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EP2356112A1 - Composés hétéroaromatiques pour une utilisation comme inhibiteurs de hif - Google Patents

Composés hétéroaromatiques pour une utilisation comme inhibiteurs de hif

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Publication number
EP2356112A1
EP2356112A1 EP09744089A EP09744089A EP2356112A1 EP 2356112 A1 EP2356112 A1 EP 2356112A1 EP 09744089 A EP09744089 A EP 09744089A EP 09744089 A EP09744089 A EP 09744089A EP 2356112 A1 EP2356112 A1 EP 2356112A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
ring
fluorine
cycloalkyl
substituted
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP09744089A
Other languages
German (de)
English (en)
Inventor
Michael Härter
Hartmut Beck
Peter Ellinghaus
Kerstin Berhoerster
Susanne Greschat
Karl-Heinz Thierauch
Frank SÜSSMEIER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Schering Pharma AG
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
Priority claimed from DE102008057364A external-priority patent/DE102008057364A1/de
Priority claimed from DE102009041241A external-priority patent/DE102009041241A1/de
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2356112A1 publication Critical patent/EP2356112A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present application relates to novel substituted aryl compounds, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of hyperproliferative and angiogenic diseases as well as those diseases which arise through a metabolic adaptation to hypoxic conditions.
  • Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • Chemotherapies often consist of combinations of cytotoxic drugs. The majority of these substances have a binding mechanism to tubulin, or they are compounds that interact with the formation and processing of nucleic acids. More recently, these include enzyme inhibitors that interfere with epigenetic DNA modification or cell cycle progression (eg, histone deacetylase inhibitors, Aurora kinase inhibitors). Since such therapies are toxic, more and more recently, targeted therapies are being used in which specific processes in the cell are blocked, without any high toxic load occurs. These include in particular inhibitors of kinases which inhibit the phosphorylation of receptors and signal transduction molecules. An example of this is imatinib, which is used very successfully for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • CML chronic myeloid leukemia
  • GIST gastrointestinal stromal tumors
  • EGFR-kinase and HER2-blocking substances such as erlotinib and VEGFR-kinase inhibitors such as sorafenib and sunitinib, which are used in renal cell carcinoma, liver carcinoma and advanced stages of GIST.
  • Bevacizumab inhibits blood vessel growth, which hinders the rapid expansion of a tumor, as it requires a connection to the blood vessel system for a continuously functioning supply and disposal.
  • hypoxia hypoxia
  • FIH factor inhibiting HIF
  • HIF can be degraded via the proteasome apparatus via the Hippel Lindau protein (part of a ubiquitin E3 ligase complex) (Maxwell, Wiesener et al., 1999). In the absence of oxygen, breakdown is avoided, the protein is up-regulated and leads to the transcription or blockade of the transcription of numerous (more than 100) other proteins (Semenza and Wang, 1992, Wang and Semenza, 1995).
  • the transcription factor HIF is formed by the regulated ⁇ - and a constitutively present ⁇ -subunit (ARNT).
  • ARNT ⁇ -subunit
  • the FTTF subunits are bHLH (basic helix loop helix) proteins which dimerize via their HLH and PAS (per-Arnt-Sim) domains, which starts their transactivating activity (Jiang, Rue et al. , 1996).
  • HIFl ⁇ protein In the most important tumor entities, overexpression of the HIFl ⁇ protein is correlated with increasing blood vessel density and increased VEGF expression (Hirota and Semenza, 2006). Equal- In time, the glucose metabolism is changed towards glycolysis, and the Krebs cycle is reduced in favor of the production of cell building blocks. This also implies a change in lipid metabolism. Such changes seem to ensure the survival of the tumors. On the other hand, if the activity of HIF is inhibited, then it would be possible to suppress the development of tumors.
  • the object of the present invention was thus to provide novel compounds which act as inhibitors of the transactivating effect of the transcription factor HIF and as such can be used for the treatment and / or prevention of diseases, in particular hyperproliferative and angiogenic diseases such as cancers
  • WO 2005/030121-A2 and WO 2007/065010-A2 claim the use of certain pyrazole derivatives for inhibiting the expression of HIF and HIF-regulated genes in tumor cells.
  • WO 2008/141731-A2 describes heteroaryl-substituted N-benzylpyrazoles as inhibitors of the HIF-regulation route for the treatment of cancers.
  • Heteroaryl-substituted 5- (1H-pyrazol-3-yl) -l, 2,4-oxadiazoles as cannabinoid receptor modulators for the treatment of various diseases are disclosed in US 2008/0255211-Al.
  • Further diaryl-substituted isoxazole and 1, 2,4-oxadiazole derivatives are described in WO 2009/029632-A1 as inhibitors of monoamine oxidase B for the treatment of psychiatric disorders.
