WO2021094209A1 - Dérivés de pyrrolo triazine carboxamide substitués en tant qu'antagonistes du récepteur de la prostaglandine ep3 - Google Patents

Dérivés de pyrrolo triazine carboxamide substitués en tant qu'antagonistes du récepteur de la prostaglandine ep3 Download PDF

Info

Publication number
WO2021094209A1
WO2021094209A1 PCT/EP2020/081248 EP2020081248W WO2021094209A1 WO 2021094209 A1 WO2021094209 A1 WO 2021094209A1 EP 2020081248 W EP2020081248 W EP 2020081248W WO 2021094209 A1 WO2021094209 A1 WO 2021094209A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
group
fluoro
alkyl
methyl
Prior art date
Application number
PCT/EP2020/081248
Other languages
English (en)
Inventor
Lisa CANDISH
Steffen Müller
Frank SÜSSMEIER
Niels Lindner
Christoph Gerdes
Elisabeth Pook
Anja BUCHMÜLLER
Fabienne Zdenka GAUGAZ
Stefanie Zimmermann
Dieter Lang
Rudolf Schohe-Loop
Markus Follmann
Simon Anthony HERBERT
Xiang Gao
Stefanie MESCH
Jan Stampfuss
Katrin PARTIKEL
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2021094209A1 publication Critical patent/WO2021094209A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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

Definitions

  • the invention relates to substituted pyrrolo triazine carboxamide derivatives and to processes for their preparation, and also /to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders.
  • Atherothrombosis is the main complication of atherosclerosis and underlies several of the most lethal human diseases, such as myocardial infarction (Ml), ischemic stroke (IS) and peripheral arterial occlusive disease (PAOD).
  • Ml myocardial infarction
  • IS ischemic stroke
  • PAOD peripheral arterial occlusive disease
  • the process is initiated by the deposition of lipids and their subsequent oxidation in the arterial wall which induces the recruitment of inflammatory cells and the formation of atherosclerotic plaques.
  • These plaques are covered by a fibrous cap which maintains the plaque content separated from the blood flow.
  • pro-inflammatory mechanisms drive inflammatory cells to produce matrix metalloproteases which digest the proteins of the fibrous cap.
  • the thinned cap is called “vulnerable”, meaning that the cap may rupture relatively easily in response to stresses.
  • the cap ruptures or its endothelial cover erodes, the plaque content comes into contact with the blood and provokes the formation of an intravascular thrombus by activating platelets and blood coagulation.
  • This process, forming a thrombus on plaques, is called atherothrombosis. If obstructive, the resulting intravascular thrombus interrupts blood flow and causes ischemia of downstream tissues with dramatic clinical consequences representing the leading cause of death and morbidity worldwide.
  • thrombosis which is the pathological formation of intra-vascular plugs.
  • the mechanisms of thrombosis encompass two intertwined pathways, the coagulation cascade and the aggregation of platelets, which once activated by a vessel injury act synergistically to build the intravascular clot obstructing the vessel lumen.
  • Anticoagulant and anti-aggregant drugs, used to prevent atherothrombosis have elicited a considerable reduction of the rate of second myocardial infarctions and a decrease of long term mortality from about 30% prior to the 1980s to less than 10% after the 2000s (Arch. Intern. Med.
  • the COX inhibitor Aspirin and the ADP receptor P2Y12 antagonist Clopidogrel are components of dual antiplatelet therapy.
  • Prasugrel and Ticagrelor are alternative P2Y12 blockers that have demonstrated reductions of cardiovascular ischemic events ( N . Engl. J. Med. 2007, 357, 2001-2015; ibid. 2009, 361, 1045-1057).
  • the coagulation factor Xa inhibitor Rivaroxaban has also shown benefits to patients with stable atherosclerotic vascular disease (N. Engl. J. Med. 2017, 377, 1319-1330).
