci-C3)-alkyl group, in another embodiment a (Ci-C2)-alkyl group, in another embodiment a methyl group, where all these alkyl groups can optionally be substituted by fluorine substituents as applies to alkyl groups in general, and also occur as a trifluoromethyl group, for example.
  • a (C3-C7)-cycloalkyl group which represents R10 or is present in a group R10 is a (C3-C6)-cycloalkyl group, in another embodiment a (C3-C 4 )-cycloalkyl group, in another embodiment a cyclopropyl group.
  • the total number of -NO2 (nitro) groups is a (C3-C7)-cycloalkyl group which represents R10 or is present in a group R10, is a (C3-C6)-cycloalkyl group, in another embodiment a (C3-C 4 )-cycloalkyl group, in another embodiment a cyclopropyl group.
  • R10 in a compound of the formula I is not greater than 2, in another embodiment it is not greater than 1.
  • groups Ar including the optional substituents R10 on Ar are 2,3-dichloro- phenyl, 2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl, 2-fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl, 2,5- dichloro-thiophen-3-yl, 8-chloro-3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-7-yl, 5-chloro- 1 ,3-dimethyl-pyrazol-4-yl, naphthalen-1 -yl, 2,4,6-trichloro-phenyl, 5-chloro-2-fluor
  • the monocyclic heterocycle which can be formed by the groups R1 1 and R12 together with the nitrogen atom carrying them, which heterocycle is thus bonded via a ring nitrogen atom, can be 4-membered, 5-membered, 6-membered or 7- membered.
  • the heterocycle formed by the groups R1 1 and R12 together with the nitrogen atom carrying them is 4-membered to 6-membered, in another embodiment it is 5-membered or 6-membered, in another embodiment it is 6-membered.
  • the further ring heteroatom which is optionally present in a heterocycle formed by the groups R1 1 and R12 together with the nitrogen atom carrying them, is selected from the series consisting of nitrogen and oxygen, in another embodiment it is a nitrogen atom, and in another embodiment it is an oxygen atom, and in another embodiment no further ring heteroatom is present.
  • substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl, which can be present in a ring formed by the groups R1 1 and R12 together with the nitrogen atom carrying them, is 1 , 2 or 3, in another embodiment 1 or 2, in another embodiment 1 .
  • substituents which can be present in a ring formed by the groups R1 1 and R12 together with the nitrogen atom carrying them are fluorine substituents, and in another embodiment they are (Ci-C 4 )- alkyl substituents, for example methyl substituents, and in another embodiment are substituents in such a ring bonded to a ring nitrogen atom selected from the series consisting of (Ci-C 4 )-alkyl.
  • heterocyclic groups from any one or more of which the heterocyclic groups formed by the groups R1 1 and R12 together with the nitrogen atom carrying them is selected in one embodiment of the invention, are azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, and 4- methylpiperazin-1 -yl.
  • one of the groups R1 1 and R12 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, and the other is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl, (C3-C7)-cycloalkyl and -(Ci-C 4 )-alkyl-(C3- C7)-cycloalkyl, in another embodiment R1 1 and R12 are independently of one another selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C7)- cycloalkyl, in another embodiment from the series consisting of hydrogen and (C-i- C 4 )-alkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, and in another embodiment they are hydrogen, i.e., in this latter embodiment the
  • group -N(R1 1 )-R12 representing R1 is the group -NH 2 (amino), or in all these embodiments R1 1 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R1 1 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl.
  • one of the groups R1 1 and R12 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, and the other is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl, (C3-C7)-cycloalkyl and -(Ci-C 4 )-alkyl-(C3- C7)-cycloalkyl,
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl and (C3-C7)- cycloalkyl, in another embodiment from the series consisting of hydrogen and (C-i- C 4 )-alkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, and in another embodiment R1 1 and R12 are hydrogen.
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R13 is hydrogen.
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl- phenyl, Het and -(Ci-C 4 )-alkyl-Het, in anther embodiment from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl and Het, in another embodiment from the series consisting of (Ci-C8)-alkyl, (C3-C7)-cycloalkyl, -(Ci-C 4 )-alkyl-(C3-C7)- cycloalkyl, -(Ci-C 4 )-alkyl-phenyl and -(Ci-C 4 )-alkyl-Het, in another embodiment from the series consisting of phenyl and Het, and in another embodiment are
  • the monocyclic ring which can be formed by R16 and R17 together with the nitrogen atom carrying them applies correspondingly to the monocyclic ring which can be formed by R16 and R17 together with the nitrogen atom carrying them.
  • the ring which can be formed by the groups R16 and R17 together with the nitrogen atom carrying them, which heterocycle is thus bonded via a ring nitrogen atom can be 4-membered, 5-membered, 6-membered or 7-membered.
  • the further ring heteroatom which is optionally present in a heterocycle formed by the groups R16 and R17 together with the nitrogen atom carrying them is selected from the series consisting of nitrogen and oxygen, in another embodiment it is a nitrogen atom, and in another embodiment it is an oxygen atom, and in another embodiment no further ring heteroatom is present.
  • substituents in a ring formed by the groups R16 and R17 together with the nitrogen atom carrying them, which are bonded to a ring nitrogen atom are, selected from the series consisting of (Ci-C 4 )-alkyl.
  • heterocyclic groups from any one or more of which the heterocyclic groups formed by the groups R16 and R17 together with the nitrogen atom carrying them is selected in one embodiment of the invention, likewise are azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, and 4-methylpiperazin-1 -yl.
  • R16 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R16 is hydrogen, and in one embodiment R17 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, -(Ci-C )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, in another embodiment from the series consisting of hydrogen, (Ci-C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C
  • R16 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (Ci-C 3 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R16 is hydrogen, and in one embodiment R17 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, -(Ci-C )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, in another embodiment from the series consisting of hydrogen, (Ci-C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -
  • a (Ci-Cs)-alkyl group representing R17 is (C-i- C 4 )-alkyl, in another embodiment (Ci-C3)-alkyl, in another embodiment (Ci-C2)-alkyl, in another embodiment methyl.
  • R18 is selected from the series consisting of hydrogen and (Ci-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, in another embodiment R18 is hydrogen, in another
  • R18 is selected from the series consisting (Ci-C 4 )-alkyl, in another embodiment from the series consisting of (Ci-C2)-alkyl, and in another embodiment R18 is methyl.
  • the monocyclic ring which can be formed by R19 and R20 together with the nitrogen atom carrying them applies correspondingly to the monocyclic ring which can be formed by R19 and R20 together with the nitrogen atom carrying them.
  • the ring which can be formed by the groups R19 and R20 together with the nitrogen atom carrying them, which heterocycle is thus bonded via a ring nitrogen atom can be 4-membered, 5-membered, 6-membered or 7-membered.
  • the further ring heteroatom which is optionally present in a heterocycle formed by the groups R19 and R20 together with the nitrogen atom carrying them is selected from the series consisting of nitrogen and oxygen, in another embodiment it is a nitrogen atom, and in another embodiment it is an oxygen atom, and in another embodiment no further ring heteroatom is present.
  • substituents in a ring formed by the groups R19 and R20 together with the nitrogen atom carrying them, which are bonded to a ring nitrogen atom are, selected from the series consisting of (Ci-C 4 )-alkyl.
  • heterocyclic groups from any one or more of which the heterocyclic groups formed by the groups R19 and R20 together with the nitrogen atom carrying them is selected in one embodiment of the invention, likewise are azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, thiomorpholin-4-yl, and 4-methylpiperazin-1 -yl.
  • R19 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the serious consisting of hydrogen and (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R19 is hydrogen, and in one embodiment R20 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, -(Ci-C )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, in another embodiment from the series consisting of hydrogen, (Ci-C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )
  • R19 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the serious consisting of hydrogen and (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R19 is hydrogen, and in one embodiment R20 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, -(Ci-C )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, in another embodiment from the series consisting of hydrogen, (Ci-C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, -(Ci-C )-alkyl-(C 3 -C 7 )
  • a (Ci-Cs)-alkyl group representing R20 is (C-i- C 4 )-alkyl, in another embodiment (Ci-C 3 )-alkyl, in another embodiment (Ci-C2)-alkyl, in another embodiment methyl.
  • R21 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of hydrogen and (Ci-C 3 )-alkyl, in another embodiment from the series consisting of hydrogen and methyl, in another embodiment R21 is hydrogen, and in another embodiment R21 is methyl.
  • R22 is selected from the series consisting of (C-i- C 4 )-alkyl, (C3-C6)-cycloalkyl and -(Ci-C2)-alkyl-(C3-C6)-cycloalkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl and (C3-C6)-cycloalkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl and -(Ci-C2)-alkyl- (C3-C6)-cycloalkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl, in another embodiment from the series consisting of (Ci-C3)-alkyl, and in another embodiment R22 is methyl.
  • R23 and R24 are independently of one another selected from the series consisting of hydrogen and (Ci-C3)-alkyl, in another embodiment from the series consisting of hydrogen and (Ci-C2)-alkyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment R23 and R24 are hydrogen.
  • R30 is in any of its occurrences, independently of its other occurrences, selected from the series consisting of halogen, (Ci-C 4 )-alkyl and -CN; in another embodiment from the series consisting of halogen, (Ci-C 4 )-alkyl and -0-(Ci-C 4 )-alkyl, in another embodiment from the series consisting of halogen and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of halogen and -CN, in another embodiment from the series consisting of halogen.
  • a group R30 which is bonded to ring nitrogen atom in a group Het is selected from the series consisting of (Ci-C 4 )-alkyl.
  • a (Ci-C 4 )- alkyl group representing R30 or occurring in R30 is in any occurrence of R30, independently of other occurrences, selected from (Ci-C3)-alkyl, in another embodiment from (Ci-C2)-alkyl, and in another embodiment it is methyl.
  • the monocyclic group Het can be 4-membered, 5-membered, 6-membered or 7- membered.
  • Het is in any of its occurrences, independently of its other occurrences, 4-membered, 5-membered or 6-membered, in another embodiment 5-membered or 6-membered, in another embodiment 5- membered, in another embodiment 6-membered, in another embodiment 5- membered, 6-membered or 7-membered.
  • Het is in any of its occurrences, independently of its other occurrences, a saturated or partially saturated heterocycle, in another embodiment a saturated heterocycle, in another embodiment a saturated or aromatic heterocycle, in another embodiment an aromatic heterocycle.
  • the ring heteroatoms in a heterocycle Het which is saturated or partially unsaturated are selected from the series consisting of nitrogen and oxygen, in another embodiment from the series consisting of oxygen and sulfur.
  • the ring heteroatoms in a heterocycle Het which is aromatic are selected from the series consisting of nitrogen and sulfur.
  • Het comprises in any of its occurrences, independently of its other occurrences, 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur.
  • Examples of groups from any one or more which Het is in any of its occurrences, independently of any other occurrence, selected in one embodiment of the invention, are oxetanyl including oxetan-2-yl and oxetan-3-yl, tetrahydrofuranyl including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydropyranyl including
  • tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl oxepanyl including oxepan-2-yl, oxepan-3-yl and oxepan-4-yl, azetidinyl including azetidin-2-yl and azetidin-3-yl, pyrrolidinyl including pyrrolidin-2-yl and pyrrolidin-3-yl, piperidinyl including piperidin-2-yl, piperidin-3-yl and piperidin-4-yl, azepanyl including azepan-2- yl, azepan-3-yl and azepan-4-yl, morpholinyl including morpholin-2-yl and morpholin- 3-yl, thiomorpholinyl including thiomorpholin-2-yl and thiomorpholin-3-yl, piperaziny
  • a subject of the invention are all compounds of the formula I wherein any one or more structural elements such as groups, residues, substituents and numbers are defined as in any of the specified embodiments or definitions of the elements, or have one or more of the specific meanings which are mentioned herein as examples of elements, wherein all combinations of one or more definitions of compounds or elements and/or specified embodiments and/or specific meanings of elements are a subject of the present invention. Also with respect to all such compounds of the formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their pharmaceutically acceptable salts are a subject of the present invention.
  • Ar is selected from the series consisting of phenyl and a 5-membered or 6- membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10; n is selected from the series consisting of 0, 1 and 2;
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14, (Ci-C 4 )-alkyl and -(Ci-C )-alkyl-0- R18;
  • R2 is selected from the series consisting of halogen, -(Ci-C 4 )-alkyl and -CN;
  • R10 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl, -N(R19)-R20, -N(R21 )-N(R19)-R20, -N(R21 )-C(0)-R22, -N0 2 , -C(0)-N(R23)-R24 and -CN, and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, -(Ci-C 4 )-alkyl and -CN;
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, or R1 1 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R1 1 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R18 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R19 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R20 is selected from the series consisting of hydrogen, (Ci-C8)-alkyl, (C3-C7)- cycloalkyl and -(Ci-C 4 )-alkyl-(C3-C7)-cycloalkyl; or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; R21 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R22 is selected from the series consisting of (Ci-C 4 )-alkyl and (C3-C7)-cycloalkyl;
  • R23 and R24 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R30 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl and -CN;
  • Het is a monocyclic, 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salt thereof.
  • Ar is selected from the series consisting of phenyl and a 5-membered or 6- membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10;
  • n is selected from the series consisting of 0 and 1 ;
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14 and (Ci-C 4 )-alkyl;
  • R2 is selected from the series consisting of halogen and -(Ci-C 4 )-alkyl
  • R10 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl, -N(R19)-R20, -N(R21 )-N(R19)-R20, -N(R21 )-C(0)-R22, -N0 2 and -CN, and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen and -(Ci-C 4 )-alkyl;
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl, or R1 1 and R12, together with the nitrogen atom carrying them, form a monocyclic, 5-membered or 6-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R1 1 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R19 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R20 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R21 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R22 is selected from the series consisting of (Ci-C 4 )-alkyl