  • the present invention relates to compounds of the general formula (I)
  • E J is a phenyl or pyridyl ring
  • R 6 and R 7 are independently hydrogen, (Ci-C 6) -alkyl or (C 3 -C 6) -cycloalkyl,
  • Trifluoromethoxy, (C r C 4 ) alkoxycarbonyl and (C 3 -C 6 ) cycloalkyl may be substituted
  • R 8 is hydrogen, amino, (C r C6) alkyl, (C 3 -C 6) cycloalkyl or 5- or 6-membered heteroaryl,
  • (Ci-Cs) alkyl up to three times with fluorine and up to twice, identically or differently, with a group selected from the group hydroxy, (C r C 4 ) alkoxy, trifluoromethoxy, (C r C 4 ) alkoxycarbonyl , (C 3 -C 6 ) -cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and 5- or 6-membered heteroaryl
  • heteroaryl groups up to three times, identically or differently, with a radical selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 ) -alkyl, trifluoromethyl, (QC 4 ) -alkoxy and trifluoromethoxy
  • R 2 is hydrogen or a substituent selected from the group fluorine, chlorine, cyano, methyl, trifluoromethyl, hydroxy, methoxy and trifluoromethoxy,
  • R 3 is methyl, ethyl or trifluoromethyl
  • R 4 is hydrogen or a substituent selected from the group halogen, cyano,
  • cycloalkyl and heterocyclic groups in turn up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, hydroxy, (C 1 -Q) -alkoxy, oxo, amino, mono- (Ci-C 4) alkylamino, di- (dC 4) alkylamino, (C 1 -C 4) - alkylcarbonylamino, (C r C4) alkoxycarbonylamino, (CrC 4) alkylcarbonyl, (C 1 - C 4) - alkoxycarbonyl, aminocarbonyl, mono- (C r C4) alkylaminocarbonyl and di (C r C4) alkyl aminocarbonyl
  • heteroaryl groups in turn up to two times by identical or different radicals selected from the series comprising fluorine, chlorine, cyano, (C r C4) alkyl and (C 1 -C 4) - alkoxy
  • (C 3 -C 6) -cycloalkyl or 4- alkyl, to 6-membered heterocyclyl, - R 9 and R 10 are independently at each occurrence hydrogen, (C 1 -C O)
  • (C 1 -C 6 ) -alkyl is up to three times fluorine and up to twice, identically or differently, with a radical selected from the group consisting of hydroxy, (C 1 -C 4 ) -alkoxy, trifluoromethoxy, amino, mono (C r C 4) -alkylamino, di- (C r C 4) alkylamino, (C 1 - C 4) alkoxycarbonyl, (C 3 -C 6) cycloalkyl, and A- to 6-membered heterocyclyl may be substituted
  • said cycloalkyl and heterocyclyl groups up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoromethyl, hydroxy, (dC 4) -alkoxy, trifluoromethoxy, oxo, amino , mono- (C r C 4) alkylamino, di- (C r C 4) alkylamino, (C r C4) alkylcarbonyl and (C r C 4) - alkoxycarbonyl can be substituted, or
  • R 9 and R 10 in the case where both are attached to a nitrogen atom together with this nitrogen atom form a 4- to 6-membered heterocycle which is another ring heteroatom from the series N, O, S or S (O) 2 may contain up to two times, the same or different, with a radical selected from the series fluorine,
  • (Ci-C 4) -alkyl Trifiuormethyl, hydroxy, (C r C4) alkoxy, oxo, amino, mono- (Ci-C 4) alkylamino, di- (C r C 4) alkylamino, (C r C 4 ) -alkylcarbonyl and (C r C 4 ) -alkoxycarbonyl may be substituted,
  • R 5 is a substituent selected from the group fluorine, chlorine, cyano, methyl, trifluoromethyl and hydroxy
  • n is the number 0, 1 or 2
  • said cycloalkyl groups in turn up to two times, identically or differently, with a radical selected from the group consisting of fluorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxy, (Q-C 4 ) -alkoxy, trifluoromethoxy and (C r C 4 ) alkoxycarbonyl may be substituted, and in which
  • R 6 and R 7 have the meanings given above
  • R 8 denotes hydrogen, (C r C6) alkyl, (C 3 -C 6) cycloalkyl or 5- or 6-membered hetero-aryl,
  • (C 1 -Co) -alkyl up to three times by fluorine and up to two times, identically or differently, with a residue selected from the series comprising hydroxyl, (Ci-C 4) -alkoxy, trifluoromethoxy, (C r C4) - Alkoxycarbonyl, (C 3 -C 6 ) cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and 5- or 6-membered heteroaryl may be substituted
  • heteroaryl groups up to three times, identically or differently, with a radical selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy and trifluoromethoxy
  • R 4 is hydrogen or a substituent selected from the group halogen, cyano,
  • said cycloalkyl and heterocyclic groups in turn up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoro- methyl, hydroxy, (Ci-C 4) alkoxy, trifluoromethoxy, oxo, amino, mono- (Ci-C 4) alkyl amino, di- (C] -C4) alkylamino, (Ci-C4) alkylcarbonylamino, (Ci-C 4) alkoxycarbonyl amino , (C r C4) alkylcarbonyl and (C r C 4) alkoxycarbonyl
  • heteroaryl groups in turn up to two times by identical or different radicals selected from the series comprising fluorine, chlorine, cyano, (C r C4) alkyl, trifluoromethyl, (C r C 4) -alkoxy and trifluoromethoxy
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • physiologically acceptable salts of the compounds according to the invention are preferred in the context of the present invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, benzenesulfonic, toluenesulfonic, naphthalenedisulfonic formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salt
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • N-oxides of pyridyl rings and tertiary cyclic amine moieties contained in compounds of this invention are also encompassed by the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • substituents have the following meaning: and (C 1 -Ca) -AlkVl in the context of the invention are a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • (C 2 -QVAlkenyl and (C 2 -Cd) -AIkCnVl are in the context of the invention a straight-chain or branched alkenyl radical having 2 to 6 or 2 to 4 carbon atoms and one double bond.
  • Preferred is a straight-chain or branched alkenyl radical having 2 to 4 Examples which may be mentioned by way of example and preferably include: vinyl, allyl, ⁇ -prop-1-en-1-yl, isopropenyl, 2-methyl-2-propen-1-yl, ⁇ -but-1-en-1-yl, w-but-2-en-1-yl and n-but-3-en-1-yl.
  • (C 2 -C 4) -AlkJnVl and (C 2 -Cd) -alkynyl are in the context of the invention a straight-chain or branched alkynyl radical having 2 to 6 or 2 to 4 carbon atoms and a triple bond. Preference is given to a straight-chain alkynyl radical having 2 to 4 carbon atoms.
  • Examples which may be mentioned by way of example include: acetyl, propionyl, -butyryl, -butyryl, M-pentanoyl and pivaloyl.
  • Tri-rCpCaValkylsilyl is in the context of the invention for a silyl group having three identical or different straight-chain or branched alkyl substituents, each having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include trimethylsilyl, tert-butyldimethylsilyl and triisopropylsilyl.
  • (C 1 -Cd) -alkoxy is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, M-propoxy, isopropoxy, n-butoxy, / is-butoxy, sec-butoxy and tert-butoxy.
  • (C 1 -C 4 -alkoxycarbonyl in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group [-C (OO) -].
  • Mono- (C 1 -C 1 ) -alkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has 1 to 4 carbon atoms.
  • Di- (C r Q> alkylamino the invention for an amino group having two identical or different straight-chain or branched alkyl substituents having in each case 1 to 4 carbon atoms is for the purposes of example and preferably be mentioned are:.
  • NN-dimethylamino NN-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-methylamino, N-isopropyl-Nn-propylamino, N, N-diisopropylamino, N - "- butyl-N-methylamino and N-tert. - butyl-N-methylamino.
  • Examples which may be mentioned by way of example and with preference are: methylaminocarbonyl, ethylaminocarbonyl, .alpha.-propylaminocarbonyl, isopropylaminocarbonyl, H-butylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N- -propylaminocarbonyl, N-isopropyl-N-methylaminocarbonyl, N, N-diisopropylaminocarbonyl, N, N-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.
