EP3137466A2 - Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation - Google Patents

Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation

Info

Publication number
EP3137466A2
EP3137466A2 EP15722673.9A EP15722673A EP3137466A2 EP 3137466 A2 EP3137466 A2 EP 3137466A2 EP 15722673 A EP15722673 A EP 15722673A EP 3137466 A2 EP3137466 A2 EP 3137466A2
Authority
EP
European Patent Office
Prior art keywords
hydrogen
alkyl
substituted
fluorine
methyl
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Withdrawn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
EP15722673.9A
Other languages
German (de)
English (en)
Inventor
Alexandros Vakalopoulos
Gaelle VALOT
Markus Follmann
Frank Wunder
Johannes-Peter Stasch
Tobias Marquardt
Lisa Dietz
Volkhart Min-Jian Li
Nicholas Charles Ray
Dominika BACHERA
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 Pharma AG
Original Assignee
Bayer 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
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3137466A2 publication Critical patent/EP3137466A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond

Definitions

  • the present application relates to novel 6-substituted imidazo [1,2-a] pyridine-3-carboxamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • cGMP cyclic guanosine monophosphate
  • NO nitric oxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of the heme, with stimulation by CO being markedly lower than by NO.
  • CO Carbon monoxide
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
  • the NO / cGMP system may be suppressed, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • the object of the present invention was to provide new substances which act as stimulators of soluble guanylate cyclase, and as such are suitable for the treatment and / or prophylaxis of diseases.
  • the present invention relates to compounds of the general formula (I)
  • A is CH 2 , CD 2 or CH (CH 3 ),
  • R is (C 3 -C 4) -cycloalkyl, pyridyl or phenyl, where (C 3 -C 4) -cycloalkyl having 1 to 4 substituents selected independently of one another from the group of fluorine, trifluoromethyl and (C 1 -C 4 -alkyl may be substituted, and wherein phenyl having 1 to 4 substituents independently of one another can be substituted from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (GC-alkyl, (C3-C5) -cycloalkyl, (Ci-G-alkoxy, difluoromethoxy and trifluoromethoxy) where pyridyl having 1 to 4 substituents independently of one another selected from the group of fluorine, chlorine, monofluoromethyl, difluoromethyl, trifluoromethyl and (GC alkyl may be substituted for hydrogen, chlorine, (GC alkyl, (GC
  • L 1 is a bond or (GC alkanediyl
  • R 7 is hydrogen, fluorine or (GC 6 ) alkyl
  • R 8 is hydrogen, fluoro, methyl or ethyl
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine, in which (C 1 -C 6 ) -alkyl may be substituted by trimethylsilyl, R 10 is hydrogen or GC 4 ) -alkyl, R 11 is hydrogen or (C 1 -C 3 ) -alkyl,
  • R 12 is hydrogen or (C 1 -C 3 ) -alkyl
  • R 16 is hydrogen, (C 1 -C 6) -alkyl or 5-membered heteroaryl, in which (C 1 -C 6) -alkyl may be substituted up to five times by fluorine, in which 5-membered ring heteroaryl is substituted by methyl, difluoromethyl or trifluoromethyl,
  • R 17 is hydrogen or methyl
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 6) -alkyl can be substituted up to five times by fluorine, R 19 is hydrogen or (C 1 -C 4 ) -alkyl,
  • R 4 is hydrogen
  • R 5 is hydrogen, chlorine, (GC 4 ) -alkyl, (C 2 -C 4 ) -alkynyl, (C 3 -C 5 ) -cycloalkyl, difluoromethoxy, trifluoromethoxy or 5- or 6-membered heteroaryl, where (Ci C 4 ) -alkyl may be substituted by (Ci-C 4 ) -alkoxy, R 6 is hydrogen, and their -oxides, salts, solvates, salts of -oxides and solvates of -oxides and salts.
  • the present invention relates to compounds of general formula (I) in which
  • A is CH 2 , CD 2 or CH (CH 3 ),
  • R 1 is (C 3 -C 7 ) -cycloalkyl, pyridyl or phenyl, with (C 3 -C 4) -cycloalkyl having 1 to 4 substituents independently selected from the group fluorine, trifluoromethyl and (C 1 -C 4 ) -alkyl, and where phenyl having 1 to 4 substituents independently of one another selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) - alkyl, (C 3 -C 5) -cycloalkyl, (C 1 -C 4 ) -alkoxy, difluoromethoxy and trifluoromethoxy, where pyridyl having 1 to 4 substituents independently of one another is selected from the group of fluorine, chlorine, monofluoromethyl, difluoromethyl, trifluor
  • L 1 is a bond or (C 1 -C 4 ) -alkanediyl
  • R 7 is hydrogen, fluorine or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 8 is hydrogen, fluorine, methyl or ethyl
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine,
  • R 10 is hydrogen or (GC 4 ) -alkyl
  • R 11 is hydrogen or (C 1 -C 3 ) -alkyl
  • R 12 is hydrogen or (C 1 -C 3 ) -alkyl, is hydrogen, R 5 is hydrogen, chlorine, (GC 4 ) -alkyl, (C 2 -C 4 ) -alkynyl, (C 3 -C 5 ) -cycloalkyl, difluoromethoxy, trifluoromethoxy or 5- or 6-membered heteroaryl, where (Ci C 1 -C 4 -alkyl may be substituted by (C 1 -C 4) -alkoxy,
  • R 6 is hydrogen, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. 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 acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid formic acid, acetic acid, trifluoro
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, 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 salts
  • 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 in which the coordination with water takes place. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 L
  • Certain isotopic variants of a compound of the invention, such as those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or drug distribution in the body; Because of the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • 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). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Carbocycle or cycloalkyl in the context of the invention is a monocyclic or bicyclic, saturated or partially unsaturated carbocycle having in each case the indicated number of ring carbon atoms and up to 3 double bonds.
  • Examples which may be mentioned by preference include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, indanyl, tetralinyl.
  • Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preferred is a linear or branched alkenyl radical having 2 to 4 carbon atoms and a double bond.
  • vinyl, allyl, isopropenyl and n-but-2-en-1-yl By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
  • Alkynyl in the context of the invention is a linear or branched alkynyl radical having 2 to 6 carbon atoms and a triple bond.