  • R30 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl and -CN;
  • Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salt thereof.
  • compounds of the formula I may be mentioned, wherein
  • Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R10; n is selected from the series consisting of 0 and 1 ;
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14 and (Ci-C 4 )-alkyl;
  • R2 is selected from the series consisting of halogen and -(Ci-C 4 )-alkyl;
  • R10 is selected from the series consisting of halogen, (Ci-C 4 )-alkyl, -0-(Ci-C 4 )-alkyl, -N(R19)-R20, -N(R21 )-N(R19)-R20, -N(R21 )-C(0)-R22, -N0 2 and -CN, and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 oxygen atoms as ring heteroatoms, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen and -(Ci-C 4 )-alkyl;
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R19 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R20 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R21 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R22 is selected from the series consisting of (Ci-C 4 )-alkyl
  • R30 is selected from the series consisting of halogen and (Ci-C 4 )-alkyl;
  • Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salt thereof.
  • Ar is selected from the series consisting of 2,3-dichloro-phenyl, 2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl, 2- fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl, 8- chloro-3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-7-yl, 5-chloro-1 ,3-dimethyl-pyrazol-4-yl, naphthalen-1 -yl, 2,4,6-trichloro-phenyl, 5-chloro-2-fluoro-phenyl, 2,4,5-trifluoro- phenyl, 2,4,5-trichloro-phenyl, 5-chloro
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14 and (Ci-C 4 )-alkyl;
  • R2 is selected from the series consisting of halogen and -(Ci-C 4 )-alkyl
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R30 is selected from the series consisting of halogen and (Ci-C 4 )-alkyl;
  • Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salt thereof.
  • compounds of the formula I may be mentioned, wherein
  • Ar is selected from the series consisting of 2,3-dichloro-phenyl, 2,5-dichloro-phenyl, 5-chloro-2-hydrazino-phenyl, 5-chloro-2-cyano-phenyl, 2-cyano-5-methyl-phenyl, 2- fluoro-5-methyl-phenyl, 2-chloro-5-methoxy-phenyl, 2,5-dichloro-thiophen-3-yl, 8- chloro-3,4-dihydro-2H-benzo[b][1 ,4]dioxepin-7-yl, 5-chloro-1 ,3-dimethyl-pyrazol-4-yl, naphthalen-1 -yl, 5-cyano-2-fluoro-phenyl, 2-cyano-5-methoxy-phenyl, 2-cyano-5- fluoro-phenyl, 2-fluoro-5-methoxy-phenyl, 4-acetylamino-2-methyl-phenyl, 2-methyl-
  • R1 is selected from the series consisting of hydrogen, -N(R1 1 )-R12, -N(R13)-C(0)- R14, -N(R13)-S(0) 2 -R15, -N(R13)-C(0)-NH-R14 and (Ci-C )-alkyl;
  • R2 is selected from the series consisting of halogen and -(Ci-C 4 )-alkyl;
  • R1 1 and R12 are independently of one another selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R13 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl;
  • R14 and R15 are independently of one another selected from the series consisting of (C3-C7)-cycloalkyl, phenyl, -(Ci-C 4 )-alkyl-phenyl, Het and -(Ci-C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
  • R30 is selected from the series consisting of halogen and (Ci-C 4 )-alkyl;
  • Het is a monocyclic, 5-membered or 6-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom; wherein all cycloalkyi groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents; in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salt thereof.
  • a subject of the invention also is a compound of the formula I which is selected from any of the specific compounds of the formula I which are disclosed herein, or is any one of the specific compounds of the formula I which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a specific salt, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula I is a subject of the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio.
  • a subject of the invention is a compound of the formula I which is selected from the series consisting of:
  • Another subject of the invention is a compound of the formula I which is selected from the series consisting of:
  • the compounds of the formula I are defined as above in their generic definition or in any of the more specific definitions or embodiments, with the proviso that the compound of the formula I is not one of the following compounds:
  • the excluded compounds are excluded as the free compounds, i.e. they are not excluded in the form of a salt with an acid or base.
  • the compounds of the formula I are defined as above in their generic definition or in any of the more specific definitions or embodiments, with the proviso that the compound of the formula I is not a compound in which simultaneously the group Ar is a phenyl group which is substituted by three identical or different halogen substituents, n is 0, and R1 is the group -NH 2 (amino), and the proviso that the compound of the formula I is not one of the following compounds:
  • the excluded compounds are excluded as the free compounds, i.e. they are not excluded in the form of a salt with an acid or base.
  • the compounds of the formula I are defined as above in their generic definition or in any of the more specific definitions or embodiments, with the proviso that the compound of the formula I is not a compound in which simultaneously the group Ar is selected from the series consisting of 2,4,6- trichloro-phenyl, 5-chloro-2-fluoro-phenyl, 2,4,5-trichloro-phenyl, 2,4,5-tri-fluoro- phenyl, 5-chloro-2,4-difluoro-phenyl, 2,3,4-trichloro-phenyl, 2,3,4-trifluoro-phenyl and 2-chloro-4-trifluoromethyl-phenyl, n is 0, and R1 is the group -NH 2 (amino), and in another embodiment the excluded compounds are excluded as the free compounds, i.e.
  • suitably substituted starting 1 H-pyrazolo[3,4-b]pyrazine derivatives can be employed as building blocks in the preparation of the compounds of formula I, which can be synthesized from suitable precursor compounds, which allow the introduction of a variety of substituents into the various positions of the 1 H- pyrazolo[3,4-b]pyrazine system and which can be chemically modified further in order to finally arrive at the compound of the formula I having the desired substituent pattern.
  • 1 H-pyrazolo[3,4-b]pyrazines use can also be made of procedures and transformations which are described in the literature with respect to indazoles.
  • the starting materials employed in the synthesis of the compounds of the formula I are commercially available or can be prepared according to procedures, or in analogy to procedures, described in the literature or herein.
  • literature articles relating to synthetic procedures and transformations which can be used in the synthesis of the compounds of the formula I the following may be mentioned: Brown et al. , Bioorg. Med. Chem. Lett. 2010, 20, 679; Knochel et al., Chem.
  • a compound of the formula II and a compound of the formula III are reacted to give a compound of the formula IV, which can already be the final compound of the formula I, or which is converted into the desired final compound of the formula I.
  • a compound of the formula II is obtained by reacting a compound of the formula V with a hydrazine of the formula VI, the obained compound of the formula II and a compound of the formula III are reacted to give a compound of the formula IV, and the compound of the formula IV converted into the compound of the formula I.
  • a compound of the formula IV can be obtained by first reacting a compound of the formula V with a compound of the formula III to give a compound of the formula VII, and then reacting the compound of the formula VII with a hydrazine of the formula VI.
  • a compound of the formula X is obtained by reacting a compound of the formula VIII with a hydrazine of the formula VI, and the obtained compound of the formula IX and a compound of the formula III are reacted to give a compound of the formula X, which can already be the final compound of the formula I, or which is converted into the desired final compound of the formula I..
  • a compound of the formula X can be obtained by first reacting a compound of the formula VIII with a compound of the formula III to give a compound of the formula XI, and then reacting the compound of the formula XI with hydrazine of the formula VI.
  • the groups R1 and R2 and the number n in the compounds of the formulae II, III, IV, V, VII, X and XI are defined as in the compounds of the formula I, and additionally can functional groups be present in protected form or in the form of a precursor group which is subsequently converted into the final group.
  • compounds of the formulae II, V, VIII and IX is a leaving group which can be replaced in a Suzuki-type reaction or Stille-type reaction, such as a halogen atom, in particular bromine or chlorine, or a sulfonyloxy group, in particular trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy or tosyloxy (4-methylbenzenesulfonyloxy).
  • the group G2 in the compounds of formulae V, VII, VIII and XI can be identical to or different from the group G1 and is a leaving group, such as a halogen atom, in particular bromine or chlorine, or a sulfonyloxy group, in particular
  • the group G3 in the compounds of formulae II, IV, VI, IX and X can be hydrogen, and in this case the compound of the formula VI thus be hydrazine, or it can be a protecting group which is suitable for protecting a ring nitrogen atom in the 1 H- pyrazolo[3,4-b]pyrazine ring system or similar ring systems such as the pyrazole ring system, for example, like a tetrahydropyran-2-yl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group, a benzyl group or a substituted benzyl group like a 4- methoxybenzyl group or a 2,5-dimethoxybenzyl group.
  • the group G4 in the compounds of formulae III, IV, VII, X and XI can already be the desired final sulfonamide group of the formula Ar-S(0)2-NH-, in which Ar is defined as in the compounds of the formula I and additionally can functional groups be present in protected form or in the form of a precursor group which is subsequently converted into the final group.
  • G4 can also be a group which can be converted into the desired final sulfonamide group of the formula Ar-S(0)2-NH- at an appropriate stage of the synthesis, for example in the compounds of the formulae IV and X, such as a precursor group like a nitro group which can be reduced to an amino group, or a protected amino group like a tert-butoxycarbonylamino group or a
  • the group G5 in the compounds of formula III is a trialkylstannyl group, for example a tri((Ci-C 4 )-alkyl)stannyl group, or a boronic acid group (-B(OH) 2 ) or a boronic acid ester group or cyclic boronic acid ester group, for example a -B(0-(Ci-C 4 )-alkyl) 2 group or a 4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl group, in particular a boronic acid group or a boronic acid ester group or cyclic boronic acid ester group, which allows performing a Suzuki-type reaction or Stille-type reaction for coupling the compounds of the formulae II, V, VIII and IX with the compounds of the formula III.
  • a trialkylstannyl group for example a tri((Ci-C 4 )-alkyl)stannyl group, or a
  • the starting compounds in the synthesis of the compounds of the formula I can also be employed, and the intermediates obtained and/or employed, in the form of salts, for example acid addition salts in case of basic compounds.
  • the intermediates can also be present in another tautomeric form, for example in the case of the
  • reaction of compounds of the formulae V, VII, VIII and XI with a hydrazine of the formula VI is generally carried out in a protic or aprotic solvent such as water, an alcohol like methanol, ethanol, trifluoroethanol, n-propanol, isopropanol, butanol, isobutanol, tert-butanol, 2-methylbutan-2-ol, 3-methyl-3-pentanol, 3-ethyl-3-pentanol, a hydrocarbon like benzene, toluene, xylene, mesitylene, a nitrile like acetonitrile, an ether like tetrahydrofuran or diglyme (di(2-methoxyethyl) ether), an amide like dimethylformamide, N-methylpyrrolidinone, dimethylacetamide, a sulfoxide like dimethylsulfoxide, or an amine like pyridine, or in
  • reaction time generally is from about 30 minutes to about 48 hours, for example from about 5 hours to about 16 hours, depending on the particulars of the specific case and the chosen temperature range.
  • the reaction can also be carried out in a microwave oven utilizing microwave radiation at temperatures from about 60 °C to about 200 °C, for example at temperatures from about 80 °C to about 120 °C.
  • the reaction time generally is from about 5 minutes to about 12 hours, for example from about 10 minutes to about 3 hours, depending on the particulars of the specific case and the chosen temperature range.
  • the compound of the formula VI can be employed in free form, i.e., not in the form of a salt, for example in the form of a solution in a solvent like ethanol or isopropanol, or in the form of an acid addition salt, for example in the form of a salt with hydrochloric acid.
  • a salt in case a salt is employed, it can be transformed into the free form prior to the reaction or in situ with an organic or inorganic base such as an amine like triethylamine, ethyldiisopropylamine, N- methylmorpholine or 1 ,8-diazabicyclo[5.4.0]unde-7-ene, an alkoxide like sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, an amide like lithium diisopropylamide or sodium amide, or an alkali metal carbonate like sodium carbonate, potassium carbonate or cesium carbonate, for example.
  • an organic or inorganic base such as an amine like triethylamine, ethyldiisopropylamine, N- methylmorpholine or 1 ,8-diazabicyclo[5.4.0]unde-7-ene, an alkoxide like sodium methoxide, sodium ethoxide, potassium me
  • reaction of compounds of the formulae II, V, VIII and IX with a compound of the formula III in which G5 is a boronic acid group or a boronic acidester group or cyclic boronic acid ester group is a Suzuki-type reaction, and is generally carried out in the presence of catalytic palladium compound, for example a palladium(ll) salt like palladium(ll) acetate or palladium(ll) chloride, which can be employed in the presence of a phosphine such as 1 , 1 '-bis(diphenylphosphino)ferrocene,
  • tricyclohexylphosphine or triphenylphosphine or a palladium complex such as tetrakis(triphenylphosphine)palladium(0), 1 , 1 '-bis(diphenylphosphino)ferrocene- palladium(ll)dichloride, palladium(O) bis(tri-tert-butylphosphin) or
  • a base for example an alkali metal carbonate or alkali metal phosphate like cesium carbonate, sodium carbonate or tripotassium phosphate, in an inert solvent, such as a hydrocarbon like benzene, toluene or xylene, or an ether like tetrahydrofuran
  • reaction time generally is from about 30 minutes to about 48 hours, for example from 30 minutes to about 16 hours, depending on particulars of the specific case and the chosen temperature range.
  • G5 is a trialkylstannyl group, i.e. Stille-type reactions.
  • the functional groups introduced into the ring system during the 1 H- pyrazolo[3,4-b]pyrazine synthesis can be chemically modified by a variety of reactions and thus the desired groups obtained.
  • a 1 H-pyrazolo[3,4- b]pyrazine carrying a hydrogen atom in position 3 can also be obtained by
  • Halogen atoms can be introduced, for example, according to well-known procedures described in the literature.
  • fluorination of the aromatic substructures of compounds of the formula I can be carried out using a variety of reagents including, for example, N-fluoro-2,4,6- trimethylpyridinium triflate.
  • a chlorination, bromination, or iodination can be accomplished by reaction with the elemental halogens or, for example, by use of N- bromosuccinimide, N-chlorosuccinimide or N-iodosuccinimide and many other reagents well known to the person skilled in the art.
  • selective halogen/metal exchange, or metalation by selective hydrogen/metal exchange, and subsequent reaction with a wide range of electrophiles various substituents can be introduced using procedures which are know per se.
  • halogen atoms, hydroxy groups after conversion into the triflate or nonaflate, for example, or primary amino groups after conversion into the diazonium salt can directly, or after conversion to the corresponding stannane or boronic acid or boronic acid ester, converted into a variety of other groups like, for example, -CN, -CF 3 , -C2F5 and ether, acid, amide, amine, alkyl or aryl groups.
  • transition metals such as palladium or nickel catalysts or copper salts, as are described in F. Diederich, P.
  • Nitro groups can be reduced to amino groups with various reducing agents, such as sulfides, dithionites, complex hydrides or by catalytic hydrogenation.