  • (C 1 -C 4 -alkylcarbonylamino represents an amino group having a straight-chain or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl radical and is bonded to the ⁇ -atom via the carbonyl group, by way of example and preferably: acetylamino , Propionylamino, "-butyrylamino, / so-butyrylamino, n-pentanoylamino and pivaloylamino.
  • (CpCY) -Alkylcarbonyloxy in the context of the invention is an oxo radical having a straight-chain or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl radical and is linked via the carbonyl group to the oxygen atom.
  • Examples which may be mentioned by way of example include: acetoxy, propionoxy, w-butyroxy, / so-butyroxy, w-pentanoyloxy and pivoyloxy.
  • CVCa VAlkoxycarbony lam ino in the context of the invention represents an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 4 carbon atoms in the alkoxy radical and is linked to the ⁇ -atom via the carbonyl group.
  • CyCfiVcycloalkyl represents a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms, by way of example and by way of preference: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 4- to 6-membered heterocyclyl is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 6 ring atoms containing one or two ring heteroatoms from the series N, O, S and / or S (O) 2 and is linked via a ring carbon atom or optionally via a ring nitrogen atom.
  • Preference is given to 4- to 6-membered heterocyclyl having one or two ring heteroatoms from the series N, O and / or S. may be mentioned by way of example: acetamido, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1 -Dioxidothiolanyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl and 1,1-dioxothiomorpholinyl , Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydro
  • 5- or 6-membered heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S. a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine, fluorine or bromine, more preferably fluorine or chlorine.
  • An oxo substituent in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one or two or three identical or different substituents is preferred. Particularly preferred is the substitution with one or two identical or different substituents.
  • the present invention relates, in particular, to those compounds of the general formula (I) in which the ring (AJ stands for a phenyl or pyridyl ring and the adjacent groups R 1 and
  • the ring (AJ is a pyridyl ring and the adjacent groups R 1 and CH 2 are bonded in 1,3- or 1,4-relative to each other at ring carbon atoms of this pyridyl ring
  • the ring (A) is a phenyl ring and the adjacent groups R 1 and CH 2 are bonded in 1,3- or 1,4-relative to one another to this phenyl ring and
  • (Ci-C 4) -alkyl and (C 2 -C 4) -alkynyl turn with a radical selected from the series comprising hydroxyl, (C r C 4) -alkoxy, trifluoromethoxy, trimethylsilyl, (C r C4) -alkoxycarbonyl and (C 3 -C 6 ) -cycloalkyl and may be substituted up to three times by fluorine
  • Oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups in turn up to two times, same or different, selected from the group fluorine, (Ci-C 4 ) alkyl, trifluoromethyl, hydroxy, (Ci-C 4 ) alkoxy , Trifluoromethoxy and (C 1 -C 4 ) -alkoxycarbonyl may be substituted,
  • R 6 and R 7 independently of one another denote hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl,
  • (C r C 4 ) -alkyl can be substituted by a radical selected from the series hydroxy, (Ci-C 4 ) - alkoxy, trifluoromethoxy and (C 3 -C 6 ) -cycloalkyl and up to three times with fluorine
  • the said cycloalkyl groups may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluoro, (C 1 -C 4 ) -alkyl, trifluoromethyl, hydroxyl, (QC 4 ) -alkoxy and trifluoromethoxy,
  • R 8 is hydrogen, amino, (C r C6) alkyl, (C 3 -C 6) cycloalkyl or 5- or 6-membered heteroaryl,
  • Tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups up to two times, identically or differently, with a radical selected from the group fluorine, (C r C 4 ) alkyl, trifluoromethyl, hydroxy, (C r C 4 ) alkoxy and (CpC 4 ) -
  • heteroaryl groups up to three times, identically or differently, with a radical selected from the group consisting of (Ci-Gi) -alkyl, trifluoromethyl, (Ci-C 4 ) - alkoxy and trifluoromethoxy
  • R 2 is hydrogen or a substituent selected from the group fluorine, chlorine, methyl, trifluoromethyl, methoxy and trifluoromethoxy,
  • R 3 is methyl, ethyl or trifluoromethyl
  • the said cycloalkyl and heterocyclyl groups in turn up to twice, identically or differently, with a radical selected from the group fluorine, (C r C 4 ) alkyl, hydroxy, (C r C 4 ) alkoxy, oxo, (C r C 4 ) -alkylcarbonyl, mono- (Ci-C 4 ) -alkylaminocarbonyl and di- (C] -C 4 ) -alky lam inocarbony 1
  • the said heteroaryl groups in turn up to twice, identically or differently, with a radical selected from the group fluorine, chlorine, cyano, (C] -C 4 ) alkyl and (C] -C 4 ) - alkoxy
  • (C] -C 4 ) -Alkoxy substituents in turn with hydroxy, (Ci-C 4 ) alkoxy, trifluoromethoxy, (Ci-C 4 ) alkoxycarbonyl, mono- (Ci-C 4 ) alkylaminocarbonyl or di (Ci -C 4 ) -alkylaminocarbonyl or may be substituted up to three times by fluorine, and in which
  • R 9 and R 10 independently of one another at each individual occurrence denote hydrogen, (C 1 -C 4 ) -alkyl, (C 3 -C 6) -cycloalkyl or 4- to 6-membered heterocyclyl,
  • cycloalkyl and heterocyclyl groups up to two times by identical or different radicals selected from the series fluorine, (Ci-C4) alkyl, tri- fluoromethyl, hydroxy, (C r C 4) -alkoxy, trifluoromethoxy , oxo and (C r C 4) alkyl carbonyl may be substituted,
  • R 9 and R 10 in the case where both are attached to a nitrogen atom together with this nitrogen atom form a 4- to 6-membered heterocycle which is another ring heteroatom from the series N, O, S or S (O) 2 and may contain up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoromethyl, hydroxy, (C r C4) alkoxy, oxo and (C r C 4 ) Alkylcarbonyl,
  • R 5 is a substituent selected from the group fluorine, chlorine and methyl
  • n is the number 0 or 1
  • the said cycloalkyl groups in turn up to two times, identically or differently, with a radical selected from the group fluorine, (Ci-C 4 ) alkyl, trifluoromethyl, hydroxy, (C 1 - C 4 ) alkoxy, trifluoromethoxy and (QC 4 ) alkoxycarbonyl may be substituted,
  • R 6 and R 7 have the meanings mentioned in the last-described embodiment
  • R 8 is hydrogen, (C 1 -C 6 ) -alkyl, (C 3 -C 6 ) -cycloalkyl or 5- or 6-membered heteroaryl,
  • Tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups up to two times, same or different, with a radical selected from the series