  • alkynyl in the context of the invention is a linear or branched alkynyl radical having 2 to 6 carbon atoms and a triple bond.
  • ethynyl n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.
  • Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 4 carbon atoms.
  • alkyl radical having 1 to 4 carbon atoms.
  • methylene 1,2-ethylene, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-propylene diyl, 1,4-butylene, butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • Alkylsulfonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfonyl group.
  • a sulfonyl group By way of example and preferably its name: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
  • a 4- to 7-membered heterocycle is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms containing one or two ring heteroatoms from the series N, O, S, SO and / or SO 2 and via a ring carbon atom or, if appropriate, a ring nitrogen atom is linked.
  • Examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-l, 4-diazepinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via 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 or fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
  • the term “treatment” or “treating” includes inhibiting, delaying, arresting, alleviating, attenuating, restricting, reducing, suppressing, Restraining or curing a disease, a disease, a disease, an injury or disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • the term “therapy” is understood to be synonymous with the term “treatment”.
  • the terms “prevention”, “prophylaxis” or “prevention” are used interchangeably in the context of the present invention and denote the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • R is pyridyl, wherein pyridyl having 1 to 3 substituents independently selected from
  • Fluorine, difluoromethyl, trifluoromethyl and methyl may be substituted
  • R 2 is hydrogen, (C 1 -C 4 -alkyl, cyclopropyl, cyclobutyl, monofluoromethyl, difluoromethyl or trifluoromethyl, where (C 1 -C 4 -alkyl may be substituted by (C 1 -C 4 -alkoxy), R 3 is a group of the formula
  • L represents a bond or (C 1 -C 4 -alkanediyl represents hydrogen, fluorine or (C 1 -C 6) -alkyl, wherein (C 1 -C 6) -alkyl can be substituted up to five times by fluorine, R 8 is hydrogen, fluorine, methyl or ethyl, R 9 is hydrogen or (GC 6 ) -alkyl, wherein (G-C6) -alkyl may be substituted up to five times with fluorine, R 10 is hydrogen or (GC 4 ) -alkyl,
  • R LL is hydrogen, R 12 is hydrogen, R 4 is hydrogen,
  • R 5 is hydrogen, chlorine, methyl, ethyl, ethynyl, cyclopropyl, difluoromethoxy, trifluoromethoxy or 5- or 6-membered heteroaryl, where methyl may be substituted by methoxy,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 ,
  • R 1 is a pyridyl group of the formula
  • R 2 is methyl
  • R 3 is a group of the formula stands, where
  • L 1 is a bond or methanediyl
  • R 7 is hydrogen or fluorine
  • R 8 is hydrogen or fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may be substituted up to five times by fluorine, R 10 is hydrogen or methyl, R 11 is hydrogen, R 12 is hydrogen R 4 is hydrogen,
  • R 5 is hydrogen, chlorine, methyl, ethyl, cycloproyl, difluoromethoxy, pyridyl, 1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 ,
  • R L is a pyridyl group of the formula
  • R 2 is methyl
  • R 3 is a group of the formula
  • L 1 is a bond
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is hydrogen, chlorine, methyl or cyclopropyl
  • R 6 represents hydrogen
  • R 2 is chlorine, (C 1 -C 4 ) -alkyl, methoxy or cyclobutyl, where (C 1 -C 4 -alkyl is substituted by (C 1 -C 4 -alkoxy, where cyclobutyl is substituted twice by fluorine, R 3 is a group of formula
  • L 1 is a bond or (C 1 -C 4 -alkanediyl, R 7 is hydrogen or fluorine,
  • R 8 is hydrogen or fluorine
  • R 9 is hydrogen or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 10 is hydrogen or (GC 4 ) -alkyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 6 represents hydrogen
  • R 13 is hydrogen or fluorine
  • R and R 5 are fluorine
  • L 1 is a bond or methanediyl
  • R 7 is hydrogen or fluorine
  • R s is hydrogen or fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chlorine, methyl, ethyl, cycloproyl, difluoromethoxy, pyridyl, IH-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl where methyl may be substituted with methoxy,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • R 13 is hydrogen or fluorine
  • R 14 and R 15 are fluorine
  • R 2 is methyl or chlorine
  • R 3 is a group of the formula
  • L 1 is a bond
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chlorine, methyl or cyclopropyl
  • R 6 represents hydrogen
  • pyridyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine and methyl,
  • R 2 is (C 1 -C 4 ) -alkyl, where (C 1 -C 4 -alkyl is substituted by (GC-alkoxy), R 3 is a group of the formula
  • L 1 is a bond or (GC alkanediyl
  • R 7 is hydrogen or fluorine
  • R s is hydrogen or fluorine
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine, R 10 is hydrogen or (GC 4 ) -alkyl, R n is hydrogen, R 3 12 is hydrogen, is hydrogen, is hydrogen, is hydrogen, chlorine, methyl, ethyl, ethynyl, cyclopropyl, difluoromethoxy or 5- or 6-membered heteroaryl,
  • R 6 represents hydrogen
  • R 13 is hydrogen or fluorine
  • R and R 5 are fluorine
  • L 1 is a bond or methanediyl
  • R 7 is hydrogen or fluorine
  • R s is hydrogen or fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chlorine, methyl, ethyl, cycloproyl, difluoromethoxy, pyridyl, IH-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl where methyl may be substituted with methoxy,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • R 13 is hydrogen or fluorine
  • R 14 and R 15 are fluorine
  • R 2 is methyl
  • R 3 is a group of the formula
  • L 1 is a bond
  • R 7 is hydrogen
  • R s is hydrogen
  • R 9 is hydrogen or (GC 4 ) -alkyl
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chlorine, methyl or cyclopropyl
  • R 6 represents hydrogen
  • R 2 is hydrogen, chlorine, (C 1 -C 4 -alkyl, methoxy, cyclopropyl, cyclobutyl, monofluoromethyl, difluoromethyl or trifluoromethyl, where (C 1 -C 4 -alkyl may be substituted by (C 1 -C 4) -alkoxy, R 3 is a Group of formula
  • L 1 is (C 1 -C 4 ) -alkanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine, in which (C 1 -C 6) -alkyl may be substituted by trimethylsilyl,
  • R 10 is hydrogen or (GC 4 ) -alkyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 16 is hydrogen, (C 1 -C 6 ) -alkyl or 5-membered heteroaryl, wherein (C 1 -C 6) -alkyl can be substituted up to five times by fluorine, in which 5-membered ring heteroaryl is substituted by methyl, difluoromethyl or trifluoromethyl,