  • PGE2 prostaglandin E2
  • Increased PGE2 concentrations have been measured in atherosclerotic vascular walls of mice and humans [Circulation 2001 , 104, 921-927; J. Exp. Med. 2007, 204, 311-320; Cardiovasc. Res. 2014, 101, 482- 491]
  • PGE2 binds on four specific receptors EP1, EP2, EP3 and EP4 on cell membranes.
  • PGE2 has been shown to interfere with human and murine platelet function via EP3 and EP4 receptors ( Eur : J. Pharmacol. 1991, 194, 63-70). Stimulation of EP3 potentiates platelet activation and aggregation induced by primary agonists like collagen or ADP, whereas stimulation of EP4 inhibits platelet activation. This PGE2-dependent balance of platelet activation and inhibition can be tipped by modulation of EP3 or EP4 receptors ( Platelets 2010, 21, 329-342; Prostaglandins & Other Upid Mediators 2015, 121, 4-16).
  • blocking the EP3 receptor by specific antagonists should be a beneficial strategy for prevention and treatment of atherothrombosis by local abrogation of platelet activation without altering hemostasis.
  • EP3 antagonists might represent a beneficial strategy in the treatment of patients with type II diabetes.
  • EP3 receptor antagonists might help to improve renal disorders and in particular to resolve bladder hyperactivity, interstitial cystitis or bladder pain syndrome.
  • antithrombotic and anti-inflammatory principles may also be particularly attractive to prevent the mutual enhancement of coagulation and platelet activation.
  • prostaglandin derivatives participate in the regulation of intraocular pressure and inflammation. Therefore, compounds modulating the respective receptors may have a benefit in the prevention and treatment of ocular diseases.
  • prostaglandin derivates play an essential role via their platelet-activating and pro- inflammatory mechanisms in inflammatory disorders like vasculitides, for example Kawasaki disease, Takayasu arteritis and Thrombangiitis obliterans (Buerger’s disease) as well as myocarditis (EMBO Mol Med 2018, e8536).
  • EP3 antagonists might contribute to the treatment and/or prophylaxis of diabetes- related end-organ manifestations like diabetic retinopathy and diabetic nephropathy.
  • prostaglandins are involved in the pathogenesis of neurological disorders like neuropathic pain, Alzheimer’s disease and Parkinson’s disease.
  • PGE2 and EP3 have been reported to play a role in the pathogenesis of respiratory disorders like chronic cough, asthma and COPD (Am J Respir Crit Care 2009, 923-928).
  • WO2017/085056 provides pyrrolo triazine derivatives as phosphodiesterase inhibitors.
  • W02006/004724, W02004/013145, W02004/009601 , WOOO/71129 and US2006/0229449 provide pyrrolo triazine derivatives as anti-cancer agents and kinase inhibitors.
  • WO2014/015830, WO2014/015675 and WO 2014/015523 provide heteroaryl compounds for the treatment of cancer.
  • WO 2015/052610 and WO 2016/103097 provide antagonists of prostaglandin EP3 receptor having a pyridinone substituted indazole, indole or quinoline derivative.
  • Amide or pyridinone based EP3 receptor antagonists are also described in ACS Med. Chem. Lett. 2010, 7, 316-320 and in Bioorg. Med. Chem. Lett. 2009, 19, 4292-4295, ibid. 2011, 27, 2806-2811, ibid. 2016, 26, 2670- 2675.
  • WO2019/219517 describes substituted dihydropyrazolo pyrazine carboxamide derivatives as antagonists of prostaglandin EP3 receptor.