  • heteroaryl groups of up to three times by identical or different radicals selected from the series (C r C 4) -alkyl, trifluoromethyl, (QC 4) -
  • cycloalkyl and heterocyclic groups in turn up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoro- methyl, hydroxy, (Ci-C 4) alkoxy, Trifluoromethoxy, oxo and (C r C 4 ) alkylcarbonyl
  • heteroaryl groups in turn up to two times by identical or different radicals selected from the series comprising fluorine, chlorine, cyano, (Ci-C 4) -alkyl, trifluoromethyl, (C r C 4) -alkoxy and trifluoromethoxy
  • R 9 and R 10 have the meanings given in the last-described embodiment
  • R Liinngg f is a heteroaryl ring of the formula
  • CCi-C 4) -alkyl and (C may be 2 -C 4) alkynyl turn with a radical selected from the group of hydroxy, methoxy, ethoxy, trifluoromethoxy, cyclopropyl and cyclobutyl, and up to three times substituted by fluorine
  • Oxetanyl and tetrahydropyranyl may in turn be substituted by methyl, ethyl, hydroxy, methoxy or ethoxy
  • the said cyclopropyl and cyclobutyl groups may in turn be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • R 6 and R 7 independently of one another denote hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl,
  • (C 1 -C 4 ) -alkyl can be substituted by one radical selected from the series hydroxy, methoxy, ethoxy, trifluoromethoxy, cyclopropyl and cyclobutyl and up to three times by fluorine,
  • R 8 is hydrogen, (C r C4) alkyl, (C 3 -C 6) cycloalkyl or 5- or 6-membered hetero aryl means,
  • (C r C 4 ) -alkyl having a radical selected from the series hydroxy, methoxy, ethoxy, trifluoromethoxy, (C 3 -C 6 ) -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl and 5- or 6-membered heteroaryl and up to three times with Fluorine can be substituted
  • Tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups up to two times, same or different, with a radical selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy
  • heteroaryl groups up to three times, identically or differently, with a radical selected from the group consisting of methyl, ethyl and trifluoromethyl
  • R 2 is hydrogen or a substituent selected from the group fluorine, chlorine, methyl and methoxy,
  • R 3 is methyl
  • the said cycloalkyl and heterocyclyl groups in turn may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy and oxo,
  • R 9 and R 10 independently of one another each occurrence represent hydrogen, (Q-C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, wherein (Ci-C 4) -alkyl with a radical selected from the series comprising hydroxyl, (C r C 4) - may be alkoxy, trifluoromethoxy, and (C 3 -C 6) cycloalkyl, and up to trisubstituted by fluorine
  • cycloalkyl groups of up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoromethyl, (Q- C4) -alkoxy and trifluoromethoxy,
  • R 9 and R 10 when both are attached to a nitrogen atom, together with this nitrogen atom form a 4- to 6-membered heterocycle which is another
  • Ring heteroatom from the series N, O, S or S (O) 2 and which may contain up to twice, identically or differently, a radical selected from the group fluorine, (C 1 -C 4 ) -alkyl, hydroxy, ( C] -C 4 ) alkoxy, oxo, acetyl and propionyl may be substituted,
  • R 5 is fluorine
  • n is the number 0 or 1
  • (C 1 -C 4 ) -alkyl and (C 2 -C 4 ) -alkynyl may in turn be substituted by one radical selected from the series hydroxy, methoxy, ethoxy, trifluoromethoxy, cyclopropyl and cyclobutyl and up to three times by fluorine
  • cyclopropyl and cyclobutyl groups may in turn be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • R 6 , R 7 and R 8 have the meanings given in the last-described embodiment
  • (C 1 -C 6 ) -alkyl in turn contains a radical selected from the group -OR 9 , -NR 9 R 10 ,
  • -CX O) -NR 9 R 1 °, (C 3 -C 6 ) -cycloalkyl and 4- to 6-membered heterocyclyl and may be substituted up to three times by fluorine
  • said cycloalkyl and heterocyclic groups in turn up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, trifluoromethyl, (C] -G t) -alkoxy, trifluoromethoxy, and oxo can be substituted
  • R 9 and R 10 have the meanings given in the last-described embodiment
  • (C 1 -C 4 ) -alkyl and (C 2 -C 4 ) -alkynyl may in turn be substituted by one radical selected from the series hydroxy, methoxy, ethoxy, trifluoromethoxy, cyclopropyl and cyclobutyl and up to three times by fluorine
  • Oxetanyl and tetrahydropyranyl may in turn be substituted by methyl, ethyl, hydroxy, methoxy or ethoxy
  • the said cyclopropyl and cyclobutyl groups may in turn be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • R 6 and R 7 independently of one another denote hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl,
  • CC r C 4 ) -alkyl may be substituted by a radical selected from the series hydroxy, methoxy, ethoxy, trifluoromethoxy, cyclopropyl and cyclobutyl and up to three times with fluorine,
  • R 8 is hydrogen, CC r C 4 ) -alkyl, (C 3 -C 6 ) -cycloalkyl or 5- or 6-membered heteroaryl,
  • Tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups up to two times, same or different, with a radical selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy
  • heteroaryl groups up to three times, identically or differently, with a radical selected from the group consisting of methyl, ethyl and trifluoromethyl
  • R 2 is hydrogen or a substituent selected from the group fluorine, chlorine, methyl and methoxy,
  • R 3 is methyl
  • the said cycloalkyl and heterocyclyl groups in turn may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy and oxo,
  • R 9 and R 10 independently of one another at each occurrence represent hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, where (Ci-GO-alkyl having one radical selected from the series hydroxy, (C r C 4 ) - alkoxy, trifluoromethoxy and (C 3 -C 6 ) cycloalkyl and may be substituted up to three times with fluorine
  • the said cycloalkyl groups may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluoro, (C 1 -C 4 ) -alkyl, trifluoromethyl, ((LVC 4 ) -alkoxy and trifluoromethoxy,
  • R 9 and R 10 when both are attached to a nitrogen atom, together with this nitrogen atom form a 4- to 6-membered heterocycle which is another
  • R 5 is fluorine
  • n is the number 0 or 1
  • cyclopropyl and cyclobutyl groups may in turn be substituted up to two times, identically or differently, by a radical selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • the said cycloalkyl and heterocyclyl groups in turn may be substituted up to two times, identically or differently, by a radical selected from the group fluorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, (QG t ) -alkoxy, trifluoromethoxy and oxo .