  • R 17 is hydrogen or methyl
  • R 1S is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 6) -alkyl may be substituted up to five times by fluorine,
  • R 19 is hydrogen or (GC 4 ) -alkyl, is hydrogen
  • R 5 is hydrogen, chlorine, methyl, ethyl, ethynyl, cyclopropyl, difluoromethoxy or 5- or 6-membered heteroaryl, where methyl may be substituted by methoxy,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • R 13 is hydrogen or fluorine
  • R 14 and R L? stand for fluorine, R 2 is methyl or methoxy, R 3 is a group of the formula
  • L 1 is methanediyl or ethanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl can be substituted up to five times by fluorine, R 10 is hydrogen or methyl, R u is hydrogen, R 12 is hydrogen R 16 is butyl, in which butyl may be substituted up to five times by fluorine, R 17 is hydrogen, R 18 is hydrogen or methyl, R 19 is hydrogen or methyl, is hydrogen, chlorine, methyl, Ethyl, cyclopropyl, difluoromethoxy, pyridyl, IH-pyrazol-1-yl, methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl, where methyl may be substituted by methoxy, R 6 is hydrogen, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
  • A is CH 2
  • R 1 is cyclohexyl, pyridyl or phenyl, wherein phenyl may be substituted with 1 to 4 substituents independently selected from the group fluorine, chlorine, bromine and methyl, wherein pyridyl having 1 to 3 substituents independently selected from the group fluorine, chlorine, bromine and methyl
  • R 2 is hydrogen, (C 1 -C 4 -alkyl, cyclopropyl, cyclobutyl, monofluoromethyl, difluoromethyl or trifluoromethyl, where (C 1 -C 4 -alkyl with (C 1 -C 4 -alkyl) Alkoxy may be substituted
  • R 3 is a group of the formula
  • L 1 is (C 1 -C 4 ) -alkanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine
  • R 10 is hydrogen or (GC 4 ) -alkyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen, is hydrogen, chlorine, methyl, ethyl, ethynyl, cyclopropyl, difluoromethoxy or 5- or 6-membered heteroaryl, where methyl may be substituted by methoxy,
  • R 6 is hydrogen, and their N-oxides, .Salze, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • preference is given to compounds of the formula (I) in which
  • A is CH 2 , a phenyl group of the formula
  • R 13 is hydrogen or fluorine
  • R and R are fluorine, methyl is methyl,
  • R 3 is a group of the formula
  • L 1 is methanediyl or ethanediyl, is fluorine
  • R is fluorine, is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 -alkyl may be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chloro, methyl, ethyl, cyclopropyl, difluoromethoxy, pyridyl, IH-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl, where methyl is methoxy may be substituted
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 , a phenyl group of the formula
  • R 13 is hydrogen or fluorine
  • R 14 and R 15 are fluorine
  • R 2 is methyl
  • R 3 is a group of the formula
  • L 1 is methanediyl or ethanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (GC 4 ) -alkyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 1 is cyclohexyl, pyridyl or phenyl, wherein phenyl may be substituted with 1 to 4 substituents independently selected from the group of fluorine, chlorine, bromine and methyl, and wherein pyridyl having 1 to 3 substituents independently selected from the group fluorine, Chlorine, bromine and methyl may be substituted,
  • R 2 is hydrogen, (GC alkyl, cyclopropyl, cyclobutyl, monofluoromethyl, difluoromethyl or trifluoromethyl, where (Ci-C alkyl may be substituted with (GC alkoxy), for a group of the formula
  • L 1 is a bond or (C 1 -C 4 -alkanediyl
  • R 7 is hydrogen, fluorine or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine
  • R 8 is hydrogen Is fluorine, methyl or ethyl
  • R 9 is hydrogen or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine
  • R 10 is hydrogen or (GC 4 ) - Alkyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is hydrogen, chloro, methyl, ethynyl, cyclopropyl, difluoromethoxy, pyridyl, 1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1, 3-oxazol-5-yl, wherein methyl substituted with methoxy,
  • R 6 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 13 is hydrogen or fluorine
  • R 14 and R 15 are fluorine, is methyl, a group of the formula
  • L L is a bond or methanediyl
  • R 7 is hydrogen or fluorine
  • R 8 is hydrogen or fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 -alkyl may be substituted up to five times by fluorine
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is chloro, methyl, cyclopropyl, difluoromethoxy, pyridyl, IH-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl, where methyl is substituted by methoxy .
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 ,
  • R 1 is a phenyl group of the formula
  • R 13 is hydrogen or fluorine
  • R 14 and R 15 are fluorine
  • R 2 is methyl
  • R 3 is a group of the formula
  • L 1 is a bond
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen or (C 1 -C 4 ) -alk in which (C 1 -C 4 ) -alkyl can be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 4 is hydrogen
  • R 5 is cyclopropyl, IH-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1, 3-oxazol-5-yl,
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • R 1 is pyridyl or phenyl, wherein phenyl may be substituted with 1 to 4 substituents independently selected from the group of fluorine, chlorine, bromine and methyl, and wherein pyridyl having 1 to 3 substituents independently selected from
  • Group of fluorine, chlorine, bromine and methyl may be substituted, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 1 is pyridyl, where pyridyl having 1 to 3 substituents independently of the group consisting of fluorine, difluoromethyl, trifluoromethyl and methyl may be substituted, and also their N Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 1 is a pyridyl group of the formula
  • # represents the point of attachment to A, as well as their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • R 1 is a phenyl group of the formula
  • R 1 ' is hydrogen or fluorine
  • R 14 and R 15 are fluorine, and their TV oxides, salts, solvates, salts of TV oxides and solvates of the TV oxides and salts.
  • R 1 is a phenyl group of the formula
  • R 13 is hydrogen
  • R 14 and R 15 are fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 2 is (C 1 -C 6) -alkyl where (C 1 -C 4 -alkyl is substituted by (C 1 -C 4) -alkoxy, and also their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts ,