  • the invention provides compounds of the formula (I) in which
  • R 1 represents CrC 6 -alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methylsulfonyl, carbamoyl, NR a R b (where R a and R b are independently selected from the group consisting of hydrogen, CrC4-alkyl, C2-C6-halogeno- alkyl and cyclopropyl) and CrC3-halogenoalkoxy, where halogenoalkoxy is substituted by 1 to 3 fluoro substituents, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting
  • R 5 represents hydrogen, CrC4-alkyl, C2-C6-halogenoalkyl substituted by 1 to 3 fluoro, cyclopropyl, methylcarbonyl or methoxycarbonyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents Ci-C 6 -alkanediyl, where alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methoxycarbonyl, carboxyl, carbamoyl, amino, dimethylamino, te/f-butoxycarbonylamino, C3-C6-cycloalkyl (which may be substituted by 1 hydroxy), azetidin-1-yl (which may be substituted by 1 or 2 fluoro), pyrrolidin-1-yl (which may be substituted by 1 or 2 fluoro) and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H- benzimidazol-5-yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, azetidinyl, 1,1- dioxothietan-3-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3- yl or pyrrolidinyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen
  • R 2 represents a group of the formula where # is the point of attachment to the triazinone ring
  • Q 1 represents CR 8A or N
  • Q 2 represents CR 8 or N
  • R 6 represents hydrogen, halogen, CrC 4 -alkyl, CrC 4 -halogenoalkyl, CrC 4 -alkoxy or CrC 4 -halogenoalkoxy,
  • R 7 represents hydrogen, halogen, CrC 4 -alkyl, CrC 4 -halogenoalkyl, CrC 4 -alkoxy, C 1 -C 4 - halogenoalkoxy or C 3 -C 6 -cycloalkyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen,
  • R 7A represents hydrogen or halogen
  • R 8 represents hydrogen or halogen
  • R 8A represents hydrogen or halogen
  • R 3 represents hydrogen, halogen, cyano, CrC 4 -alkyl, CrC 2 -halogenoalkyl, methoxy or cyclopropyl,
  • R 4 represents hydrogen, halogen, CrC 4 -alkyl, CrC 4 -halogenoalkyl, C 3 -C 6 -cycloalkyl or C 1 -C 3 - alkoxymethyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom’s normal valence under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2”.
  • halogen or “halogeno” like in combinations e.g. in halogenoalkyl means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, even more particularly fluorine or chlorine.
  • Ci-C 4 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, 1, 2, 3, 4 or 5 carbon atoms, and 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g.
  • 1.2-dimethylbutyl or 1,3-dimethylbutyl group or an isomer thereof.
  • said group has 1, 2, 3 or 4 carbon atoms (“Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • Ci-C 6 -halogenoalkyl represents a linear or branched, saturated, monovalent hydrocarbon group in which the term “alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said Ci-C 6 -halogenoalkyl group is, for example fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,
  • Ci-C4-halogenoalkoxy and “Ci-C3-halogenoalkoxy” represents a linear or branched, saturated, monovalent Ci-C4-alkoxy or Ci-C3-alkoxy group (where alkoxy represents a straight- chain or branched, saturated, monovalent alkoxy radical having 1 to 4 or 1 to 3 carbon atoms, by way of example and with preference methoxy, ethoxy, n-propoxy, isopropoxy), in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said Ci-C3-halogenoalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C3-C6-cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms.
  • Said C3-C6-cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • Ci-C 6 -alkanediyl and “C2-C5-alkanediyl” represents a linear or branched, divalent alkyl radical having 1 to 6 or 2 to 5 carbon atoms, by way of example and with preference methylene (-CH2-), ethan-1 , 1-diyl [-CH(CH 3 )-], ethan-1,2-diyl [-(CH 2 )H, propan- 1,1-diyl [-CH(CH 2 CH 3 )-], propan-1, 2-diyl [-CH2CH(CH3)-], 2-methylpropan-1, 1-diyl ⁇ -CH[CH(C 113)2]- ⁇ , 2-methylpropan- 1,3-diyl ⁇ -CH 2 [CH(CH 3 )]CHr- ⁇ , butan- 1,1-diyl ⁇ -CH[(CH 2 )2CH 3 ]- ⁇ , butan-1, 2-diyl
  • Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, and also the compounds encompassed by formula (I) and specified hereinafter as working example(s), and the salts, solvates and solvates of the salts thereof, to the extent that the compounds encompassed by formula (I) and specified hereinafter are not already salts, solvates and solvates of the salts.