  • R 9 and R 10 have the meanings given in the last-described embodiment
  • R Liinngg ((D D)) represents a heteroaryl ring of the formula
  • R 1 is methyl or the group -NR 6 R 8 , wherein R 6 is hydrogen, methyl, ethyl or cyclopropyl,
  • R 8 (C r C4) alkyl or (C 3 -C 6) -cycloalkyl
  • (C r C 4 ) -alkyl having a radical selected from the group hydroxy, methoxy, ethoxy, (C 3 -C 6 ) -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl and 5- or 6-membered heteroaryl and up to three times substituted with fluorine can be
  • Tetrahydrofuranyl, tetrahydropyranyl and said cycloalkyl groups up to two times, same or different, with a radical selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy
  • heteroaryl group up to three times, identically or differently, with a radical selected from the group consisting of methyl, ethyl and trifluoromethyl
  • R 2 is hydrogen
  • R 3 is methyl
  • said cycloalkyl and heterocyclyl groups in turn up to twice, identically or differently, with a radical selected from the group fluorine, (C r C 4 ) alkyl, trifluoromethyl, (Ci-C 4 ) alkoxy, trifluoromethoxy and oxo substituted could be, wherein the said (C 1 -C 4 ) -alkyl substituent in turn may be substituted by methoxy, trifluoromethoxy or ethoxy,
  • R 9 and R 10 are independently at each occurrence hydrogen, (Ci-C4) - alkyl or (C 3 -C 6) -cycloalkyl,
  • (Ci-C 4) -alkyl with a radical selected from the series comprising hydroxyl, (C r C 4) - may be alkoxy, trifluoromethoxy, and (C 3 -C 6) cycloalkyl, and up to trisubstituted by fluorine
  • the said cycloalkyl groups may be substituted up to twice, identically or differently, by a radical selected from the group consisting of fluorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy and trifluoromethoxy,
  • R 9 and R 10 when both are attached to a nitrogen atom, together with this nitrogen atom form a 4- to 6-membered heterocycle which is another
  • R 5 is fluorine
  • n is the number 0 or 1
  • the said cycloalkyl and heterocyclyl groups in turn up to two times, identically or differently, with a radical selected from the group fluorine, (C r C 4 ) alkyl, trifluoromethyl, (QG t ) -alkoxy, trifluoromethoxy and oxo substituted could be,
  • R 9 and R 10 have the meanings given in the last-described embodiment
  • ⁇ denotes the point of attachment to the adjacent CH 2 group
  • the ring f represents a heteroaryl ring of the formula
  • O - N represents N-O, in which
  • R 6 and R 7 independently of one another are hydrogen, (C) -C 4 ) -alkyl or (C 3 -C 6 ) -cycloalkyl,
  • (C 1 -C 4 ) -alkyl may be substituted by a radical selected from the series hydroxy, methoxy, ethoxy, cyclopropyl and cyclobutyl and up to three times by fluorine,
  • R 2 is hydrogen
  • (Ci-Q) -alkyl in turn having a radical selected from the group -OR 9 , -NR 9 R 10 ,
  • the said cycloalkyl and heterocyclyl groups in turn up to two times, identically or differently, with a radical selected from the group fluorine, (Ci-C 4 ) alkyl, trifluoromethyl, (Ci-C 4 ) alkoxy, trifluoromethoxy and Oxo may be substituted,
  • R 9 and R 10 independently of one another each time hydrogen, (Ci-C 4 ) -
  • (C 1 -C 4 ) -alkyl can be substituted by one radical selected from the series hydroxy, (C 1 -C 4 ) -alkoxy, trifluoromethoxy and (C 3 -C 6 ) -cycloalkyl and up to three times by fluorine
  • cycloalkyl groups of up to two times by identical or different radicals selected from the series fluorine, (C r C4) alkyl, Trifiuormethyl, (C r C 4) -alkoxy and trifluoromethoxy,
  • Nitrogen atom form a 4- to 6-membered heterocycle which may contain a further ring heteroatom from the series N, O, S or S (O) 2 and which up to two times, identically or differently, with a radical selected from the series fluorine, (Ci-C 4) alkyl, hydroxy, (C r C4) alkoxy, oxo, acetyl and propionyl may be substituted, R 5 is fluorine
  • n is the number 0 or 1
  • (C 1 -C 6 ) -alkyl in turn contains a radical selected from the group -OR 9 , -NR 9 R 10 ,
  • the said cycloalkyl and heterocyclyl groups in turn up to twice, identically or differently, with a radical selected from the group fluorine, (C r C 4 ) alkyl, trifluoromethyl, (Q-Gi) -alkoxy, trifluoromethoxy and oxo can be substituted
  • R 9 and R 10 have the meanings given in the last-described embodiment
  • Process A (with the variants Al and A.2, see Schemes 1 and 2) is characterized in that compounds of the formula (FV) in which B, D, E, R 3 , R 4 , R 5 and n are as above have been described and in which the indicated hydrogen atom is bonded to a nitrogen atom of the ring B, are reacted with compounds of formula (II) or (Ul) in which A, R 1 and R 2 have the meanings described above and in which Y 1 generally represents an atom or a group from which or with the aid of which, if appropriate, the substituent R 1 can be constructed or introduced, and in which X is a leaving group.
  • FV compounds of the formula (FV) in which B, D, E, R 3 , R 4 , R 5 and n are as above have been described and in which the indicated hydrogen atom is bonded to a nitrogen atom of the ring B, are reacted with compounds of formula (II) or (Ul) in which A, R 1 and R 2 have the meaning
  • Examples of Y 1 are chlorine, bromine, iodine, cyano, nitro, hydroxy, formyl, carboxyl and alkoxycarbonyl; Examples of X are chlorine, bromine, iodine, methanesulfonate (mesylate), trifluoromethanesulfonate (triflate) and 4-methylbenzenesulfonate (tosylate).
  • Imidazole-l, 4-diyl This reaction is preferably carried out using a base such as potassium tert. Butylate or sodium hydride in solvents such as tetrahydrofuran or toluene at temperatures between 0 0 C and the boiling point of the solvent.
  • process B (Schemes 3 and 4), the ring D is built up, the ring D here being a 1,2,4-oxadiazole. Method B is also used in various modifications. tion (variants Bl and B.2).
  • Process variant B.2 is similar to process variant A.2 with regard to the partial reactions which relate to the conversion of the radical Y 1 into the substituent R 1 . In the following, therefore, only the variant B1 will be shown in more detail (scheme 3).