  • R 2 is methyl, wherein methyl is substituted by methoxy, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 2 is methyl, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 2 is chlorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 2 is methoxy, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • L 1 is methanediyl or ethanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may be substituted up to five times by fluorine, R 10 is hydrogen or methyl,
  • R 11 is hydrogen
  • R 12 is hydrogen
  • R 16 is butyl, in which butyl may be substituted up to five times by fluorine, R 17 is hydrogen,
  • R 18 is hydrogen or methyl
  • R 19 is hydrogen or methyl, and their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • R 3 is a group of the formula stands, where
  • R 16 is butyl, in which butyl may be substituted up to five times by fluorine,
  • R 17 is hydrogen
  • R LS is hydrogen or methyl
  • R 19 is hydrogen or methyl, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula
  • L 1 is a bond or (C 1 -C 4 -alkanediyl
  • R 7 is hydrogen or fluorine
  • R 8 is hydrogen or fluorine
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 -alkyl may be substituted up to five times by fluorine, R 10 is hydrogen or (GC 4 ) -alkyl, R 11 is hydrogen,
  • R 12 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula
  • L 1 is a bond
  • R 7 is hydrogen
  • R 8 is hydrogen
  • R 9 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula stands, where
  • L 1 is methanediyl or ethanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula
  • * is the point of attachment to the carbonyl group
  • L 1 is methanediyl
  • R 7 is fluorine
  • R 8 is fluorine
  • R 9 is hydrogen or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine,
  • R 10 is hydrogen or methyl
  • R 11 is hydrogen
  • R 12 is hydrogen, and their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • R 5 is chlorine, methyl, ethyl, cyclopropyl, difluoromethoxy, trifluoromethoxy or 5- or 6-membered heteroaryl, wherein methyl is substituted by methoxy, and their oxides, salts, solvates, salts of oxides and solvates of the oxides and salts.
  • R 5 is chloro, methyl, cyclopropyl, difluoromethoxy, pyridyl, 1H-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1,3-oxazol-5-yl wherein methyl is substituted with methoxy , and their oxides, salts, solvates, salts of oxides and solvates of the oxides and salts.
  • R 5 represents cyclopropyl, 1-pyrazol-1-yl, 1-methyl-1H-pyrazol-4-yl or 1, 3-oxazol-5 yl, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
  • Another object of the invention is a process for the preparation of compounds of the formula (I) according to the invention characterized in that
  • R 1 , R 2 , R 4 and R 6 each have the meanings given above
  • R 5A has the meanings given for R 5 or is bromine
  • T 1 is (C 1 -C 4 ) -alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid to give a carboxylic acid of the formula (III)
  • R 1 , R 2 , R 4 and R 6 are each as defined above, and
  • R 5A has the meanings given for R 5 or is bromine, and reacting these in succession in an inert solvent under amide coupling conditions with an amine of the formula (IV)
  • R 5A is bromine, the compounds in an inert solvent in the presence of a suitable transition metal catalyst, optionally in the presence of a suitable base, with a compound of the formula (IV-A),
  • R is as defined above, and is hydrogen or (Ci-C alkyl, or both radicals T 2 together form a -C (CH 3 ) 2 C (CH 3 ) 2 bridge, reacting, or a compound of formula (III-A)
  • the compounds of the formulas (I-A) form a subset of the compounds of the formula (I) according to the invention.
  • the free bases of (IV) may be released from the optionally amino-protecting compounds (IV), e.g. by using acids such as hydrogen chloride and trifluoroacetic acid in suitable solvents such as diethyl ether, dichloromethane, 1,4-dioxane, water, methanol, ethanol and mixtures thereof.
  • acids such as hydrogen chloride and trifluoroacetic acid
  • suitable solvents such as diethyl ether, dichloromethane, 1,4-dioxane, water, methanol, ethanol and mixtures thereof.
  • Inert solvents for process steps (III) + (IV) -> (I) and (III-A) + (IV) -> (IA) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, Toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, N, N-dimethylacetamide , N, N'-Dimethylpropyleneurea (DMPU) or N
  • Suitable condensing agents for the amide formation in process steps (III) + (IV) - (I) and (III-A) + (IV) - (IA) are, for example, carbodiimides such as ⁇ , ⁇ '-Oiet yl-, / V, / V'-dipropyl, '-diisopropyl, / V, / V'-dicyclohexylcarbodiimide (DCC) or / V- (3-dimethylaminopropyl) - / V'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as / V , / V'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulphate or 2-ethyl-butyl-5-methylisoxazolium perchlorate,
  • TBTU is used in conjunction with N-methylmorpholine, HATU in conjunction with N, N-diisopropylethylamine or 1-chloro-A ⁇ A ⁇ -trimethylprop-l-en-lamin.
  • the condensations (III) + (IV) -> (I) and (III-A) + (IV) -> (IA) is generally in a temperature range of -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C performed.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • carboxylic acid of the formula (III) can also first be converted into the corresponding carboxylic acid chloride and this then reacted directly or in a separate reaction with an amine of the formula (IV) to give the compounds according to the invention.
  • the formation of carboxylic acid chlorides from carboxylic acids is carried out by the methods known in the art, for example by treatment with thionyl chloride, sulfuryl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.
  • the hydrolysis of the ester group T 1 of the compounds of formula (II) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, wherein in the latter the initially formed salts are converted by treatment with acid into the free carboxylic acids ,
  • the ester cleavage is preferably carried out with acids.
  • the ester cleavage is preferably carried out by hydrogenolysis with palladium on activated carbon or Raney nickel.
  • Suitable inert solvents for this reaction are water or the organic solvents customary for ester cleavage.
  • These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide , It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol.
  • the usual inorganic bases are suitable. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the ester cleavage is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably at + 0 ° C to + 50 ° C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • the coupling with (IV-A) takes place in a solvent which is inert under the reaction conditions.