  • inventive compounds may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else, if appropriate, of conformational isomers (enantiomers and/or diastereomers, including those in the case of rotamers and atropisomers).
  • the present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof.
  • the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, especially HPLC chromatography on an achiral or chiral phase.
  • the compounds of the present invention may exist as tautomers.
  • the compounds of formula (I) encompass the tautomer of formula (la)
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the term “enantiomerically pure” is understood to mean that the compound in question with respect to the absolute configuration of the chiral centre is present in an enantiomeric excess of more than 95%, preferably more than 97%.
  • the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
  • An isotopic variant of an inventive compound is understood here as meaning a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to 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 CI, 82 Br, 123 l, 124 l, 129 l and 131 1.
  • Particular isotopic variants of a compound according to the invention may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
  • the incorporation of isotopes, for example of deuterium may lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the inventive compounds may therefore in some cases 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 those skilled in the art, for example by the methods described further below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention.
  • the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, tri ethyl amine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, ethylenediamine, N- methylpiperidine and choline.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • ammonium salts derived
  • the present invention includes all possible salts of the compounds according to the invention as single salts, or as any mixture of said salts, in any ratio.
  • Solvates in the context of the invention are described as those forms of the inventive compounds which form a complex in the solid or liquid state by coordination with solvent molecules.
  • the compounds according to the invention may contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. Hydrates are a specific form of the solvates in which the coordination is with water. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds according to the invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised in a known manner.
  • the present invention includes all such possible N-oxides.
  • the present invention additionally also encompasses prodrugs of the inventive compounds.
  • prodrugs encompasses compounds which for their part may be biologically active or inactive but are converted during their residence time in the body into compounds according to the invention (for example by metabolism or hydrolysis).
  • treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states.
  • therapy is understood here to be synonymous with the term “treatment”.
  • prevention means prevention, prophylaxis and “preclusion” are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.
  • the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
  • the end point of the line marked by # in each case does not represent a carbon atom or a CH2 group, but is part of the bond to the atom to which R 2 is attached.
  • R 1 represents CrC 6 -alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy and methylsulfonyl, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 hydroxy substituents, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR 5 , and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl, ethyl and phenyl, where the phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, chloro
  • R 5 represents CrC4-alkyl, C2-C6-halogenoalkyl substituted by 1 to 3 fluoro, methylcarbonyl or methoxycarbonyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents Ci-C 6 -alkanediyl, where alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxycarbonyl, amino, dimethylamino, tert- butoxycarbonylamino, C3-C6-cycloalkyl (which may be substituted by 1 hydroxy), azetidin-1-yl (which may be substituted by 1 or 2 fluoro), pyrrolidin-1-yl (which may be substituted by 1 or 2 fluoro) and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrazinyl, pyrazolyl, imidazolyl, 2-oxo-2,3-dihydro-1H- benzimidazol-5-yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, azetidinyl, 1,1- dioxothietan-3-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3- yl or pyrrolidinyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, CrC4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, di- fluoromethoxy, dimethylaminomethyl, aminosulfonyl and pyrrolidin-1
  • Q 1 represents CR 8A or N
  • Q 2 represents CR 8 or N
  • R 6 represents hydrogen, halogen, CrC 4 -alkyl, CrC 4 -halogenoalkyl or CrC 4 -alkoxy
  • R 7 represents hydrogen, halogen, CrC 4 -alkyl, CrC 4 -alkoxy or C 3 -C 6 -cycloalkyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen
  • R 7A represents hydrogen or halogen
  • R 8 represents hydrogen or halogen
  • R 8A represents hydrogen or halogen
  • R 3 represents hydrogen, halogen, cyano, CrC 4 -alkyl, methoxy or cyclopropyl