  • reaction of the compounds of the formula (VI) with the compounds of the formula (VIII) is carried out in the presence of coupling reagents, for example 1H-benzotriazol-1-ol and N- [3- (dimethylamino) propyl] -N'- ethylcarbodiimide hydrochloride, as well as in the presence of tertiary amine bases, such as, for example, triethylamine, and in suitable solvents, for example N, N-dimethylformamide.
  • the reactants are first reacted with each other for some time at room temperature before the mixture is then heated to temperatures in the range of +80 0 C to +140 0 C.
  • the compounds of formula (VI) may first be converted to the corresponding carboxylic acid chlorides.
  • chlorination reagents such as oxalyl chloride or thionyl chloride
  • inert solvents such as dichloromethane or chloroform
  • the reaction is preferably carried out at room temperature and in the presence of a catalytic amount of N, N-dimethylformamide.
  • the acid chloride thus obtained is subsequently reacted with the compounds of the formula (VIII).
  • the compounds of the formula (VI) are reacted with the aminoalcohols of the formula (LX) in the presence of coupling reagents, for example 0- (7-azabenzotriazol-1-yl) -N, N, N'N'-tetramethyluronium hexafluorophosphate , reacted to intermediates of formula (X).
  • the reaction is carried out at room temperature in the presence of tertiary amine bases, such as triethylamine, in polar aprotic solvents such as N, N-dimethylformamide.
  • the subsequent cyclization to the compounds of the formula (XI) is achieved with the aid of a cyclization reagent, such as, for example, and preferably with Burgess reagent (carbomethoxysulfamoyltriethylammonium hydroxide).
  • a cyclization reagent such as, for example, and preferably with Burgess reagent (carbomethoxysulfamoyltriethylammonium hydroxide).
  • suitable solvents such as tetrahydrofuran
  • the final oxidation to the 1,3-oxazole derivatives of formula (IB) can be carried out with various oxidizing agents; is preferred the oxidation with activated manganese dioxide in tetrahydrofuran at the boiling point of the solvent.
  • the substituent R 1 in the target compounds of the formula (I) is the group -NR 6 R 8 , in which R 6 and R 8 have the meanings described above, and Y 1 is chlorine, bromine or iodine
  • the intermediates of the Formula (V) with amines of the formula (XII) implemented (see Scheme 6).
  • a tertiary amine as auxiliary base such as NN-diisopropylethylamine
  • the reaction preferably takes place in solvents such as diethylene glycol dimethyl ether or N-methylpyrrolidinone, or the compounds of the formula (XII), used in excess, are themselves solvents.
  • the reaction is carried out at elevated temperature, preferably in a temperature range between +80 0 C and +200 0 C. Reactions in the upper part of said temperature interval are preferably carried out in closed pressure vessels in a microwave oven.
  • the substituent R 1 in the target compounds of the formula (I) is an optionally substituted alkynyl or alkyl group and Y 1 is chlorine, bromine or iodine
  • the intermediates of the formula (V) can be reacted, for example, with propargyl alcohol (XIII ) are converted into products of the formula (ID) (see Scheme 7).
  • the reaction is preferably carried out at room temperature in an aprotic solvent such as tetrahydrofuran in the presence of an amine base such as triethylamine and a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide (variant of the so-called “Sonogashira coupling").
  • an aprotic solvent such as tetrahydrofuran
  • an amine base such as triethylamine
  • a palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) and copper (I) iodide (variant of the so-called “Sonogashira coupling"
  • An optional subsequent reduction of the alkyne bond to products of formula (IE) is carried out with hydrogen, preferably under normal pressure or at elevated pressure of up to about 100 bar in the presence of a metal catalyst, preferably based on platinum, palladium or
  • Scheme 9 describes the preparation of pyrazole and imidazole derivatives of the formula (VII) starting from compounds of the formula (XV) in which the ring B is 1H-pyrazole-1, 3-diyl or 1H-imidazole-1, 4 Diyl is attached, the hydrogen indicated to the N 'nitrogen atom of the ring B is bound and R 3 has the meaning given above.
  • These compounds are reacted with the compounds of the formula (III) to give intermediates of the formula (XVI).
  • the reaction conditions here are the same as those described in Process A.2 (Scheme 2).
  • the ester hydrolysis in the second reaction step takes place under standard conditions, for example with sodium hydroxide in methanol or ethanol as solvent at temperatures ranging from room temperature to +60 0 C.
  • Scheme 9 Construction of compounds of formula (VII)
  • Such compounds of the formula (IF) can be prepared by reacting an N-hydroxyamidine of the formula (VIII)
  • Y is chlorine, bromine or iodine
  • Y is chlorine, bromine or iodine
  • the starting compounds of the formulas (II), (III), (VIII), (IX), (XII), (XIII), (XIV), (XV), (XVII), (XX), (XXII) and (XXTV ) are either commercially available or described as such in the literature, or they can be prepared in a manner obvious to one skilled in the art, analogously to methods published in the literature. Numerous detailed instructions as well as literature references for the preparation of the starting materials can be found in the Experimental Section in the section on the preparation of the starting compounds and intermediates.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention are highly potent inhibitors of the HIF regulation pathway and have good bioavailability after peroral administration.
  • the compounds according to the invention are particularly suitable for the treatment of hyperproliferative disorders in humans and in mammals in general.
  • the compounds can inhibit, block, reduce or decrease cell proliferation and cell division and, on the other hand, potentiate apoptosis.
  • the hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include, among others, psoriasis, keloids, scarring and other proliferative disorders of the skin, benign diseases such as benign prostatic hyperplasia (BPH), and in particular the group of tumor diseases.
  • benign diseases such as benign prostatic hyperplasia (BPH)
  • BPH benign prostatic hyperplasia
  • tumor diseases include, but are not limited to, breast carcinomas and breast tumors (ductal and lobular forms, also in situ), respiratory tumors (small cell and non-small cell carcinoma, bronchial carcinoma).
  • brain tumors eg of the brain stem and the hypothalamus, astrocytoma, medulloblastoma, ependymoma as well as neuro-ectodermal and pineal tumors
  • tumors of the digestive organs esophagus, stomach, gallbladder, small intestine, large intestine, rectum
  • liver tumors eg hepatocellular carcinoma , Cholangiocarcinoma and mixed-hepatocellular cholangiocarcinoma
  • tumors of the head and neck laarynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity
  • skin tumors squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, melanoma skin cancer and non-melanoma skin cancer
  • Tumors of the soft tissues including soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas,
  • lymphomas include leukemias and myeloproliferative diseases, eg acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and Haarzeil leukemia, as well as AIDS-correlated lymphomas, Hodgkin's disease. Lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Burkitt lymphomas and lymphomas in the central nervous system.