  • suitable solvents are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as 1,2-dimethoxyethane (DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), / V-methylpyrrolidone (NMP), pyridine, acetonitrile, toluene or even water. It is likewise possible to use
  • the reaction can be carried out with (IV-A) in the presence of a suitable palladium and / or copper catalyst.
  • a suitable palladium catalyst for example, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (tri-tert-butyl-phosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and corresponding dichloromethane complex, optionally in combination with additional phosphine ligands such as (2-biphenyl ) di-ieri.-butylphosphine, 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (SPhos), dicyclohex
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, / V-methylmorpholine, / V- Methylpiperidine, diisopropylethylamine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO ® ) or potassium
  • the reaction with (IV-A) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably at + 80 ° C to + 150 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (V) + (VI) - (I) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, Xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, -Dimefhylformamid, / V-Dimefhylacetamid, dimethyl sulfoxide, N, N'-Dimefhylpropylenharnstoff (DMPU), N-methylpyrroli
  • Suitable bases for process step (V) + (VI) - (I) are the customary inorganic or organic bases.
  • These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium optionally with the addition of an alkali iodide such as sodium iodide or potassium iodide, alkali metal alcoholates such as sodium or Potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) - amide or lithium diisopropylamide, or organic amines such as triethylamine, / V -Methylmorpholine, / V-methylpiperidine, A ⁇ -diisopropyl-ethylamine, pyridine
  • the reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • the amino-protecting group used is preferably ieri-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z).
  • a protective group for a hydroxy or carboxyl function tert-butyl or benzyl is preferably used.
  • the cleavage of these protecting groups is carried out by conventional methods, preferably by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as dioxane, diethyl ether, dichloromethane or acetic acid; optionally, the cleavage can also be carried out without an additional inert solvent.
  • benzyl and benzyloxycarbonyl as a protective group can these are also removed by hydrogenolysis in the presence of a palladium catalyst.
  • the cleavage of the protective groups mentioned can optionally be carried out simultaneously in a one-pot reaction or in separate reaction steps.
  • reaction steps (IA) - (V) The removal of the benzyl group in reaction steps (IA) - (V) is carried out here by customary methods known from protective group chemistry, preferably by hydrogenolysis in the presence of a palladium catalyst such as palladium on activated carbon in an inert solvent such as, for example, ethanol or ethyl acetate [ see also eg T.W. Greene and P.G.M. Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].
  • a palladium catalyst such as palladium on activated carbon
  • an inert solvent such as, for example, ethanol or ethyl acetate
  • R 1 , R 4 , R 5 and R 6 in each case have the meanings given above, and this is subsequently reacted in an inert solvent with a compound of the formula (IX) in which R 2 and T 1 each have the meanings given above, is reacted.
  • These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane , 1,2-dichloroethane, acetonitrile, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • ethanol is used.
  • the ring closure is generally carried out in a temperature range from + 50 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.
  • the ring closure (VIII) + (IX) -> (II) or (VII) + (IX) -> (X) is optionally carried out in the presence of water-withdrawing reaction additives, for example in the presence of molecular sieve (4 ⁇ pore size) or by means of water.
  • the reaction (VIII) + (IX) -> (II) or (VII) + (IX) -> (X) is carried out using an excess of the reagent of the formula (IX), for example with 1 to 20 equivalents of the reagent ( IX), optionally with the addition of bases (such as sodium bicarbonate) wherein the addition of this reagent can be carried out once or in several portions.
  • Typical reaction conditions for such Mitsunobu condensations of phenols with alcohols can be found in the literature, e.g. Hughes, D.L. Org. Read. 1992, 42, 335; Dembinski, R. Eur. J. Org. Chem. 2004, 2763.
  • an activating reagent e.g. Diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)
  • a phosphine reagent e.g. Triphenylphosphine or tributylphosphine
  • an inert solvent e.g. THF, dichloromethane, toluene or DMF
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular the compounds listed under R 3 , starting from the compounds of formula (I) obtained by the above method.
  • transformations are carried out by customary methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amino acidification, esterification, ester cleavage, etherification, Ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
  • 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 open up a further treatment alternative and thus represent an enrichment of pharmacy.
  • the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
  • the compounds of the invention potentiate the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
  • the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and the ventricles as well as conduction disorders such as atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles , AV-junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis,
  • cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
  • Cardiac insufficiency in valvular heart failure mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac arrest, diastolic Heart failure and systolic heart failure and acute phases d he worsening of existing chronic heart failure.
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and obesity combined hyperlipidaemias and the metabolic syndrome.
  • the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis , rheumatic diseases and to promote wound healing.
  • the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS Feiine's urological syndrome
  • FUS Feiine's urological syndrome
  • diseases of the urogenital system including neurogenic overactive bladder (OAB) and (