  • a reduction of a nitro group may also be carried out simultaneously with a reaction performed on another functional group, for example when reacting a group like a cyano group with hydrogen sulfide or when hydrogenating a group.
  • Amino groups can then be modified according to standard procedures, for example alkylated by reaction with optionally substituted alkyl halogenides like chlorides, bromides or iodides or sulfonyloxy compounds like tosyloxy, mesyloxy or
  • trifluoromethylsulfonyloxy compounds preferably in the presence of a base like potassium carbonate, cesium carbonate, sodium hydride or potassium tert-butoxide, or by reductive amination of carbonyl compounds, or acylated by reaction with activated carboxylic acid derivatives such as acid chlorides, anhydrides, activated esters or others or by reaction with carboxylic acids in the presence of an activating agent, or sulfonylated by reaction with sulfonyl chlorides. Ester groups can be hydrolyzed to the corresponding carboxylic acids which after activation can then be reacted with amines under standard conditions.
  • ester or acid groups can be reduced to the corresponding alcohols by many standard procedures, and the resulting hydroxy compounds alkylated.
  • Ether groups for example benzyloxy groups or other easily cleavable ether groups, can be cleaved to give hydroxy groups which can then be reacted with a variety of agents, for example etherification agents or activating agents allowing replacement of the hydroxy group by other groups.
  • a hydroxy group can also be converted into a leaving group and reacted with various reaction partners under the well-known conditions of the Mitsunobu reaction (0. Mitsunobu, Synthesis 1981 , 1 ), or by further procedures (cf. A. Tunoori, D. Dutta, G. Gunda, Tetrahedron Lett.
  • the cyano group can, in a later step, be transformed by hydrolysis into carboxylic acid derivatives or by reduction into aminomethyl groups. Nitro groups can be transformed by reduction like catalytic hydrogenation into amino groups.
  • protective groups which may be mentioned, are benzyl protective groups, for example benzyl ethers of hydroxy compounds and benzyl esters of carboxylic acids, from which the benzyl group can be removed by catalytic hydrogenation in the presence of a palladium catalyst, tert-butyl protective groups, for example tert-butyl esters of carboxylic acids, from which the tert-butyl group can be removed by treatment with trifluoroacetic acid, acyl protective groups, for example ester and amides of hydroxy compounds and amino compounds, which can be cleaved again by acidic or basic hydrolysis, or alkoxycarbonyl protective groups, for example tert-butoxycarbonyl derivatives of amino compounds, which can be cleaved again by treatment with trifluor
  • Solid phase techniques can also be prepared by solid phase techniques.
  • the solid phase may also be regarded as having the meaning of a protecting group, and cleavage from the solid phase as removal of the protective group.
  • the use of such techniques is known to a person skilled in the art (cf. Burgess K (Ed.), Solid Phase Organic Synthesis, New York, Wiley, 2000).
  • a phenolic hydroxy group can be attached to a trityl-polystyrene resin, which serves as a protecting group, and the molecule cleaved from the resin by treatment with trifluoroacetic acid or another acid at a later stage of the synthesis.
  • Another subject of the present invention are the novel starting compounds and intermediates occurring in the synthesis of the compounds of the formula I, including the compounds of the formulae II, III, IV, V, VII, VIII, IX, X and XI, wherein the groups R1 , R2, G1 , G2, G3, G4 and G5 and the number n are defined as above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their salts, and their use as synthetic intermediates or starting compounds. All general explanations, specifications of embodiments and definitions of numbers and groups given above with respect to the compounds of the formula I apply correspondingly to the said intermediates and starting compounds.
  • a subject of the invention are in particular the novel specific starting compounds and intermediates described herein. Independently thereof whether they are described as a free compound and/or as a specific salt, they are a subject of the invention both in the form of the free
  • the compounds of the present invention are SGK inhibitors, which are capable of inhibiting an exaggerated, or inappropriate, activity of SGK in pathological conditions and are therefore suitable for the prophylaxis and therapy of the diseases mentioned above and below.
  • they are highly active inhibitors of the SGK-1 enzyme.
  • They are selective SGK-1 inhibitors inasmuch as they do not substantially inhibit or promote the activity of other enzymes and receptors whose activation or inhibition is not desired.
  • the activity of the compounds of the formula I can be determined, for example, in the assays described below or in other in vitro, ex vivo or in vivo assays known to the person skilled in the art.
  • the ability of the compounds to inhibit the SGK enzyme may be measured by methods similar to those described in D. Perrin et al., Expert Opin. Drug Discov. (2010) 5, 51 -63, and by the assay described below.
  • one embodiment of the invention comprises compounds which have an IC50 value of ⁇ 1 ⁇ , in another embodiment of ⁇ 0.1 ⁇ , in another embodiment of ⁇ 0.01 ⁇ , for SGK-1 inhibition as determined in the assay described below, and which in a further embodiment do not substantially influence the activity of other enzymes and receptors whose inhibition or activation is not desired.
  • the ability of the compounds to inhibit the SGK- 1 mediated glycogen synthase kinase 3beta (GSK3beta) phosphorylation in a cellular setting may be measured by methods similar to those described by H. Sakoda et al. J. Biol. Chem. 2003, 278, 25802-25807, and by the method described below.
  • the ability of the compounds to inhibit SGK1 dependent activation of epithelial Na + channel (ENaC) currents in cell monolayers may be measured by methods similar to those described by D. Alvarez de la Rosa et al., Am. J. Physiol. Cell Physiol.
  • the inappropriate SGK-1 activity referred to herein is any SGK-1 activity that deviates from the expected normal SGK- 1 activity.
  • Inappropriate SGK-1 activity may take the form of, for example, an abnormal increase in activity, or an aberration in the timing and/or control of SGK-1 activity. Such inappropriate activity may result then, for example, from
  • the compounds of the formula I and their pharmaceutically acceptable salts are generally suitable for the prophylaxis and/or therapy of conditions in which the inappropriate activity of SGK-1 enzyme plays a role or has an undesired extent, or which can favorably be influenced by inhibiting the SGK-1 enzyme or decreasing the activity, or for the prevention, alleviation or cure of which an inhibition of SGK-1 or a decrease in the activity is desired by the physician.
  • the compounds of the present invention are suitable for the treatment of all disorders in the progression of which an enhanced activity of SGK enzyme is involved. These include the indications described in the introduction.
  • the invention relates in particular to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for the treatment of degenerative joint disorders and degenerative cartilage changes including osteoarthritis, osteoarthrosis, rheumatoid arthritis, spondylosis,
  • collagenoses periodontal disorders, wound-healing disturbances, diabetes including diabetes mellitus, diabetic nephropathy, diabetic neuropathy, diabetic angiopathy and microangiopathy, obesity, metabolic syndrome (dyslipidaemia), systemic and pulmonary hypertension, cerebral infarctions, cardiovascular diseases including cardiac fibrosis after myocardial infarction, cardiac hypertrophy and heart failure, arteriosclerosis, renal diseases including glomerulosclerosis, nephrosclerosis, nephritis, nephropathy and electrolyte excretion disorder, any type of fibrosis and inflammatory processes including liver cirrhosis, lung fibrosis, fibrosing pancreatitis, rheumatism, arthritis, gout, Crohn's disease, chronic bronchitis, radiation fibrosis, sclerodermatitis, cystic fibrosis, scar formation, Alzheimer's disease, pain including acute pain like pain following injuries, post-operative pain, pain in association with an
  • the treatment of diseases is to be understood herein as generally meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals which are susceptible thereto and are in need of such a prophylaxis or prevention, with the aim of a prevention or suppression of their occurrence or of an attenuation in the case of their occurrence.
  • patients who on account of their disease history are susceptible to myocardial infarction
  • the prophylactic or preventive medicinal treatment the occurrence or re-occurrence of a myocardial infarct can be prevented or its extent and sequelae decreased.
  • the treatment of diseases can occur both in acute cases and in chronic cases.
  • the compounds of the formula I and their pharmaceutically acceptable salts can therefore be used in animals, in particular in mammals and specifically in humans, as a pharmaceutical or medicament on their own, in mixtures with one another, or in the form of pharmaceutical compositions.
  • a subject of the present invention also are the compounds of the formula I and their pharmaceutically acceptable salts for use as a pharmaceutical.
  • a subject of the present invention also are pharmaceutical compositions and medicaments which comprise at least one compound of the formula I and/or a pharmaceutically acceptable salt thereof as an active ingredient, in an effective dose for the desired use, and a pharmaceutically acceptable carrier, i.e.
  • a subject of the present invention also are the compounds of the formula I and their pharmaceutically acceptable salts for use in the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of degenerative joint disorders, degenerative cartilage changes, diabetes, cardiovascular diseases, fibrosis, inflammatory processes, pain, tumors or cerebral infarctions, wherein treatment of diseases comprises their therapy and prophylaxis as mentioned above, or for use as an inhibitor of serum and glucocorticoid regulated kinase (SGK).
  • SGK serum and glucocorticoid regulated kinase
  • a subject of the present invention also are the use of the compounds of the formula I and their pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example inhibitor the treatment of degenerative joint disorders, degenerative cartilage changes, diabetes, cardiovascular diseases, fibrosis, inflammatory processes, pain, tumors or cerebral infarctions, wherein treatment of diseases comprises their therapy and prophylaxis as mentioned above, or a medicament for inhibition of serum and glucocorticoid regulated kinase (SGK).
  • a subject of the present invention also are methods for the treatment of the diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example the treatment of degenerative joint disorders, degenerative cartilage changes, diabetes,
  • cardiovascular diseases cardiovascular diseases, fibrosis, inflammatory processes, pain, tumors or cerebral infarctions, wherein treatment of diseases comprises their therapy and prophylaxis as mentioned above, and a method for inhibiting serum and glucocorticoid regulated kinase (SGK), which comprise administering an efficacious amount of at least one compound of the formula I and/or a pharmaceutically acceptable salt thereof to a human or an animal which is in need thereof.
  • SGK serum and glucocorticoid regulated kinase
  • parenteral administration can be carried out, for example, intravenously, intraarticularly, intraperitoneally, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously, transdermal ⁇ or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
  • the preferred form of administration depends on the particulars of the specific case.
  • compositions adapted for transdermal administration can be administered as plasters for extended, close contact with the epidermis of the recipient.
  • formulations such as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils can be used.
  • suitable formulations are topical ointments or creams, for example.
  • the active ingredient can be employed either with a paraffinic or a water-miscible cream base.
  • the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • compositions according to the invention are prepared in a manner known per se and familiar to the person skilled in the art by admixing one ore more pharmaceutically acceptable inert inorganic and/or organic vehicles and excipients with one or more compounds of the formula I and/or pharmaceutically acceptable salts thereof, and bringing them into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine.
  • suitable form for dosage and administration which can then be used in human medicine or veterinary medicine.
  • lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts.
  • fats, waxes, semisolid and liquid polyols, natural or hardened oils for example, can be used.
  • solutions for example injection solutions, or of emulsions or syrups water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, for example, can be used, and for the production of microcapsules, implants or rods copolymers of glycolic acid and lactic acid, for example, can be used.
  • the pharmaceutical compositions normally contain from about 0.5 % to 90 % by weight of the compounds of the formula I and/or their pharmaceutically acceptable salts. The amount of the active ingredient of the formula I and/or its pharmaceutically
  • acceptable salts in the pharmaceutical compositions normally is from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg per unit dose.
  • the amount may deviate from the indicated ones
  • the pharmaceutical compositions can contain excipients, or auxiliaries or additives, such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I, and/or their pharmaceutically acceptable salts.
  • a pharmaceutical composition contains two or more compounds of the formula I
  • the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical composition. For example, a highly potent compound with a shorter duration of action may be combined with a long- acting compound of lower potency.
  • the flexibility permitted with respect to the choice of substituents in the compounds of the formula I allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds.
  • the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
  • An appropriate dosage can be established using clinical approaches known to the person skilled in the art.
  • the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 mg/kg to about 100 mg/kg, preferably from about 0.1 mg/kg to about 50 mg/kg, in particular from about 0.1 mg/kg to about 10 mg/kg, in each case in mg per kg of body weight.
  • the daily dose can be divided, in particular in the case of the
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of the SGK enzyme.
  • the compounds may be provided in a
  • a compound of the present invention can be used as a reference in an assay to compare its known activity to a compound with an unknown activity.
  • the compounds of the formula I can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active compounds, which may be obtained from the compounds of the formula I by introduction of substituents or modification of functional groups, for example.
  • an acid such as trifluoroacetic acid or acetic acid was used, for example when trifluoroacetic acid was employed to remove an acid-labile protecting group containing a tert-butyl group, or when a compound was purified by chromatography using an eluent which contained such an acid, in some cases, depending on the work-up procedure, for example the details of a freeze-drying process, the compound was obtained partially or completely in the form of a salt of the acid used, for example in the form of the salt with acetic acid salt or trifluoroacetic acid salt.
  • the names of the example compounds and the structural formulae such contained trifluoroacetic acid or acetic acid is not specified.
  • the prepared compounds were in general characterized by spectroscopic data and chromatographic data, in particular mass spectra (MS) and/or nuclear magnetic resonance (NMR) spectra.
  • MS mass spectra
  • NMR nuclear magnetic resonance
  • electrospray ionization ESI+ or ES-