  • R 4 represents hydrogen, CrC 4 -alkyl, CrC 4 -halogenoalkyl or C 3 -C 6 -cycloalkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • R 1 represents CrC 6 -alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 substituent selected from the group consisting of hydroxy, methoxy and methylsulfonyl, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 hydroxy substituent, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR 5 , and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl and phenyl, where the phenyl may be substituted by 1 substituent selected from the group consisting of fluoro, chloro and cyano, and
  • R 5 represents CrC4-alkyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1 H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents Ci-C 6 -alkanediyl, where alkanediyl may be substituted by 1 substituent selected from the group consisting of hydroxy, dimethylamino, te/f-butoxycarbonylamino and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrazinyl, pyrazolyl, 2-oxo-2,3-dihydro-1 H-benzimidazol-5- yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, 1,1-dioxothietan-3-yl, 1 ,1- dioxidotetrahydrothiophen-3-yl or 4,5,6,7-tetrahydro-1 H-indazol-3-yl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, methoxy, difluoromethoxy, dimethylaminomethyl, aminosulfonyl and pyrrolidin-1-ylmethyl, where pyridinyl may be substituted by 1 methoxy substituent, where pyrazolyl may be substituted by 1 to 3 substituents independently selected from
  • Q 1 represents CR 8A or N
  • Q 2 represents CR 8 or N
  • R 6 represents hydrogen, halogen, CrC4-alkyl or CrC4-alkoxy
  • R 7 represents hydrogen, halogen or CrC4-alkyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen,
  • R 7A represents hydrogen or halogen
  • R 8 represents hydrogen or halogen
  • R 8A represents hydrogen
  • R 3 represents hydrogen, halogen, cyano, CrC4-alkyl, methoxy or cyclopropyl
  • R 4 represents hydrogen, CrC4-alkyl, CrC4-halogenoalkyl or C3-C6-cycloalkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • R 1 represents CrC 6 -alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy and methylsulfonyl, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 hydroxy substituents, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR 5 , and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl, ethyl and phenyl, where the phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, chloro
  • R 5 represents CrC4-alkyl, C2-C6-halogenoalkyl substituted by 1 to 3 fluoro, methylcarbonyl or methoxycarbonyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents Ci-C 6 -alkanediyl, where alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, amino, dimethylamino, terf-butoxycarbonylamino, C3- C 6 -cycloalkyl (which may be substituted by 1 hydroxy), azetidin-1-yl (which may be substituted by 1 or 2 fluoro), pyrrolidin-1-yl (which may be substituted by 1 or 2 fluoro) and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrazinyl, pyrazolyl, 2-oxo-2,3-dihydro-1H-benzimidazol-5- yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, azetidinyl, 1,1-dioxothietan-3-yl, 1,1-dioxidotetrahydrothiophen-3-yl, 4,5,6,7-tetrahydro-1H-indazol-3-yl or pyrrolidinyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, CrC4-alkyl, methoxy, trifluoromethyl, trifluoromethoxy, di- fluoromethoxy, dimethylaminomethyl, aminosulfonyl and pyrrolidin-1-ylmethyl, where
  • R 2 represents a group of the formula where # is the point of attachment to the triazinone ring
  • Q 1 represents CR 8A .
  • Q 2 represents CR 8 .
  • R 6 represents hydrogen, halogen or CrC4-alkyl
  • R 7 represents hydrogen, halogen, CrC4-alkyl or C3-C6-cycloalkyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen
  • R 7A represents hydrogen
  • R 8 represents hydrogen
  • R 8A represents hydrogen
  • R 3 represents hydrogen, halogen, cyano, CrC4-alkyl, methoxy or cyclopropyl
  • R 4 represents hydrogen, CrC4-alkyl, CrC4-halogenoalkyl or C3-C6-cycloalkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • R 1 represents CrC 6 -alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 substituent selected from the group consisting of hydroxy, methoxy and methylsulfonyl, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 hydroxy substituent, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR 5 , and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl and phenyl, where the phenyl may be substituted by 1 substituent selected from the group consisting of fluoro, chloro and cyano, and
  • R 5 represents CrC4-alkyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents Ci-C 6 -alkanediyl, where alkanediyl may be substituted by 1 substituent selected from the group consisting of hydroxy, dimethylamino, te/f-butoxycarbonylamino and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrazinyl, pyrazolyl, 2-oxo-2,3-dihydro-1H-benzimidazol-5- yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, 1,1-dioxothietan-3-yl, 1,1- dioxidotetrahydrothiophen-3-yl or 4,5,6,7-tetrahydro-1 H-indazol-3-yl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, methoxy, difluoromethoxy, dimethylaminomethyl, aminosulfonyl and pyrrolidin-1-ylmethyl, where pyridinyl may be substituted by 1 methoxy substituent, where pyrazolyl may be substituted by 1 to 3 substituents independently selected from the group
  • Q 1 represents CR 8A .