  • treatment or “treating” is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and improving living conditions that are affected by this disease, such as cancer.
  • the compounds according to the invention act as modulators of the HIF regulation pathway and are therefore also suitable for the treatment of diseases which are associated with a detrimental expression of the HIF transcription factor.
  • the term "harmful expression of HIF” herein means a non-normal physiological presence of HIF protein. This may be due to excessive synthesis of the protein (due to mRNA or translation), reduced degradation or insufficient counterregulation in the function of the transcription factor.
  • HIF-1 ⁇ and HIF-2 ⁇ regulate more than 100 genes.
  • HIF also plays an important role in the stem cells, in particular the tumor stem cells, which are reported to have elevated HIF levels.
  • the inhibition of the HIF-regulation pathway by the compounds of the present invention also therapeutically influences tumor stem cells which do not have a high proliferation rate and are therefore only insufficiently affected by cytotoxic substances (see Semenza, 2007, Weidemann and Johnson, 2008).
  • HIF inhibitors - such as the compounds of the present invention - are therapeutically useful in those contexts in which, for example, adaptation of cells to hypoxic situations causes additional damage, as damaged cells, if not functioning properly, can cause further damage.
  • An example of this is the formation of epileptic foci in partially destroyed tissue after strokes.
  • cardiovascular disease when ischemic processes occur in the heart or brain as a result of thromboembolic events, inflammation, wounding, intoxication or other causes. These can lead to damage such as a locally slowed down action potential, which in turn can cause arrhythmias or chronic heart failure.
  • transient form e.g. Through apnea, an essential increase in blood pressure may occur under certain circumstances, which can lead to known sequelae such as stroke and myocardial infarction.
  • the inhibition of the HIF-regulation pathway as achieved by the compounds according to the invention can therefore also be used in diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion damage, stroke and macular degeneration as well as for the recovery of the nerve function be helpful after traumatic injury or severance.
  • diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion damage, stroke and macular degeneration as well as for the recovery of the nerve function be helpful after traumatic injury or severance.
  • HIF is one of the factors controlling the transition from an epithelial to a mesenchymal cell type, which is particularly important for the lung and kidney
  • the compounds of the invention can also be used to access HIF-associated lung and kidney fibroses prevent or curb.
  • Other diseases for the treatment of which the compounds according to the invention can be used are inflammatory joint diseases, such as various forms of arthritis, as well as inflammatory bowel diseases, such as, for example, Crohn's disease.
  • Chugwash polycythemia is mediated by HIF-2 ⁇ activity during erythropoiesis, among others in the spleen.
  • the compounds according to the invention as inhibitors of the HIF regulation route, are therefore also suitable for suppressing the excessive formation of erythrocytes here and thus for alleviating the effects of this disease.
  • the compounds of the present invention may also be used to treat diseases associated with excessive or abnormal angiogenesis. These include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996), neovascular glaucoma, psoriasis , retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, / n-5 / e «/ - restenosis and restenosis after vascular implantation.
  • diseases associated with excessive or abnormal angiogenesis include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996)
  • Increased blood supply is also associated with cancerous neoplastic tissue, leading to accelerated tumor growth.
  • the growth of new blood and lymph vessels facilitates the formation of metastases and thus the spread of the tumor.
  • New lymphoid and blood vessels are also detrimental to allografts in immune-privileged tissues, such as the eye, which, for example, increases susceptibility to rejection.
  • Compounds of the present invention can therefore also be used to treat any of the aforementioned disorders, e.g. by inhibiting growth or reducing the number of blood vessels. This can be achieved via inhibition of endothelial cell proliferation or other mechanisms to prevent or attenuate vascularization and via reduction of neoplastic cells by apoptosis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of Erkran- kungen, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers.
  • the combination of the compounds according to the invention with other substances which are customary for cancer therapy or else with radiotherapy is therefore particularly indicated since hypoxic regions of a tumor respond only slightly to the aforementioned conventional therapies, whereas the compounds of the present invention in particular exert their activity there.
  • Suitable combination active ingredients are:
  • the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without this enumeration being exhaustive:
  • the compounds of the present invention can also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer.
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer.
  • Inhibitors of the HIF-regulatory pathway can also provide positive effects in combination with other anti-angiogenic therapies, such as Avastin, axitinib, DAST, recentin, sorafenib, or sunitinib.
  • Combination with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side-effect profile.
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
  • Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, cojunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
  • capsules e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients include excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (For example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example,
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ , 30 mm x 3.00 mm
  • Eluent A 1 L of water + 0.5 ml of 50% formic acid
  • eluent B
  • Device Type MS Waters Micromass Quattro Micro
  • Device type HPLC Agilent 1100 series
  • Eluent A 1 L water + 0.5 ml 50% formic acid
  • eluent B 1 L acetonitrile + 0.5 ml 50% formic acid
  • Oven 50 ° C .
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 ⁇ MAX-RP 100A Mercury 20mm x 4mm; Eluent A: 1 L water + 0.5 ml 50% formic acid, eluent B: 1 L acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A ⁇ 3.0 min 5% A ⁇ 4.0 min 5% A ⁇ 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 210 nm.
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 0 C, 30 ° C / min ⁇ 310 0 C (3 min hold).
  • Device Type MS Waters ZQ
  • Device type HPLC Agilent 1100 series
  • UV DAD Column: Thermo Hypersil GOLD 3 ⁇ , 20 mm x 4 mm
  • Eluent A 1 L water + 0.5 ml 50% formic acid
  • eluent B 1 L acetonitrile + 0.5 ml 50% formic acid
  • Flow 2 ml / min
  • UV detection 210 nm.
  • a suspension of dichloro (dimethyl) titanium prepared in a heptane / dichloromethane mixture as follows: The mixture was cooled 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane at -30 0 C, was added dropwise 100 ml (100 mmol) a 1 M solution of dimethylzinc in heptane and stirred for 30 min at -30 0 C after. This suspension was then cooled to -40 0 C and a solution of 10 g (39.5 mmol) l- (4-bromophenyl) -2,2,2-trifluoroethanone added in 50 ml of dichloromethane.