  • the title compound was prepared by adding 2,3-dichloro-benzenesulfonyl chloride (1 1 .2 g) and 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenylamine (10.0 g) to a reaction vessel containing a magnetic stirring bar, followed by 200 ml dry DCM and 4.1 ml pyridine. The reaction mixture was stirred at RT for 20 h before being cooled on an ice-bath and quenched with 1 M aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid and extracted three times with EtOAc.
  • the reaction mixture was cooled to RT and diluted with acetic acid (20%).
  • the precipitated product was collected by filtration and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA).
  • the fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid as a solid, which was dissolved in 1 ml of a water/acetonitrile mixture.
  • the crude product was purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the pure product in the form of its salt with trifluoroacetic acid as a solid, which was dissolved in 1 ml of a water/acetonitrile mixture. 0.5 ml of a 1 M aqueous hydrochloric acid was added and the solution was again lyophilized to yield the title compound in the form of 2,5- dichloro-N-[2-fluoro-4-(1 H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]benzenesulfonamide hydrochloride. Yield: 2.2 mg.
  • the title compound was prepared in 6% yield according to the procedure described in example 1 , employing 5-chloro-2-fluoro-benzenesulfonyl chloride instead of 2,3- dichloro-benzenesulfonyl chloride and 2-fluoro-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenylamine instead of 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenylamine as starting material.
  • the following modification was made.
  • the title compound was prepared in 4% yield according to the procedure described in example 1 , employing 2-fluoro-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenylamine instead of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-phenylamine as starting material.
  • the following modification was made.
  • the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid.
  • 3,5-Dichloro-pyrazine-2-carbaldehyde (5.0 g) was dissolved in dry tetrahydrofuran (100 ml) in a reaction vessel equipped with a magnetic stirring bar under an argon atmosphere. The solution was cooled on an ice-bath before slow addition of 10.3 ml methylmagnesium bromide solution (3M in tetrahydrofuran), keeping the internal temperature in the reaction vessel below 5°C. After the addition the cooling bath was removed and the reaction mixture stirred for another 10 min. Then the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (100 ml) and extracted with EtOAc (3 x 200 ml). The combined aqueous phases were dried over sodium sulfate, filtered and evaporated to afford 1 -(3,5-dichloro-pyrazin-2- yl)-ethanol as a dark brown oil. Yield: 5.23g (96%).
  • N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide 230 mg was suspended in a mixture of 2 ml iPrOH and 2 ml 35% hydrazine in water at RT and heated to 120°C by microwave irradiation (Biotage InitiatorTM apparatus) for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3 x 30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by recrystallisation from an acetone-water mixture afforded the title compound as a pale yellow solid after drying under vacuum. Yield: 81 .6 mg (38%).
  • Example 1 2,5-Dichloro-N-[4-(3-methyl-1 H-pyrazolo[3,4-b]pyrazin-6- yl)phenyl]benzenesulfonamide
  • the title compound was prepared in 5% yield according to the procedure described in example 10, employing 2,5-dichloro-benzenesulfonyl chloride instead of 2,3- dichloro-benzenesulfonyl chloride as starting material. The following modification was made.
  • the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid.
  • the title compound was prepared in 9% yield according to the procedure described in example 10, employing 5-chloro-2-fluoro-benzenesulfonyl chloride instead of 2,3- dichloro-benzenesulfonyl chloride as starting material.
  • the following modification was made.
  • the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid.
  • the title compound was prepared in 14% yield according to the procedure described in example 13, employing 2-chloro-5-methoxy-benzenesulfonyl chloride instead of 5- chloro-2-cyano-benzenesulfonyl chloride as starting material.
  • the title compound was prepared by adapting the procedures described in example 19, employing 2,5-dichlorothiophene-3-sulfonyl chloride instead of 2-fluoro-5-methyl- benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 19, employing 5-chloro-1 ,3-dimethyl-pyrazole-4-sulfonyl chloride instead of 2-fluoro- 5-methyl-benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in exampl 24, employing cyclopropanecarbonyl chloride instead of 2,3-dichloro-benzoyl chloride.
  • the title compound was prepared by adapting the procedures described in exampl 19, employing naphthalene-1 -sulfonyl chloride instead of 2-fluoro-5-methyl- benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 1 , employing 5-chloro-2-fluoro-benzenesulfonyl chloride instead of 2,3-dichloro- benzenesulfonyl chloride as starting material. The following modification was made.
  • the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a
  • the title compound was prepared by adapting the procedures described in example 19, employing 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride instead of 2-fluoro- 5-methyl-benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 19, employing 2,4,5-trifluoro-benzenesulfonyl chloride instead of 2-fluoro-5-methyl- benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 19, employing 2,4,5-trichloro-benzenesulfonyl chloride instead of 2-fluoro-5-methyl- benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 19, employing 5-chloro-2,4-difluoro-benzenesulfonyl chloride instead of 2-fluoro-5- methyl-benzenesulfonyl chloride.
  • the title compound was prepared by adapting the procedures described in example 19, employing 2,3,4-trifluoro-benzenesulfonyl chloride instead of 2-fluoro-5-methyl- benzenesulfonyl chloride.
  • Example 49 1 -[6-[4-[(2-Fluoro-5-methyl-phenyl)sulfonylamino]phenyl]-1 H- pyrazolo[3,4-b]pyrazin-3-yl]-3-(3-pyridyl)-urea
  • Example 50 1 -(4-Chlorophenyl)-3-[6-[4-[(2-fluoro-5-methyl- phenyl)sulfonylamino]phenyl]-1 H-pyrazolo[3,4-b]pyrazin-3-yl]-urea
  • the title compound was prepared in 1 % yield according to the procedure described in example 10, employing 4-acetylamino-2-methyl-benzenesulfonyl chloride instead of 2,3-dichloro-benzenesulfonyl chloride as starting material. The following modification was made.
  • the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid.
  • the title compound was prepared in 18% yield according to the procedure described in example 10, employing 2-methyl-5-nitro-benzenesulfonyl chloride instead of 2,3- dichloro-benzenesulfonyl chloride as starting material.
  • the following modification as made The crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1 % TFA). The fractions containing the product were lyophilized to yield the title compound in the form of its salt with trifluoroacetic acid.
  • MS (ES+): m/e 425.2 (M+H).
  • the ability of the compounds of the invention to inhibit SGK-1 was assessed in an enzymatic activity assay by determining their effect on the ability of the isolated SGK enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a labeled substrate peptide, and in cellular assays by determining their effect on cellular function.
  • the SGK-1 dependent phosphorylation of glycogen synthase kinase 3beta (GSK3beta) in U20S cells was measured, in another one, a functional electrophysiological assay, the SGK-1 dependent activation of epithelial Na + channel (ENaC) currents in A6 cell monolayers, and in another one chondrocyte hypertrophic differentiation in mouse chondrogenic ATDC5 cells.
  • ENaC epithelial Na + channel
  • the compounds were tested for serum and glucocorticoid-regulated kinase 1 (SGK- 1 ) inhibitory activity in a substrate phosphorylation assay designed to measure the ability of the isolated enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a fluorescein-labeled substrate peptide, using
  • the synthesized fluorescent labeled peptide substrate contained (5(6)-Carboxyfluorescein)-RPRAATF-NH 2 .
  • the phosphorylated substrate peptide and non-phosphorylated substrate peptide were separated with caliper life science's lab-chip technology based on a micro fluidics method. All fluid flow was established on the chip by applying a vacuum of a few psi to the waste well transporting fluid from various sources through interconnecting channels.
  • the enzyme reaction was carried out in a buffer containing 25 mM Tris-HCI (pH 7.4), 5 mM MgCI 2 , 2 mM MnCI 2 , 2 mM DTT, and 0.03% bovine serum albumine.
  • the enzyme was pre-incubated with the test compound for 30 min at 24°C.
  • the kinase reaction was initiated by addtion of the substrate mixture containing the peptide substrate (final concentration 1 ⁇ ) and ATP (final concentration 10 ⁇ ). After 60 min incubation at 37°C, the enzyme reaction was terminated by adding a buffer containing 100 mM Hepes (pH 7.4) and 35 mM EDTA.
  • glycogen synthase kinase 3beta (GSK3beta) is a
  • glucocorticoid-regulated Kinase 1 (SGK-1 ) was determined in a cellular assay which measures the SGK-1 dependent phosphorylation of GSK3beta in U20S cells (ATCC HTB-96) overexpressing recombinant SGK-1 and GSK3beta after transfection with recombinant BacMam viruses.
  • U20S cells were cultured in 1 : 1 Dulbecco modified Eagle medium / Ham's F12 and 10% heat inactivated fetal calf serum (FCS Gold) at 37°C, 7% C0 2 and 95% relative humidity.
  • Cells were harvested and mixed with BacMam virus containing expression constructs for human SGK-1 (amino acids S61 - L431 with serine 422 replaced by aspartate) at an MOI (multiplicity of infection) of 50 and BacMam virus containing expression constructs for human GSK3beta at an MOI of 125.
  • Cell suspension mixed with BacMam viruses was seeded in 96 well CLEAR plates (Greiner) at 3x10 4 cells per well in 250 ⁇ _ medium.
  • 1 ⁇ _ of a selective Akt-inhibitor was added (final concentration 2 ⁇ ).
  • 1 ⁇ _ of a solution of the test compound at 250 x final concentration was added.
  • IC50 values were calculated using the ratio of phosphorylated GSK3beta to total GSK3beta to compensate for unspecific effects and are given in Table 2. Table 2. IC50 values for inhibition of SGK-1 dependent phosphorylation of GSK3beta in U20S cells by example compounds
  • SGK-1 is up-regulated in A6 cells in response to induction of a hypoosmotic shock (Alvarez de la Rosa et al.; J. Gen. Physiol. 124 (2004), 395-407).
  • a hypoosmotic shock Alvarez de la Rosa et al.; J. Gen. Physiol. 124 (2004), 395-407.
  • ENaC function in the plasma membrane is upregulated and the effect of SGK-1 inhibitors on functional ENaC surface expression can be investigated with Ussing chamber technology.
  • A6 cells The renal Xenopus laevis cell line A6 (Rafferty, K. A.; Mass culture of amphibia cells: methods and observations concerning stability of cell type. In: Biology of Amphibian Tumors, edited by M. Mizell. New York: Springer-Verlag, 1969, p. 52-81 ) was used for the experiments. Cells were grown in cell culture flasks (Nunc) at 28°C in a humidified atmosphere with 4% CO2.
  • the culture medium contained a 7:3 mixture of Leibovitz's L-15 (Sigma-Aldrich), / Coon's (Sigma-Aldrich) media supplemented with 10% fetal bovine serum (PAA), 20 % sterile water, 25 mM NaHC0 3 (Sigma-Aldrich), 100 U/ml penicillin (PAA) and 100 pg/ml streptomycin (PAA).
  • the osmolality of the medium was 270 mOsml/kg H 2 0).
  • Cells were detached with accutase (PAA) and seeded for electrophysiological measurements into transwell filter inserts (polyester 0.4 pm pore size, Corning) at a density of 0.4x10 6 cells/filter.
  • PPA accutase
  • Cells were cultivated for 7-10 days, and confluent A6 cell monolayers were identified by repetitive resistance measurements in cell culture medium using an EVOM 2 ohmmeter (World Precision Instruments). Monolayers with a resistance of >10 kOhm were considered confluent.
  • Filters with confluent A6 cells were transferred into a continuously perfused Ussing- chamber, and electrophysiological parameters were measured under open circuit conditions using a transepithelial clamp amplifier (EP Design).
  • EP Design transepithelial clamp amplifier
  • Short circuit current was calculated by Ohm's law.
  • ENaC epithelial Na + channel
  • A9 monolayers were first equilibrated for 5 min with isoosmotic Ringer-solution from both the luminal and basolateral side of the cell layer. Amiloride was applied to the luminal site to establish the basal ENaC-dependent current (l'sc b asai)- Cell layers were then perfused from the basolateral side for 10 min with compounds in isotonic buffer or control isotonic buffer. SGK signaling leading to increased ENaC activity and subsequent increase in I'sc was stimulated by application of hypoosmotic Ringer- solution for 45 min to both sides of the A6 cell layer.
  • the ATDC5 cell assay was used as in vitro model to determine the effects of the compounds of the invention on chondrocyte hypertrophic differentiation by monitoring the expression levels of collagen type X (Coll 0a1 ) as specific marker of chondrocyte hypertrophy.
  • ATDC5 cells are a clonal mouse embryonic cell line derived from multipotent AT805 teratocarcinoma cells (Atsumi T, Miwa Y, Kimata K, Ikawa Y.; A chondrogenic cell line derived from a differentiating culture of AT805 teratocarcinoma cells. Cell Differ. Dev. 30 (1990), 109-1 16).
  • the cells can undergo insulin-dependent chondrogenic cell differentiation entailing distinct differentiation stages starting from an undifferentiated, subconfluent stage, a condensation stage, a cartilage nodule formation stage and a calcification stage within 45 days of in vitro culture.
  • Chondrogenic differentiation can be shown by measuring the expression of the cartilage main collagen (Col2a1 ) and aggrecan (AGC1 ) and glycosaminoglycan- staining with Alcian Blue within two weeks after insulin-triggered differentiation, and hypertrophic differentiation can be monitored by the expression of collagen type X (Col10a1 ), a specific marker of chondrocyte hypertrophy within 21 days of in vitro culture.
  • collagen type X Col10a1
  • Thyroid hormone triiodothyronine promotes hypertrophic differentiation of growth plate chondrocytes (Robson H, Siebler T, Stevens DA, Shalet SM, Williams GR; Thyroid hormone acts directly on growth plate chondrocytes to promote hypertrophic differentiation and inhibit clonal expansion and cell proliferation. Endocrinology. 141 (2000):3887-3897). Addition of BMP2 and T3 can accelerate ATDC5 hypertrophic differentiation leading to the strong induction Col10a1 expression between 10-14 days. SGK-inhibitors were added to differentiating ATDC5 cells for 14 days and Col10a1 gene expression was quantified to determine effects on chondrocyte hypertrophic differentiation.
  • ATDC5 cells were maintained in 300cm2 tissue culture flasks in D MEM/Ham's F12 + 5% FCS supplemented with 10 g/ml human transferrin, 30 nM sodium selenite, 50 pg/ml kanamycin and grown at 37°C in 5% CO2 in 95% air.
  • 9.9 x 10 4 cells were plated in 24 well plates and grown for 2 days.
  • Medium was exchanged with DMEM/Ham's F12 + 5% FCS supplemented with 10 pg/ml human transferrin, 30 nM sodium selenite, 50 pg/ml ascorbic acid and 1 pg/ml BMP2.
  • the assay was run in triplicates, compounds were added in 10% DMSO, and medium changed every 2-3 days including supplementation of compound.
  • 1 ⁇ T3 was used as additional supplement in the cell culture.
  • Cells were lysed in 600 ⁇ of RLT-buffer (Qiagen) and total RNA was isolated using the RNA-easy Mini RNA isolation Kit (Qiagen) which was run on a Qiacube system (Qiagen) according to the supplier's instructions.
  • RNA was isolated in 30 ⁇ of pure water and the RNA content measured by UV-spectroscopy (Nanodrop, Peqiab).
  • For cDNA synthesis 50 ng total RNA was reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Product Number 4368813) according to the manufacturers instructions.
  • a 20 ⁇ reaction was set up, containing 4 mM dNTPs, random primers, RNAse inhibitor and 1 ⁇ MultiScribe reverse transcriptase and incubated for 10 min at 25°C, 120 min at 37°C, 5 min at 85°C.
  • Taqman Fast PCR reaction was performed in a 20 ⁇ volume using Taqman Fast Advanced Master Mix (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) (Applied Biosystems, product number 4444965) and Taqman Gene expression assays for RPL37a (Applied Biosystems, product number 4444965) (Applied Biosystems, product number 4444965)
  • Fluoresecence data were collected and converted to Ct-Values and expressed values were calculated based on the comparative Ct method (Nat. Protoc. 3 (2008), 1 101 -1 108); Analyzing real-time PCR data by the comparative C(T) method).