  • Q 2 represents CR 8 .
  • R 6 represents hydrogen, halogen or CrC4-alkyl
  • R 7 represents hydrogen, halogen or CrC4-alkyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen,
  • R 7A represents hydrogen
  • R 8 represents hydrogen
  • R 8A represents hydrogen
  • R 3 represents hydrogen, halogen, cyano, CrC4-alkyl, methoxy or cyclopropyl
  • R 4 represents hydrogen, CrC4-alkyl, CrC4-halogenoalkyl or C3-C6-cycloalkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • R 1 represents CrCs-alkyl, C2-C4-halogenoalkyl, C3-C6-cycloalkyl, bicyclo[1.1.1]pentan-1-yl, 2,3-dihydro-1 H-inden-1-yl or the group -L-R E , where alkyl may be substituted by 1 substituent selected from the group consisting of hydroxy, methoxy and methylsulfonyl, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 hydroxy substituent, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR 5 , and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl and phenyl, where the phenyl may be substituted by 1 substituent selected from the group consisting of fluoro, chloro and cyano, and
  • R 5 represents methyl, and where bicyclo[1.1.1]pentan-1-yl may be substituted by 1 fluoro substituent, and where 2,3-dihydro-1H-inden-1-yl may be substituted by 1 hydroxy substituent, and
  • L represents C2-Cs-alkanediyl, where alkanediyl may be substituted by 1 substituent selected from the group consisting of hydroxy, dimethylamino, te/f-butoxycarbonylamino and morpholin-4-yl, and additionally by up to 3 fluoro,
  • R E represents phenyl, pyridinyl, pyrazinyl, pyrazolyl, 2-oxo-2,3-dihydro-1H-benzimidazol-5- yl, indolyl, 2,3-dihydro-benzodioxinyl, C3-C6-cycloalkyl, 1,1-dioxothietan-3-yl, 1,1- dioxidotetrahydrothiophen-3-yl or 4,5,6,7-tetrahydro-1 H-indazol-3-yl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, methoxy, difluoromethoxy, dimethylaminomethyl, aminosulfonyl and pyrrolidin-1-ylmethyl, where pyridinyl may be substituted by 1 methoxy substituent, where pyrazolyl may be substituted by 1 to 3 substituents independently selected
  • R 2 represents a group of the formula where # is the point of attachment to the triazinone ring
  • Q 1 represents CR 8A
  • Q 2 represents CR 8
  • R 6 represents hydrogen, chloro or methyl
  • R 7 represents hydrogen, fluoro, chloro or methyl, with the proviso, that at least one of R 6 and R 7 is not hydrogen,
  • R 7A represents hydrogen
  • R 8 represents hydrogen
  • R 8A represents hydrogen
  • R 3 represents hydrogen, chloro or methyl
  • R 4 represents hydrogen, methyl, isopropyl, trifluoromethyl or cyclopropyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • R 2 represents 4-chlorophenyl, 3- chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylphenyl, 3-fluoro- 4-methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-chloro-4-trifluoromethoxyphenyl, 3,4-dichlorophenyl,
  • R 2 represents 4-chlorophenyl, 3- chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 3,4-dimethylphenyl, 3-fluoro-4- methylphenyl, 3-chloro-2-fluoro-phenyl, 5-chloro-2-fluoro-phenyl or 4-chloro-2-fluoro-phenyl.