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, renal immunological diseases such as renal transplant rejection, immune complex-induced renal disease, toxicant-induced nephropathy, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF
  • the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
  • they are useful for improving cognitive dysfunction, concentration performance, learning performance, or memory performance as they do especially in situations / diseases / syndromes such as mild cognitive impairment, age-related learning and memory disorders, age-associated memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia, post-partum Traumatic traumatic brain injury, general concentration disorders, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease , progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia, or Korsakoff's psychosis.
  • mild cognitive impairment age-related learning and
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addiction.
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis atitis
  • Peritonitis rheumatoid diseases
  • inflammatory skin diseases and inflammatory ocular diseases.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic diseases, scleroderma, morphea, keloids, hypertrophic scarring (also after surgery), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
  • the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention further relates to the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • 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 prophylaxis 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 prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned disorders.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticides co-receptor antagonists and diuretics; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid rea
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds of the invention are used in combination with a beta-receptor blocker, as exemplified and preferably Propranolol, Atenolol, Timolol, Pindolol, Alprenolol, Oxprenolol, Penbutolol, Bupranolol, Metiprolanol, Nadolol, Mepindolol, Carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol administered.
  • a beta-receptor blocker as exemplified and preferably Propranolol, Atenolol, Timolol, Pindolol, Alprenol
  • the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin all-antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the present invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics
  • Hydrochlorothiazide chlorthalidone
  • xipamide xipamide
  • indapamide indapamide
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the 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. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, 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 as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, rapidly disintegrating in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
  • the parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • involvement of resorption eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • par- enteral administration are suitable as application forms, inter alia, 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 plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • compositions 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.
  • adjuvants include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as
  • the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg kg of body weight.
  • MS Instrument Type Waters ZMD; HPLC instrument type: Waters 1525; Column: Phenomenex Luna 3 ⁇ C18 (2) 30 mm x 4.6 mm; mobile phase A: water 0.1% formic acid, mobile phase B: acetonitrile 0.1% formic acid; Gradient: 0.0 min 95% A -> 0.5 min 95% A -> 4.5 min 5% A -> 5.5 min 5% A; Flow rate: 2 ml / min; UV detection: DAD.
  • MS Instrument Type Waters Micromass ZQ2000; HPLC instrument type: Waters Acquity UPLC system; Column: Acquity UPLC BEH C18 1.7 micron 100 mm x 2.1 mm; mobile phase A: water 0.1% formic acid, mobile phase B: acetonitrile 0.1% formic acid; Gradient: 0.0 min 95% A -> 0.4 min 95% A -> 6.0 min 5% A -> 6.8 min 5% A; Flow rate: 0.4 ml / min; UV detection: PDA.
  • Method C MS Instrument Type: Waters ZQ; HPLC instrument type: HPl 100 series; Column: Phenomenex Luna 3 ⁇ C18 (2) 30 mm x 4.6 mm; mobile phase A: water 0.1% formic acid, mobile phase B: acetonitrile 0.1% formic acid; Gradient: 0.0 min 95% A -> 0.5 min 95% A -> 4.5 min 5% A -> 5.5 min 5% A; Flow rate: 2 ml / min; UV detection: PDA.
  • Method D Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; mobile phase A: 1 1 water + 0.25 ml 99% formic acid, mobile phase B: 1 liter acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A-> 1.2 min 5% A-> 2.0 min 5% A Furnace: 50 ° C; Flow rate: 0.40 ml / min; UV detection: 210 - 400 nm.
  • Method E Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 x 1 mm; mobile phase A: 1 1 water + 0.5 ml 50% formic acid, mobile phase B: 1 1 acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A-> 0.1 min 90% A -> 1.5 min 10% A -> 2.2 min 10% A Furnace: 50 ° C; Flow rate: 0.33 ml / min; UV detection: 210 nm.
  • LC-MS methods preparative: Method F:
  • MS Instrument Type Agilent 1260 Infinity Purification System. Agilent 6100 series single quadrupole LC / MS; Column: XSEELECT CSH Prep C18 5 ⁇ OBD, 30 x 150 mm; mobile phase A: 0.1% aqueous formic acid, mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 10% - 95%, 22 min, centered around a special focused gradient; Flow rate: 60 ml / min. Sample: Inject a 20-60 mg / ml solution in DMSO (+ if necessary formic acid and water).
  • MS Instrument Type Agilent 1260 Infinity Purification System.
  • Sample Inject a 20-60 mg / ml solution in DMSO (+ if necessary formic acid and water).
  • Method I Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC I ISS T3 1.8 ⁇ 30 x 2 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% ⁇ 1 .2 min 5% A-> ⁇ 2.0 min 5% A Furnace: 50 ° C; Flow: 0.60 ml / min; UV detection: 208-400 nm.
  • Method J Instrument: Thermo Fisher-Scientific DSQ; chemical ionization; Reactant gas NH3; Source temperature: 200 ° C; Ionization energy 70eV.
  • Method M Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLC Acquity; Column: Waters BEH C18 1.7 ⁇ 50 x 2.1 mm; Eluent A: 1 l of water + 0.01 mol of ammonium formate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 95% A -> 0.1 min 95% A -> 2.0 min 15% A -> 2.5 min 15% A ⁇ 2.51 min 10% A -> 3.0 min 10% A; Oven: 40 ° C; Flow: 0.5 ml / min; UV detection: 210 nm. Method N (LC-MS., Analytical):
  • Device type MS Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 ⁇ ; Eluent A: 1 liter of water + 0.01% of formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B-> 2.5 min 95% B -> 3.5 min 95% B; Oven: 50 ° C; Flow: 0.90 ml / min; UV detection: 210 nm / Optimum Integration Path 210-300 nm