  • Step 4 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarbonitrile
  • Step 5 N -hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarboxirnidamide
  • Step 1 4- (2-fluoropropan-2-yl) benzenecarbonitrile
  • Step 2 4- (2-Fluo-2-propen-2-yl) -N'-hydroxybenzenecarboximidamide
  • Step 3 2- ⁇ 3 - [4- (Dibenzylamino) phenyl] oxetan-3-yl ⁇ ethanol
  • Step 4 ⁇ 3 - [4- (Dibenzylamino) phenyl] oxetan-3-yl ⁇ acetaldehyde
  • Step 7 4- (3-Methyloxetan-3-yl) benzenecarbonitrile
  • Step 8 N'-hydroxy-4- (3-methyloxetan-3-yl) benzenecarboximidamide
  • Step 1 4- (3-Hydroxyoxetan-3-yl) benzenecarbonitrile
  • Step 2 4- (3-Fluorooxetan-3-yl) benzenecarbonitrile
  • Step 3 4- (3-Fluorooxetan-3-yl) -N'-hydroxybenzenecarboxime idam id
  • Step 1 4- (3-Methoxyoxetan-3-yl) benzenecarbonitrile
  • Step 1 4- (4-hydroxytetrahydro-2H-pyran-4-yl) benzenecarbonitrile
  • Step 2 4- (4-fluorotetrahydro-2H-pyran-4-yl) benzenecarbonitrile
  • Step 3 4- (4-fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide
  • Step 1 4- (4-Methoxytetrahydro-2H-pyran-4-yl) benzenecarbonitrile
  • the compounds listed in the following table were prepared by the method described in Example 23A from 5-methyl-1H-pyrazole 1-3-carboxylic acid, 5- (trifluoromethyl) -1H-pyrazole-3-carboxylic acid, 5-nitro-1H-pyrazole 3-carboxylic acid or 2-methyl-1H-imidazole-4-carboxylic acid hydrate and the corresponding N'-Hydroxybenzolcarboximidamiden prepared.
  • the reaction time during which it was stirred initially at RT was 0.5 to 4 h.
  • At 140 0 C was subsequently heated for 1 to 15 h.
  • Step 1 Ethyl 3 - [(tripropan-2-ylsilyl) oxy] benzenecarboxylate
  • Step 2 ⁇ 3 - [(Tripropan-2-ylsilyl) oxy] phenyl ⁇ methanol
  • Step 1 Ethyl 1 - [(6-chloro-pyridin-3-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate
  • Step 2 1 - [(6-Chloropyridin-3-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid
  • Step 2 Methyl 1 - [(6-chloropyridin-3-yl) methyl] -5-methyl-1H-pyrrole-3-carboxylate
  • Step 3 1 - [(6-Chloropyridin-3-yl) methyl] -5-methyl-1H-pyrrole-3-carboxylic acid
  • Step 1 Methyl 5-methyl-1 - (4-methylbenzyl) -1 H -pyrrole-3-carboxyyl lat
  • Step 2 Methyl 5- [hydroxy (4-methylphenyl) methyl] -1-methyl-1H-pyrrole-3-carboxylate
  • Step 1 Ethyl 4-hydroxy-5- (4-methylphenyl) -2-oxopent-3-enoate

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  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés aryles substitués, un procédé permettant de les préparer, leur utilisation pour le traitement et/ou la prévention de maladies ainsi que leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prévention de maladies, en particulier pour le traitement et/ou la prévention de maladies hyperprolifératives et angiogèniques, ainsi que des maladies qui se produisent par une adaptation métabolique à des états hypoxiques. De tels traitements peuvent avoir lieu en tant que monothérapie ou également en combinaison avec d'autres médicaments ou autres mesures thérapeutiques.
EP09744089A 2008-11-14 2009-10-31 Composés hétéroaromatiques pour une utilisation comme inhibiteurs de hif Withdrawn EP2356112A1 (fr)

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DE102008057364A DE102008057364A1 (de) 2008-11-14 2008-11-14 Substituierte Aryl-Verbindungen und ihre Verwendung
DE102009041241A DE102009041241A1 (de) 2009-09-11 2009-09-11 Substituierte Aryl-Verbindungen und ihre Verwendung
PCT/EP2009/007807 WO2010054764A1 (fr) 2008-11-14 2009-10-31 Composés hétéroaromatiques pour une utilisation comme inhibiteurs de hif

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MX2012012960A (es) * 2010-05-08 2012-12-17 Bayer Ip Gmbh Heterociclilbencilpirazoles sustituidos y uso de los mismos.
SA111320519B1 (ar) * 2010-06-11 2014-07-02 Astrazeneca Ab مركبات بيريميدينيل للاستخدام كمثبطات atr
UY34200A (es) 2011-07-21 2013-02-28 Bayer Ip Gmbh 3-(fluorovinil)pirazoles y su uso
EP2768826A1 (fr) * 2011-10-17 2014-08-27 Bayer Intellectual Property GmbH Oxadiazolyl-pyridinones et -pyridazinones substituées servant d'inhibiteurs de hif
EP2888253A4 (fr) 2012-08-24 2016-01-06 Univ Texas Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
US9018380B2 (en) * 2012-08-24 2015-04-28 Boar of Regents, The University of Texas System Heterocyclic modulators of HIF activity for treatment of disease
EP3061754A4 (fr) * 2013-10-23 2017-03-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique
DK3110420T3 (da) 2014-02-25 2019-05-13 Board Of Regents Univ Of Texas System Salte af heterocykliske modulatorer af hif-aktivitet til behandling af sygdomme
JP6571077B2 (ja) 2014-06-13 2019-09-04 武田薬品工業株式会社 含窒素複素環化合物
EP3015459A1 (fr) * 2014-10-30 2016-05-04 Sanofi Dérivés de benzylhydroxyde, leur préparation et utilisation thérapeutique
US10953036B2 (en) 2017-11-20 2021-03-23 University Of Georgia Research Foundation, Inc. Compositions and methods of modulating HIF-2A to improve muscle generation and repair
CA3090133A1 (fr) * 2018-01-30 2019-08-08 Pi Industries Ltd. Nouveaux oxadiazoles

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WO2007065010A2 (fr) * 2005-12-02 2007-06-07 Hif Bio, Inc. Composes anti-angiogenese

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WO2008141731A2 (fr) * 2007-05-18 2008-11-27 Bayer Healthcare Ag Dérivés pyrazoles à substitution hétéroaryle utiles pour le traitement de troubles hyperprolifératifs et de maladies associées à l'angiogenèse

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UY32236A (es) 2010-06-30
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WO2010054764A1 (fr) 2010-05-20
AR074337A1 (es) 2011-01-12
IL212174A0 (en) 2011-06-30
RU2011123672A (ru) 2012-12-20
US20110301122A1 (en) 2011-12-08
AU2009315930A1 (en) 2010-05-20
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CA2743424A1 (fr) 2010-05-20
KR20110082570A (ko) 2011-07-19

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