Landscapes

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

Abstract

La présente invention concerne des N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides de formule I, dans laquelle Ar, R1, R2 et n ont les significations indiquées dans les revendications. Les composés de formule I sont des composés pharmacologiquement actifs de valeur qui modulent l'activité protéine kinase, spécifiquement l'activité de la kinase sérique et régulée par les glucocorticoïdes (SGK), en particulier de l'isoforme 1 de la kinase sérique et régulée par les glucocorticoïdes (SGK-1, SGK1), et ils conviennent au traitement de maladies dans lesquelles l'activité SGK est inappropriée, par exemple des troubles articulaires dégénératifs ou des processus inflammatoires liés comme l'ostéarthrite ou le rhumatisme. L'invention concerne en outre des procédés de préparation des composés de formule I, leur utilisation comme composés pharmaceutiques et des compositions pharmaceutiques les comprenant.
PCT/EP2011/066220 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques WO2013041119A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
SG11201400551UA SG11201400551UA (en) 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals
AU2011377409A AU2011377409B2 (en) 2011-09-19 2011-09-19 N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals
CA2846369A CA2846369C (fr) 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl-sulfonamides et leurs utilisation comme produits pharmaceutiques
KR1020147010212A KR20140064975A (ko) 2011-09-19 2011-09-19 Ｎ­［４­（１Ｈ­피라졸로［３，４­ｂ］피라진­６­일）­페닐］­설폰아미드 및 약제로서의 이의 용도
PCT/EP2011/066220 WO2013041119A1 (fr) 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques
IL231097A IL231097A0 (en) 2011-09-19 2014-02-23 N-[4-(h 1 -pyrazolo[-b3,4]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2011/066220 WO2013041119A1 (fr) 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques

Publications (1)

Publication Number Publication Date
WO2013041119A1 true WO2013041119A1 (fr) 2013-03-28

Family

ID=44799999

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/066220 WO2013041119A1 (fr) 2011-09-19 2011-09-19 N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl-sulfonamides et leurs utilisation comme produits pharmaceutiques

Country Status (6)

Country Link
KR (1) KR20140064975A (fr)
AU (1) AU2011377409B2 (fr)
CA (1) CA2846369C (fr)
IL (1) IL231097A0 (fr)
SG (1) SG11201400551UA (fr)
WO (1) WO2013041119A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130072493A1 (en) * 2011-09-19 2013-03-21 Sanofi N-[4-(1H-PYRAZOLO[3,4-b]PYRAZIN-6-YL)-PHENYL]-SULFONAMIDES AND THEIR USE AS PHARMACEUTICALS
WO2015048531A1 (fr) * 2013-09-26 2015-04-02 Beth Israel Deaconess Medical Center, Inc. Inhibition de la sgk1 dans le traitement d'affections cardiaques
US9174993B2 (en) 2011-09-19 2015-11-03 Sanofi N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals
WO2018106459A1 (fr) 2016-12-07 2018-06-14 New Era Pharma, Inc. Composés et compositions pharmaceutiques pour moduler l'activité sgk, et leurs procédés
TWI629275B (zh) * 2013-03-13 2018-07-11 賽諾菲公司 Ｎ－（４－（氮雜吲唑－６－基）－苯基）－磺醯胺及其作為醫藥之用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061130A1 (fr) 2002-01-10 2003-07-24 Cirrus Logic, Inc. Filtre de boucle a faible gigue pour systeme de boucle a verrouillage de phase
US20050070542A1 (en) 2003-09-03 2005-03-31 Hodgetts Kevin J. 5-Aryl-pyrazolo[4,3-d]pyrimidines, pyridines, and pyrazines and related compounds
DE102005015255A1 (de) * 2005-04-04 2006-10-05 Merck Patent Gmbh Acylhydrazide
DE102007002717A1 (de) * 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
US20100029653A1 (en) 2006-09-15 2010-02-04 Bayer Schering Pharma Aktiengesellschaft Pyrazolopyridine, indazole, imidazopyridine, imidazopyrimidine, pyrazolopyrazine and pyrazolopyridine derivatives as stimulators of guanylate cyclase for cardiovascular disorders

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003061130A1 (fr) 2002-01-10 2003-07-24 Cirrus Logic, Inc. Filtre de boucle a faible gigue pour systeme de boucle a verrouillage de phase
US20050070542A1 (en) 2003-09-03 2005-03-31 Hodgetts Kevin J. 5-Aryl-pyrazolo[4,3-d]pyrimidines, pyridines, and pyrazines and related compounds
DE102005015255A1 (de) * 2005-04-04 2006-10-05 Merck Patent Gmbh Acylhydrazide
US20100029653A1 (en) 2006-09-15 2010-02-04 Bayer Schering Pharma Aktiengesellschaft Pyrazolopyridine, indazole, imidazopyridine, imidazopyrimidine, pyrazolopyrazine and pyrazolopyridine derivatives as stimulators of guanylate cyclase for cardiovascular disorders
DE102007002717A1 (de) * 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate

Non-Patent Citations (123)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Synthesis", 1991, PERGAMON
"Organic Reactions", JOHN WILEY & SONS
"Solid Phase Organic Synthesis", 2000, WILEY
0. MITSUNOBU, SYNTHESIS, 1981, pages 1
A. F. LITTKE, G. F. FU, ANGEW. CHEM. INT. ED., vol. 41, 2002, pages 4176 - 4211
A. KATRITZKY, C. REES, E. SCRIVEN: "Comprehensive Heterocyclic Chemistry II", 1996, ELSEVIER SCIENCE
A. R. MUCI, S. L. BUCHWALD, TOPICS IN CURRENT CHEMISTRY, vol. 219, 2002, pages 131 - 209
A. TUNOORI, D. DUTTA, G. GUNDA, TETRAHEDRON LETT., vol. 39, 1998, pages 8751
AKUTSU,N., LIN.R., BASTIEN.Y., BESTAWROS,A., ENEPEKIDES,D.J., BLACK,M.J., WHITE,J.H.: "Regulation of gene Expression by 1 alpha,25-dihydroxyvitamin D3 and Its analog EB1089 under growth-inhibitory conditions in squamous Carcinoma Cells", MOL ENDOCRINOL, vol. 15, 2001, pages 1127 - 1139, XP002227920, DOI: doi:10.1210/me.15.7.1127
ALLISTON,T.N., GONZALEZ-ROBAYNA,J.J., BUSE,P., FIRESTONE,G.L., RICHARDS,J.S.: "Expression and localization of serum/glucocorticoid-induced kinase in the rat ovary: relation to follicular growth and differentiation", ENDOCRINOLOGY, vol. 141, 2000, pages 385 - 395
ALLISTON,T.N., MAIYAR,AC., BUSE,P., FIRESTONE,G.L., RICHARDS,J.S.: "Follicle stimulating hormone-regulated expression of serum/glucocorticoid-inducible kinase in rat ovarian granulosa cells: a functional role for the Sp1 family in Promoter activity", MOL ENDOCRINOL, vol. 11, 1997, pages 1934 - 1949, XP000881799, DOI: doi:10.1210/me.11.13.1934
ALVAREZ DE LA ROSA ET AL., J. GEN. PHYSIOL., vol. 124, 2004, pages 395 - 407
ALVAREZ,D.I.R., ZHANG,P., NARAY-FEJES-TOTH,A., FEJES-TOTH,G., CANESSA,C.M.: "The serum and glucocorticoid kinase sgk increases the abundance of epithelial sodium Channels in the plasma membrane of Xenopus oocytes", J BIOL CHEM, vol. 274, 1999, pages 37834 - 37839
ANDALUZ ET AL., J. HETEROCYCL. CHEM., vol. 26, 1989, pages 949
ATSUMI T, MIWA Y, KIMATA K, IKAWA Y: "A chondrogenic cell line derived from a differentiating culture of AT805 teratocarcinoma cells", CELL DIFFER. DEV., vol. 30, 1990, pages 109 - 116, XP025437182, DOI: doi:10.1016/0922-3371(90)90079-C
AUGUSTYNOWICZ-KOPEC ET AL., FARMACO, vol. 60, 2005, pages 513
B. YANG, S. BUCHWALD, J. ORGANOMET. CHEM., vol. 576, 1999, pages 125
BELAIBA,R.S., DJORDJEVIC,T., BONELLO,S., ARTUNC,F., LANG,F., HESS,J., G6R!ACH,A.: "The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin", CIRC RES, vol. 98, no. 6, 2006, pages 828 - 836
BHARGAVA,A., FULLERTON,M.J., MYLES,K., PURDY,TM., FUNDER,J.W., PEARCE,D., COLE,T.J.: "The serumand glucocorticoid-induced kinase is a physiological mediator of aldosterone action", ENDOCRINOLOGY, vol. 142, 2001, pages 1587 - 1594
BIONDI,RM., KIELOCH,A., CURRIE,R.A., DEAK,M., ALESSI,D.R.: "The PIF- binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB", EMBO J, vol. 20, 2001, pages 4380 - 4390
BOEHMER,C, WAGNER,C.A, BECK,S., MOSCHEN,L., MELZIG,J., WERNER,A., LIN,J.T., LANG,F., WEHNER,F.: "The shrinkage-activated Na(+) conductance of rat hepatocytes and its possible correlation to rENaC", CELL PHYSIOL BIOCHEM, vol. 10, 2000, pages 187 - 194
BOEHMER,C., OKUR,F., SETIAWAN, I., BROER,S., LANG,F.: "Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB", BIOCHEM BIOPHYS RES COMMUN, vol. 306, 2003, pages 156 - 162
BOEHMER,C., WILHELM,V., PALMADA,M., WALLISCH,S., HENKE,G., BRINKMEIER,H., COHEN,P., PIESKE,B., LANG,F.: "Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium Channel SCN5A", CARDIOVASC RES, vol. 57, 2003, pages 1079 - 1084
BRENNAN,F.E., FULLER,P.J.: "Rapid upregulation of serum and glucocorticoidregulated kinase (sgk) gene expression by corticosteroids in vivo", MOL CELL ENDOCRINOL, vol. 166, 2000, pages 129 - 136
BROWN ET AL., BIOORG. MED. CHEM. LETT., vol. 20, 2010, pages 679
COOPER,M.S., BUJALSKA,L., RABBITT,E., WALKER,E.A, BLAND,R., SHEPPARD,M.C, HEWISON,M., STEWART, P.M.: "Modulation of 11 beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation", J BONE MINER RES, vol. 16, 2001, pages 1037 - 1044
D. ALVAREZ DE LA ROSA ET AL., AM. J. PHYSIOL. CELL PHYSIOL., vol. 284, 2003, pages 404 - 414
D. ALVAREZ DE LA ROSA ET AL., J. GEN. PHYSIOL., vol. 124, no. 4, October 2004 (2004-10-01), pages 395 - 407
D. CHAN, K. MONACO, R. WANG, M. WINTERS, TETRAHEDRON LETT., vol. 39, 1998, pages 2933
D. CRICH, H. DYKER, R. J. HARRIS, J. ORG. CHEM., vol. 54, 1989, pages 257
D. J. CAMP, I. D. JENKINS, J. ORG. CHEM., vol. 54, 1989, pages 3045
D. L.HUGHES, R. A.REAMER, J. J.BERGAN, E. J. J.GRABOWSKI, J. AM. CHEM. SOC., vol. 110, 1998, pages 6487
D. NICHOLS, S. FRESCAS, D. MARONA-LEWICKA, X. HUANG, B. ROTH, G. GUDELSKY, J. NASH, J. MED. CHEM, vol. 37, 1994, pages 4347
D. PERRIN ET AL., EXPERT OPIN. DRUG DISCOV., vol. 5, 2010, pages 51 - 63
DAVIES,S.P., REDDY,H, CAIVANO,M., COHEN,P.: "Specificity and mechanism of action of some commonly used protein kinase inhibitors", BIOCHEM J, vol. 351, 2000, pages 95 - 105, XP000979108, DOI: doi:10.1042/0264-6021:3510095
DEBONNEVILLE,C, FLORES,S.Y., KAMYNINA,E., PLANT,P.J., TAUXE,C, THOMAS,M.A., MUNSTER,C., CHRAIBI,A., PRATT,J.H., HORISBERGER,J.D.: "Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) Channel cell surface expression", EMBO J, vol. 20, 2001, pages 7052 - 7059, XP001181355, DOI: doi:10.1093/emboj/20.24.7052
F. DIEDERICH, P. STANG: "Metal-catalyzed Cross- coupling Reactions", 1998, WILEY-VCH
F. QING ET AL., J. CHEM. SOC. PERKIN TRANS., 1997, pages 3053
FALETTI,C.J., PERROTTI,N., TAYLOR,S.L, BLAZER-YOST,B.L.: "sgk: an essential convergence point for peptide and Steroid hormone regulation of ENaCmediated Na+ transport", AM J PHYSIOL CELL PHYSIOL, vol. 282, 2002, pages C494 - C500
FENG,Y., WANG,Q., WANG,Y., YARD,B., LANG,F.: "SGK1-mediated fibronectin formation in diabetic nephropathy", CELL PHYSIOL BIOCHEM, vol. 16, no. 4-6, 2005, pages 237 - 244
FILLON,S., KLINGEL,K., WARNTGES,S., SAUTER,M., GABRYSCH,S., PESTEL,S., TANNEUR,V., WALDEGGER,S., ZIPFEL,A., VIEBAHN,R.: "Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis", CELL PHYSIOL BIOCHEM, vol. 12, 2002, pages 47 - 54, XP009120338, DOI: doi:10.1159/000047826
FIRESTONE,G.L., GIAMPAOLO,J.R., O'KEEFFE,B.A.: "Stimulus-dependent regulation of serum and glucocortieoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity", CELL PHYSIOL BIOCHEM, vol. 13, 2003, pages 1 - 12
FRIEDRICH,B., FENG,Y., COHEN,P., RISER,T, VANDEWALLE,A., BROER,S., WANG,J., PEARCE, D., LANG,F.: "The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithlial Na(+) Channel alpha, beta, gamma-EnaC", PFLUGERS ARCH, vol. 445, no. 6, 2003, pages 693 - 696
FUNDER,J.: "Mineralocorticoids and cardiac fibrosis: the decade in review", CLIN EXP PHARMACOL PHYSIOL, vol. 28, 2001, pages 1002 - 1006, XP001181356, DOI: doi:10.1046/j.1440-1681.2001.03586.x
GAMPER,N., FILLON,S., HUBER,S.M., FENG,Y., KOBAYASHI,T., COHEN,P., LANG,F.: "IGF-1 up-regulates K+ Channels via P13-kinase, PDK1 and SGK1", PFLUGERS ARCH, vol. 443, 2002, pages 625 - 634
GONZALEZ-ROBAYNA,I.J., ALLISTON,T.N., BUSE,P., FIRESTONE,G.L., RICHARDS,J.S.: "Functional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells", MOL ENDOCRINOL, vol. 13, 1999, pages 1318 - 1337
GONZALEZ-ROBAYNA,I.J., FALENDER,A.E., OCHSNER,S., FIRESTONE,G.L., RICHARDS,J.S.: "Follicle-Stimulating hormone (FSH) stimulates phosphorylation and activation of protein kinase B (PKB/Akt) and serum and glucocorticoid-Induced kinase (Sgk): evidence for A kinase-independent signaling by FSH in granulosa cells", MOL ENDOCRINOL, vol. 14, 2000, pages 1283 - 1300
GREENE, WUTS: "Protective Groups in Organic Synthesis", 1991, WILEY
GUARNERI ET AL., J. HETEROCYCL. CHEM., vol. 23, 1986, pages 585
H. SAKODA ET AL., J. BIOL. CHEM., vol. 278, 2003, pages 25802 - 25807
HAJOS ET AL., J. ORG. CHEM., vol. 73, 2008, pages 3900
HAYASHI,M., TAPPING,R.I., CHAO,T.H., LO,J.F., KING,C.C., YANG,Y., LEE,J.D.: "BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase", J BIOL CHEM, vol. 276, no. 12, 2001, pages 8631 - 8634
HENKE,G., MAIER,G., WALLISCH,S., BOEHMER,C., LANG,F: "Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1", J CELL PHYSIOL, vol. 199, no. 2, 2004, pages 194 - 199
HOFMANN ET AL., JOURNAL FUER PRAKTISCHE CHEMIE, vol. 332, 1990, pages 584
HOUBEN-WEYL: "Methoden der Organischen Chemie", GEORG THIEME VERLAG
IMAIZUMI,K., TSUDA,M., WANAKA,A., TOHYAMA,M., TAKAGI,T.: "Differential expression of sgk mRNA, a member of the Ser/Thr protein kinase gene family, in rat brain after CNS injury", BRAIN RES MOL BRAIN RES, vol. 26, 1994, pages 189 - 196, XP025983704, DOI: doi:10.1016/0169-328X(94)90090-6
J. EIGUERO: "Comprehensive Heterocyclic Chemistry", vol. 3, 1996, ELSEVIER
J. HARTWIG, ANGEW. CHEM., vol. 110, 1998, pages 2154
J. PELLETIER, S. KINCAID, TETRAHEDRON LETT., vol. 41, 2000, pages 797
J. TSUJI: "Palladium Reagents and Catalysts", 1996, WILEY
KLINGEL,K., WARNTGES,S., BOCK,J., WAGNER,C.A., SAUTER,M., WALDEGGER,S., KANDOLF,R., LANG,F.: "Expression of cell volume-regulated kinase h-sgk in pancreatic tissue", AM J PHYSIOL GASTROINTEST LIVER PHYSIOL, vol. 279, 2000, pages G998 - G1002, XP009012226
KNOCHEL ET AL., CHEM. COMMUN., vol. 37, 2009, pages 5615
KOBAYASHI,T., COHEN,P.: "Activation ofserumand glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1 ) and PDK2", BIOCHEM J, vol. 339, 1999, pages 319 - 328
KOBAYASHI,T., DEAK,M., MORRICE,N., COHEN,P.: "Characterization of the structure and regulation of two novel isoforms of serumand glucocorticoidinduced protein kinase", BIOCHEM J, vol. 344, 1999, pages 189 - 197
KUMAR,J.M., BROOKS,D.P., OLSON,B.A., LAPING,N.J.: "Sgk, a putative serine/threonine kinase, is differentially expressed in the kidney of diabetic mice and humans", J AM SOC NEPHRAL, vol. 10, 1999, pages 2488 - 2494
LANG,F., HENKE,G., EMBARK,H.M., WALDEGGER,S., PALMADA,M., BOHMER.C., VALLON,V.: "Regulation of channels by the serum and glucocorticoid-inducible kinase - implications for transport, excitability and cell proliferation", CELL PHYSIOL BIOCHEM, vol. 13, no. 1, 2003, pages 41 - 50
LANG,F., KLINGEL,K., WAGNER,C.A., STEGEN,C., WARTTGES,S., FRIEDRICH,B., LANZENDORFER,M., MELZIG,J., MOSCHEN,L., STEUER,S.: "Deranged transcriptional regulation of cell-volume-sensitive kinase hSGK in diabetic nephropathy", PROC NATL ACAD SCI U. S. A, vol. 97, 2000, pages 8157 - 8162, XP001181880, DOI: doi:10.1073/pnas.97.14.8157
LEE,E., LEIN,E.S., FIRESTONE,G.L.: "Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible preotein kinase (sgk) during embryogenesis", MECH DEV, vol. 103, no. 1-2, 2001, pages 177 - 181
LIU,D., YANG,X., SONGYANG,Z.: "Identification of CISK, a new member of the SGK kinase family that promotes IL-3-dependent survival", CURR BIOL, vol. 10, 2000, pages 1233 - 1236
LOFFING,J., FLORES,S.Y., STAUB,O.: "Sgk kinases and their role in epithelial transport", ANNU REV PHYSIOL, vol. 68, 2006, pages 461 - 490
LOFFING,J., ZECEVIC,M., FERAILLE,E., KAISSLING,B., ASHER,C, ROSSIER,B.C., FIRESTONE,G.L., PEARCE,D., VERREY, F.: "Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting System: possible role of SGK", AM J PHYSIOL RENAL PHYSIOL, vol. 280, 2001, pages F675 - F682
M. BELLER, C. BOLM: "Transition Metals for Organic Synthesis", 1998, WILEY-VCH
M. R. NETHERTON, G. C. FU, TOPICS IN ORGANOMETALLIC CHEMISTRY, vol. 14, 2005, pages 85 - 108
M. SMITH, J. MARCH: "March's Advanced Organic Chemistry", 2001, WILEY-VCH
MAITTE ET AL., J. HETEROCYCL. CHEM., vol. 20, 1983, pages 1645
MCCORMICK,J.A., BHALLA,V., PAO,A.C., PEARCE,D.: "SGK1: a rapid aldosterone-induced regulator of renal sodium reabsorption", PHYSIOLOGY (BETHESDA, vol. 20, 2005, pages 134 - 9
MIZUNO,H., NISHIDA,E.: "The ERK MAP kinase pathway mediates induction of SGK (serumand glucocorticoid-inducible kinase) by growth factors", GENES CELLS, vol. 6, 2001, pages 261 - 268
NAT. PROTOC., vol. 3, 2008, pages 1101 - 1108
OTOMASU ET AL., CHEM. PHARM. BULL., vol. 32, 1984, pages 3361
P. KOCIENSKI: "Protecting Groups", 1994, THIEME
P. LAM, C. CLARK, S. SAUBERN, J. ADAMS, M. WINTERS, D. CHAN, A. COMBS, TETRAHEDRON LETT., vol. 39, 1998, pages 2941
P. LIDSTROM, J. TIERNEY, B. WATHEY, J. WESTMAN, TETRAHEDRON, vol. 57, 2001, pages 9225
PARK,J., LEONG,M.L, BUSE,P., MAIYAR,AC., FIRESTONE,G.L, HEMMINGS,B.A.: "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3- kinasestimulated signaling pathway", EMBO J, vol. 18, 1999, pages 3024 - 3033
PERROTTI,N., HE,R.A., PHILLIPS,S.A., HAFT,C.R., TAYLOR,S.I.: "Activation of serumand glucocorticoid-induced protein kinase (Sgk) by cyclic AMP and insulin", J BIOL CHEM, vol. 276, 2001, pages 9406 - 9412
Q. CHEN ET AL., TETRAHEDRON LETT., vol. 32, 1991, pages 7689
R. C. LAROCK: "Comprehensive Organic Transformations", 1999, WILEY-VCH
RAFFERTY, K. A: "Biology of Amphibian Tumors", 1969, SPRINGER-VERLAG, article "Mass culture of amphibia cells: methods and observations concerning stability of cell type", pages: 52 - 81
RICHARDS,J.S., FITZPATRICK,S.L., CLEMENS,J.W., MORRIS,J.K., ALLISTON,T., SIROIS,J.: "Ovarian cell differentiation: a cascade of multiple hormones, cellular Signals, and regulated genes", RECENT PRAG HORM RES, vol. 50, 1995, pages 223 - 254
ROBSON H, SIEBLER T, STEVENS DA, SHALET SM, WILLIAMS GR: "Thyroid hormone acts directly on growth plate chondrocytes to promote hypertrophic differentiation and inhibit clonal expansion and cell proliferation", ENDOCRINOLOGY, vol. 141, 2000, pages 3887 - 3897
ROZANSKY,D.J., WANG,J., DOAN,N., PURDY,T., FAULK,T., BHARGAVA,A., DAWSON,K., PEARCE,D.: "Hypotonie induction of SGK1 and Na+ transport in A6 cells", AM J PHYSIOL RENAL PHYSIOL, vol. 283, 2002, pages F105 - F113
S. BUCHWALD ET AL., J. AM. CHEM. SOC., vol. 123, 2001, pages 7727
S. BUCHWALD ET AL., ORGANIC LETT., vol. 4, 2002, pages 581
S. KANG ET AL., SYNLETT, vol. 3, 2002, pages 427
SAKODA,H., GOTOH,Y., KATAGIRI,H., KUROKAWA,M., ONO,H., ONISHI,Y., ANAI,M., OGIHARA,T., FUJISHIRO,M., FUKUSHIMA,Y.: "Differing roles of Akt and serumand glucocorticoid-regulated kinase in glucose metabolism, DNA synthesis, and oncogenic activity", J. BIOL. CHEM., vol. 278, 2003, pages 25802 - 25807
SHENOLIKAR,S., WEINMAN,E.J.: "NHERF: targeting and trafficking membrane proteins", AM J PHYSIOL RENAL PHYSIOL, vol. 280, 2001, pages F389 - F395
SHIGAEV,A., ASHER,C., LATTER,H., GARTY,H., REUVENY,E.: "Regulation of sgk by aldosterone and its effects on the epithelial Na(+) Channel", AM J PHYSIOL RENAL PHYSIOL, vol. 278, 2000, pages F613 - F619
SHUKUNAMI C, OHTA Y, SAKUDA M, HIRAKI Y: "Sequential progression of the differentiation program by bone morphogenetic protein-2 in chondrogenic cell line ATDC5", EXP. CELL RES., vol. 241, 1998, pages 1 - 11
SHUKUNAMI C, SHIGENO C, ATSUMI T, ISHIZEKI K, SUZUKI F, HIRAKI Y.: "Chondrogenic differentiation of clonal mouse embryonic cell line ATDC5 in vitro: differentiation-dependent gene expression of parathyroid hormone (PTH)/PTH- related peptide receptor", J. CELL. BIOL., vol. 133, 1996, pages 457 - 468, XP002969341, DOI: doi:10.1083/jcb.133.2.457
SIO ET AL., FARMACO SCI., vol. 37, 1982, pages 116
SNYDER,P.M., OLSON,D.R., THOMAS,B.C.: "Serum and glucocorticoidregulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ Channel", J BIOL CHEM, vol. 277, 2002, pages 5 - 8
STANOVNIK ET AL., HETEROCYCLES, vol. 19, 1982, pages 339
STAUB,O., GAUTSCHI,L., ISHIKAWA,T., BREITSCHOPF,K., CIECHANOVER,A., SCHILD,L., ROTN,D: "Regulation of stability and function of the epithelial Na+ Channel (ENaC) by ubiquitination", EMBO J, vol. 16, 1997, pages 6325 - 6336
T. FUCHIKAM ET AL., TETRAHEDRON LETT., vol. 32, 1991, pages 91
T. SAKAMOTO, K. OHSAWA, J. CHEM. SOC. PERKIN TRANS, 1999, pages 2323
TISLER ET AL., MONATSHEFTE FUR CHEMIE, vol. 113, 1982, pages 731
TOWNSEND ET AL., TETRAHEDRON LETT., vol. 45, 2004, pages 4105
V. FARINA, V. KRISHNAMURTHY, W. SCOTT: "The Stille Reaction", 1994, WILEY
VALLON,V., LANG,F.: "New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure", CURR OPIN NEPHROL HYPERTENS, vol. 14, no. 1, 2005, pages 59 - 66
VALLON,V., WULFF,P., HUANG,D.Y., LOFFING,J., VOELKL,H., KUH,D., LANG,F.: "Role of Sgk1 in salt and potassium homeostasis", AM J PHYSIOL REGUL INTEGR COMP PHYSIOL, vol. 288, no. 1, 2005, pages R4 - R10
W. STADLBAUER: "Houben-Weyl, Methoden der Organischen Chemie", vol. E8B, GEORG THIEME VERLAG
W. STADLBAUER: "Houben-Weyl, Science of Synthesis", vol. 12.2, 2002, GEORG THIEME VERLAG, pages: 227 - 324
WAGNER,C.A., BROER,A., ALBERS,A., GAMPER,N., LANG,F., BROER,S.: "The heterodimeric amino acid transporter 4F2hc/LAT1 is associated in Xenopus oocytes with a non-selective cation Channel that is regulated by the serine/threonine kinase sgk-1", J PHYSIOL, vol. 526, 2000, pages 35 - 46
WAGNER,C.A., OTT,M., KLINGEL,K., BECK,S., MELZIG,J., FRIEDRICH,B., WILD,K.N., BROER,S., MOSCHEN,L., ALBERS,A.: "Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) Channel (ENaC) and CFTR: implications for cystic fibrosis", CELL PHYSIOL BIOCHEM, vol. 11, 2001, pages 209 - 218
WALDEGGER,S., BARTH,P., RABER,G., LANG,F.: "Cloning and characterization of a putative human serine/threonine protein kinase transcriptionally modified during anisotonic and isotonic alterations of cell volume", PROC NATL ACAD SCI U.S.A, vol. 94, 1997, pages 4440 - 4445, XP002079929, DOI: doi:10.1073/pnas.94.9.4440
WALDEGGER,S., GABRYSCH,S., BARTH.,P., FILLON,S., LANG,F.: "h-sgk serinethreonine protein kinas[theta] as transcriptional target of p38/MAP kinase pathway in HepG2 human hepatoma cells", CELL PHYSIOL BIOCHEM, vol. 10, 2000, pages 203 - 208
WALDEGGER,S., KLINGEL,K., BARTH,P., SAUTER,M., RFER.M.L., KANDOLF,R., LANG,F.: "h-sgk serine-threonine protein kinase gene as transcriptional target of transforming growth factor beta in human intestine", GASTROENTEROLOGY, vol. 116, 1999, pages 1081 - 1088, XP005688400, DOI: doi:10.1016/S0016-5085(99)70011-9
WANG,J., BARBRY,P., MAIYAR,AC., ROZANSKY,D.J., BHARGAVA,A., LEONG,M., FIRESTONE,G.L., PEARCE,D.: "SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport", AM J PHYSIOL RENAL PHYSIOL, vol. 280, 2001, pages F303 - F313
WARNTGES,S., FRIEDRICH,B., HENKE,G., DURANTON,C, LANG,P.A., WALDEGGER,S., MEYERMANN,R., KUHL,D., SPECKMANN,E.J., OBERMULLER,N.: "Cerebral localization and regulation of the cell volume-sensitive serumand glucocorticoid-dependent kinase SGK1", PFLUGERS ARCH, vol. 443, 2002, pages 617 - 624
WARNTGES,S., KLINGEL,K., WEIGERT,C, FILLON,S., BUCK,M., SCHLEICHER,E., RODEMANN,H.P., KNABBE,C, KANDOLF, R., LANG,F.: "Excessive transcription of the human serum and glucocorticoid dependent kinase hSGK1 in lung fibrosis", CELL PHYSIOL BIOCHEM, vol. 12, 2002, pages 135 - 142, XP009048241, DOI: doi:10.1159/000063790
WEBSTER,M.K., GOYA,L, GE,Y., MAIYAR,A.C, FIRESTONE,G.L.: "Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum", MOL CELL BIOL, vol. 13, 1993, pages 2031 - 2040, XP002054150
WEBSTER,M.K., GOYA,L., FIRESTONE,G.L.: "Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase", J BIOL CHEM, vol. 268, 1993, pages 11482 - 11485, XP000882780
YUN,C.C., CHEN.Y., LANG,F.: "Glucocorticoid activation of Na(+)/H(+) exchanger isoform 3 revisited. The roles of SGK1 and NHERF2", J BIOL CHEM, vol. 277, 2002, pages 7676 - 7683
YUN,C.C.: "Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3", CELL PHYSIOL BIOCHEM, vol. 13, 2003, pages 29 - 40