  • R 2 represents 4-chlorophenyl, 3- chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methylphenyl, 3-fluoro- 4-methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-chloro-4-trifluoromethoxyphenyl, 3,4-dichlorophenyl,
  • R 2 represents 4-chlorophenyl, 3- chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 3,4-dimethylphenyl or 3-fluoro-4- methylphenyl.
  • R 3 represents hydrogen, chloro, cyano, methyl, methoxy or cyclopropyl.
  • R 4 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl or cyclopropyl.
  • R x represents CrCs-alkyl, where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methoxycarbonyl, carboxyl, carbamoyl, amino, dimethylamino, fe/f-butoxycarbonylamino, C3-C6-cycloalkyl (which may be substituted by 1 hydroxy), azetidin- 1-yl (which may be substituted by 1 or 2 fluoro), pyrrolidin-1-yl (which may be substituted by 1 or 2 fluoro) and morpholin-4-yl, and additionally by up to 3 fluoro, and R y represents hydrogen, halogen, CrC4-alkyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, dimethylaminomethyl, aminosulfonyl or pyrrolidin-1-ylmethyl.
  • the compounds of the formula (l-X) are a subgroup of the compounds of the formula (I).
  • the invention further provides a process for preparing compounds of the formula (I), or salts thereof, solvates thereof or solvates of the salts thereof, wherein [A1] the compounds of the formula (II)
  • X 3 represents chlorine, bromine or iodine, are reacted with compounds of the formula (XXIII)
  • R 2 _X 4 (XXIII), in which R 2 is as defined above, and
  • X 4 represents -B(OH) 2 , a boronic ester, preferably pinacol boronate, or -BF 3 -K + , under Suzuki coupling conditions to give compounds of the formula (I).
  • the reaction [A1] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0°C to 50°C at atmospheric pressure.
  • the reaction [A1] can also be carried out without a solvent only in one base if the base is a liquid at room temperature.
  • Suitable dehydrating agents are, for example, carbodiimides such as N,N ’-diethyl-, N,N’- dipro- pyl- N,N ’-diisopropyl-, A/,/ ⁇ /-dicydohexylcarbodiimide, A/-(3-dimethylaminoisopropyl)-/ ⁇ /'-ethylcarbo- diimide hydrochloride (EDCI) (optionally in the presence of pentafluorophenol (PFP)), /V-cyclohexyl- carbodiimide-A/'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1 ,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3- sulphate or 2-terf-butyl-5-methyl-isox
  • Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or /V-methylmorpholine.
  • alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or /V-methylmorpholine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-methylpyrrolidone or acetonitrile, or mixtures of the solvents; preference is given to dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene or toluene
  • other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-
  • the compounds of the formula (II) are known or can be synthesized from the corresponding starting compounds by known processes.
  • reaction according to process [A2] is generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, optionally in a microwave, preferably in a temperature range from room temperature to 150°C at atmospheric pressure to 3 bar.
  • Catalysts are, for example, palladium catalysts customary for Suzuki reaction conditions, preference being given to catalysts such as dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(O), palladium(ll) acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium, bis(diphenylphosphaneferrocenyl)palladium(ll) chloride, 1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1 ,4-naphthoquinone)palladium dimer, allyl(chloro)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)palladium, palladium(ll) acetate/ dicyclohexyl(2’,4’
  • Additional reagents are, for example, potassium acetate, caesium carbonate, potassium carbonate or sodium carbonate, potassium tert-butoxide, caesium fluoride or potassium phosphate, where these may be present in aqueous solution; preferred are additional reagents such as potassium carbonate or aqueous potassium phosphate solution.
  • Inert solvents are, for example, ethers such as dioxane, tetrahydrofuran or 1 ,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, or carboxamides such as dimethylformamide or dimethylacetamide, alkyl sulphoxides such as dimethyl sulphoxide, or N-methylpyrrolidone or acetonitrile, or mixtures of the solvents with alcohols such as methanol or ethanol and/or water; preference is given to tetrahydrofuran, dioxane or acetonitrile.