  • MS instrument type HP 6130 MSD; HPLC instrument type: Agilent 1290 Series; UV DAD; Column: Waters Acquity HSS T3 1.8 ⁇ 2.1 mm x 75 mm; Eluant A: ammonium acetate (10mM) + water / methanol / acetonitrile (9.0: 0.6: 0.4), eluent B: ammonium acetate (10mM) + water / methanol / acetonitrile (1.0: 5.4 : 3.6); Gradient: A / B: 80/20 (0.0 min) -> (1.5 min) -> 0/100 (1.5 min); Flow rate: 0.6 ml / min; Oven: 35 ° C; UV detection: 215 and 238 nm.
  • the starting compounds, intermediates and embodiments may be present as hydrates.
  • a quantitative determination of the water content was not.
  • the hydrates may have an influence on the NMR spectrum and possibly shift the water signal in H-NMR and / or greatly broaden it.
  • the percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.
  • the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • Example 5A rac- ⁇ 1 - [( ⁇ 6-bromo-8- [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] -2- methylbutan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • Butyl ester (Example 18A) in 30 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (120 g silica gel cartridge, eluent: cyclohexane / ethyl acetate, gradient 0% to 100%). This gave 2.9 g of the target product (94% of theory).
  • the reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 50%). This gave 90 mg of the target product (90% of theory).
  • Example 7A rac- ⁇ 1 - [( ⁇ 6-Cyclopropyl-8- [(2,6-difluorobenzyl) oxy] -2-methylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] -2- methylbutan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • the reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 50%). This gave 56 mg of the target product (60% of theory).
  • Example 8A rac - ⁇ 1 - [( ⁇ 8 - [(2,6-Difluorobenzyl) oxy] -2-methyl-6- (1H-pyrazol-1-yl) imidazo [1,2-a] pyridine-3 - yl ⁇ carbonyl) amino] -2-methylbutan-2-yl ⁇ carbamic acid ieri.-butyl ester
  • Example 9A rac- ⁇ 1- [( ⁇ 8 - [(2,6-difluorobenzyl) oxy] -6- (methoxymethyl) -2-methylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] - 2-methyl-butan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • Example 10A rac- ⁇ 1- [( ⁇ 8 - [(2,6-difluorobenzyl) oxy] -2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-one yl) imidazo [l, 2-a] pyridin-3-yl ⁇ carbonyl) amino] -2-methyl-butan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • Example 12A rac- ⁇ 1- [( ⁇ 8 - [(2,6-difluorobenzyl) oxy] -6- (difluoromethoxy) -2-methylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] - 2-methyl-butan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • Example 13A rac- ⁇ 1 - [( ⁇ 8- [(2,6-Difluorobenzyl) oxy] -2-methyl-6- (1,3-oxazol-5-yl) imidazo [1,2-a] pyridine 3-yl ⁇ carbonyl) amino] -2-methylbutan-2-yl ⁇ carbamic acid, ieri-butyl ester
  • the reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 50%). This gave 43 mg of the target product (44% of theory).
  • Example 16A rac- ⁇ 1- [( ⁇ 8 - [(2,6-difluorobenzyl) oxy] -2- (methoxymethyl) -6-methylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] - 2-methyl-butan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • Example 40A 4-Butyl ⁇ 3- [( ⁇ 8- [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl ⁇ carbonyl) amino] - 2,2-difluoropropyl ⁇ carbamate trifluoroacetate
  • Example 41A rac- ⁇ 1 - [( ⁇ 8 - [(2,6-Difluorobenzyl) oxy] -2-methyl-6- (1-methyl-1H-pyrazol-4-yl) -imidazo [1, 2-a ] pyridin-3-yl ⁇ carbonyl) amino] -2-methyl-butan-2-yl ⁇ carbamic acid tert-butyl ester ieri.
  • the reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 0% to 50%). This gave 50 mg of the target product (50% of theory).
  • Enantiomer B 4.24 g (> 99% ee)
  • reaction solution was taken up in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
  • product fractions were combined, concentrated and dried under high vacuum. 151 mg of the target compound (66% of theory, purity 97%) were obtained.
  • reaction solution was taken up in acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
  • product fractions were combined, concentrated and dried under high vacuum. 168 mg of the target compound (75% of theory, purity 99%) were obtained.
  • Enantiomer B 3.53 g (> 98% ee)
  • the aqueous phase was acidified to pH 2 by the addition of a 1 M solution of hydrochloric acid and the product was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. This gave 480 mg of the target compound (63% of theory).
  • the crude product was purified by preparative HPLC (RP-C18, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the product fractions were taken up in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution.
  • the combined aqueous phases were extracted twice with dichloromethane.
  • the combined organic phases were dried over sodium sulfate, filtered and evaporated. 16 mg of the title compound (23% of theory) were obtained.
  • the crude product was purified by preparative HPLC (RP-C18, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the product fractions were taken up in dichloromethane and a little methanol and washed twice with saturated aqueous sodium bicarbonate solution.
  • the combined aqueous phases were extracted twice with dichloromethane.
  • the combined organic phases were dried over sodium sulfate, filtered and evaporated. 11 mg of the title compound (17% of theory) were obtained.
  • the reaction mixture was evaporated, dissolved in acetonitrile / water, combined with TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the concentrated product fractions were dissolved in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution.
  • the combined aqueous phases were extracted twice with dichloromethane.
  • the combined organic phases were dried over sodium sulfate, filtered and concentrated. There were obtained 96 mg of the target compound (94% of theory).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux imidazo[1,2-a]pyridine-3-carboxamides substitués, leurs procédés de production, leur utilisation seuls ou en association pour la thérapeutique et/ou la prophylaxie de maladies ainsi que leur utilisation pour la production de médicaments destinés à la thérapeutique et/ou à la prophylaxie de maladies, notamment à la thérapeutique et/ou à la prophylaxie de maladies cardiovasculaires.
EP15722673.9A 2014-05-02 2015-04-29 Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation Withdrawn EP3137466A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14166909 2014-05-02
PCT/EP2015/059282 WO2015165933A2 (fr) 2014-05-02 2015-04-29 Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation

Publications (1)

Publication Number Publication Date
EP3137466A2 true EP3137466A2 (fr) 2017-03-08

Family

ID=50693465

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15722673.9A Withdrawn EP3137466A2 (fr) 2014-05-02 2015-04-29 Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation

Country Status (6)

Country Link
US (1) US20170050961A1 (fr)
EP (1) EP3137466A2 (fr)
JP (1) JP2017514900A (fr)
CN (1) CN106470995A (fr)
CA (1) CA2947387A1 (fr)
WO (1) WO2015165933A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9624214B2 (en) 2012-11-05 2017-04-18 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
WO2015140199A1 (fr) 2014-03-21 2015-09-24 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation
WO2018184976A1 (fr) 2017-04-05 2018-10-11 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation
CN110577528A (zh) * 2019-09-29 2019-12-17 杰达维（上海）医药科技发展有限公司 咪唑并[1,2-a]吡啶-6-醇的制备方法

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2013014082A (es) * 2011-05-30 2014-03-21 Astellas Pharma Inc Compuestos de imidazopiridina.
US9126998B2 (en) * 2012-11-05 2015-09-08 Bayer Pharma AG Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US8796305B2 (en) * 2012-11-05 2014-08-05 Bayer Pharma Aktiengesellschaft Carboxy-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US9624214B2 (en) * 2012-11-05 2017-04-18 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US8778964B2 (en) * 2012-11-05 2014-07-15 Bayer Pharma Aktiengesellschaft Hydroxy-substituted imidazo[1,2-a]-pyridinecarboxamides and their use
MX2015006856A (es) * 2012-11-30 2016-02-17 Astellas Pharma Inc Compuestos imidazopiridina.
WO2014195333A1 (fr) * 2013-06-04 2014-12-11 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridines à substitution 3-aryle et leur utilisation
CA2947372A1 (fr) * 2014-05-02 2015-11-05 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridine carboxamides substitues par chlore en position 6 et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
US20170057958A1 (en) * 2014-05-02 2017-03-02 Bayer Pharma Aktiengesellschaft Enantiomers of the n-(2-amino-5-fluoro-2-methylpentyl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide, as well as of the di- and trifluoro derivatives for the treatment of cardiovascular diseases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
US20170050961A1 (en) 2017-02-23
CA2947387A1 (fr) 2015-11-05
WO2015165933A2 (fr) 2015-11-05
CN106470995A (zh) 2017-03-01
WO2015165933A3 (fr) 2016-02-25
JP2017514900A (ja) 2017-06-08

Similar Documents

Publication Publication Date Title
EP3004094B1 (fr) Imidazo[1,2-a]pyridines à substitution 3-aryle et leur utilisation
EP3107920B1 (fr) 3-(pyrimidin-2-yl)imidazo[1,2-a]pyridines
WO2015082411A1 (fr) Imidazo[1,2-a]pyridine-3-carboxamides aryl et hétéroaryl substitués et leur utilisation
WO2014068095A1 (fr) Imidazo[1,2-a]pyridincarboxamides carboxy-substitués et leur utilistaion comme stimulants de la guanylate cyclase soluble
EP3119777A1 (fr) Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation
WO2014131760A1 (fr) Pyrimidines annelées à subsitution trifluorométhyle et utilisation correspondante
DE102010043379A1 (de) Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung
WO2015018808A1 (fr) Imidazo[1,2-a]pyrazincarboxamides substitués et leur utilisation
EP3030562A1 (fr) Pyrazolo[1,5-a]pyridine-3-carboxamides substitués et leur utilisation
EP3119778A1 (fr) Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation
WO2015004105A1 (fr) Benzyl-1h-pyrazolo[3,4-b]pyridine et utilisation de cette dernière
EP3137464A1 (fr) Imidazo[1,2-a]pyridines utilisées en tant que stimulateurs de la guanylate cyclase pour traiter des maladies cardiovasculaires
EP3227286B1 (fr) Pyrazolo[1,5-a]pyridines et imidazo[1,2-a]pyrazines substituées et leur utilisation
EP3137466A2 (fr) Imidazo[1,2-a]pyridine-carboxamides substitués en 6 et leur utilisation
WO2015165970A1 (fr) Imidazo[1,2-a]pyridine carboxamides substitués par chlore en position 6 et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP3227287B1 (fr) Imidazo[1,2-a]pyridines à substitution hétéroaryle et leur utilisation
WO2016023885A1 (fr) Quinoline-4-carboxamides substitués et leur utilisation
EP3137463A1 (fr) Énantiomères du n-(2-amino-5-fluor-2-méthylpentyl)-8-[(2,6-difluorbenzyl)oxy]-2-méthylimidazo[1,2-a]pyridine-3-carboxamide et de ses dérivés difluorés et trifluorés pour traiter des maladies cardiovasculaires
WO2016030362A1 (fr) Pyrimidines condensées substituées et leur utilisation
WO2016030354A1 (fr) Pyrimidines annelées amino-substituées et leur utilisation
EP3253758B1 (fr) Dérivés substitués-n de carboxamide 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazine-3- en tant que stimulateurs de la guanylatcyclase soluble (gcs) pour le traitement de maladies cardiovasculaires
WO2018184976A1 (fr) Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation
EP3286185A1 (fr) Pyrazolo[1,5-a]pyridine-3-carboxamides substitués et leur utilisation

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20161202

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20180221

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20180704