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130072493A1 (en) * 2011-09-19 2013-03-21 Sanofi N-[4-(1H-PYRAZOLO[3,4-b]PYRAZIN-6-YL)-PHENYL]-SULFONAMIDES AND THEIR USE AS PHARMACEUTICALS
US9174993B2 (en) 2011-09-19 2015-11-03 Sanofi N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals
US9221828B2 (en) 2011-09-19 2015-12-29 Sanofi N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfonamides as pharmaceuticals
TWI629275B (zh) * 2013-03-13 2018-07-11 賽諾菲公司 Ｎ－（４－（氮雜吲唑－６－基）－苯基）－磺醯胺及其作為醫藥之用途
WO2015048531A1 (fr) * 2013-09-26 2015-04-02 Beth Israel Deaconess Medical Center, Inc. Inhibition de la sgk1 dans le traitement d'affections cardiaques
US9974788B2 (en) 2013-09-26 2018-05-22 Beth Israel Deaconess Medical Center, Inc. Inhibition of SGK1 in the treatment of heart conditions
US10456398B2 (en) 2013-09-26 2019-10-29 Beth Israel Deaconess Medical Center, Inc. Inhibition of SGK1 in the treatment of heart conditions
CN110337433A (zh) * 2016-12-07 2019-10-15 新时代医药科技南京有限公司 用于调节sgk活性的化合物和药物组合物及其方法
KR20190086673A (ko) * 2016-12-07 2019-07-23 뉴 에라 파마, 인코퍼레이티드 Sgk 활성을 조절하기 위한 화합물 및 약학 조성물 및 이의 방법
WO2018106459A1 (fr) 2016-12-07 2018-06-14 New Era Pharma, Inc. Composés et compositions pharmaceutiques pour moduler l'activité sgk, et leurs procédés
JP2020506877A (ja) * 2016-12-07 2020-03-05 ニュー エラ ファーマ，インク． Ｓｇｋ活性を調節するための化合物及び医薬組成物、並びにその方法
AU2017373758B2 (en) * 2016-12-07 2021-12-16 Orimos Therapeutics Co., Ltd. Compounds and pharmaceutical compositions for modulating SGK activity, and methods thereof
US11236083B2 (en) 2016-12-07 2022-02-01 Orimos Therapeutics Co., Ltd. Compounds and pharmaceutical compositions for modulating SGK activity, and methods thereof
CN110337433B (zh) * 2016-12-07 2023-02-28 南京奥利墨斯医药科技有限公司 用于调节sgk活性的化合物和药物组合物及其方法
JP7233715B2 (ja) 2016-12-07 2023-03-07 オリモス セラピューティクス カンパニー， リミテッド Ｓｇｋ活性を調節するための化合物及び医薬組成物、並びにその方法
KR102678781B1 (ko) * 2016-12-07 2024-06-27 오리모스 테라퓨틱스 씨오., 엘티디. Sgk 활성을 조절하기 위한 화합물 및 약학 조성물 및 이의 방법

Also Published As

Publication number Publication date
AU2011377409A1 (en) 2014-03-20
SG11201400551UA (en) 2014-04-28
CA2846369A1 (fr) 2013-03-28
AU2011377409B2 (en) 2017-05-25
IL231097A0 (en) 2014-03-31
CA2846369C (fr) 2018-11-13
KR20140064975A (ko) 2014-05-28

Similar Documents

Publication Publication Date Title
EP2570415B1 (fr) N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phényl]-sulfonamides et leur utilisation en tant que produits pharmaceutiques
AU2014230805B2 (en) N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides and their use as pharmaceuticals
JP5330430B2 (ja) プロテインキナーゼｂ阻害剤としてのピロロ［２，３−ｄ］ピリミジン誘導体
AU2011377409B2 (en) N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides and their use as pharmaceuticals
US9221828B2 (en) N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]sulfonamides as pharmaceuticals
JP5827849B2 (ja) Ｎ−［４−（１Ｈ−ピラゾロ［３，４−ｂ］ピラジン−６−イル）−フェニル］−スルホンアミド及び薬剤としてのその使用
CN103012407B (zh) N-[4-(1H-吡唑并[3,4-b]吡嗪-6-基)-苯基]-磺酰胺类及其作为药物的用途

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: 11769810

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 231097

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2846369

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2011377409

Country of ref document: AU

Date of ref document: 20110919

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20147010212

Country of ref document: KR

Kind code of ref document: A

122 Ep: pct application non-entry in european phase

Ref document number: 11769810

Country of ref document: EP

Kind code of ref document: A1