  • ethers such as dioxane, tetrahydrofuran or 1 ,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide or dimethylacetamide
  • alkyl sulphoxides such as dimethyl
  • R 2 , R 3 and R 4 are as defined above and
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with a base.
  • the reaction [B] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or alkoxides such as potassium tert- butoxide or sodium tert- butoxide, preference is given to lithium hydroxide or sodium hyroxide.
  • Inert solvents are, for example, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvents with water; preference is given to a mixture of tetrahydrofuran and water or ethanol and water.
  • the compounds of the formula (IV) are known or can be prepared [C] by reacting compounds of the formula (V) in which
  • R 2 , R 3 and R 4 are as defined above, R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with nitrile compounds of the formula (VI)
  • R 2 is as defined above, in the presents of a base.
  • the reaction [C] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or alkoxides such as potassium tert- butoxide or sodium tert- butoxide, preference is given to potassium tert- butoxide.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1 ,2-dichloroethane, alcohols such as methanol, ethanol, /so-propanol or te/f-butanol, ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2- dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents; preference is given to tert- butanol.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1 ,2-dichloroethane
  • alcohols such as methanol, ethanol, /so-propanol or
  • the compounds of the formula (VI) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds of the formula (IV) are known or can also be prepared
  • R 2 , R 3 and R 4 are as defined above and
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with aldehyde compounds of the formula (VIII)
  • R 2 is as defined above, in the presents of a copper(ll) salt.
  • the reaction [D] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Copper(ll) sorces are, for example, copper(ll)chloride, copper(ll)bromide, copper(ll)iodide or copper(ll)oxide; preference is given to copper(ll)chloride.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1 ,2-dichloroethane, alcohols such as methanol, ethanol, /so-propanol or te/f-butanol, ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2- dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethyl sulfoxide dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents; preference is given to dimethyl sulfoxide.
  • the compounds of the formula (VIII) are known or can be synthesized from the corresponding starting compounds by known processes.
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with an ammonia equivalent in the presence of an acid.
  • the reaction [E] is generally carried out without a solvent, preferably in a temperature range from room temperature up to 150°C at atmospheric pressure.
  • Ammonia equivalents are, for example, ammonium acetate, ammonium formate, ammonium propionate, or ammonium chloride; preference is given to ammonium acetate.
  • Acids are, for example, organic acids such was formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or mineral acids such as, for example, hydrogen chloride, or hydrogen bromide; preference is given to acetic acid.
  • R 2 , R 3 and R 4 are each as defined above,
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with an ammonia equivalent in the presence of an acid.
  • the reaction [F] is generally carried out without a solvent, preferably in a temperature range from room temperature up to 150°C at atmospheric pressure.
  • Ammonia equivalents are, for example, ammonium acetate, ammonium formate, ammonium propionate, or ammonium chloride; preference is given to ammonium acetate.
  • Acids are, for example, organic acids such was formic acid, acetic acid, propionic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or mineral acids such as, for example, hydrogen chloride, or hydrogen bromide; preference is given to acetic acid.
  • reaction [F] can be performed without acid in the presence of ammonia and inert solvents, preferably in a temperature range from room temperature up to 225°C under microwave irradiation.
  • Ammonia equivalents are, for example, ammonium acetate, ammonium formate, ammonium propionate, or ammonium chloride; preference is given to ammonium acetate.
  • Inert solvents are, for example, alcohols such as methanol, ethanol or iso-propanol, ethers such as methyl tert-butyl ether, 1 ,2-dimethoxyethane, dioxane ortetrahydrofuran, or other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide or acetonitrile, or mixtures of solvents, or mixtures of solvents; preference is given to methanol.
  • alcohols such as methanol, ethanol or iso-propanol
  • ethers such as methyl tert-butyl ether, 1 ,2-dimethoxyethane, dioxane ortetrahydrofuran
  • other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide or acetonitrile, or mixtures of solvents, or mixtures of solvents; preference is given to methanol.
  • R 2 is as defined above and
  • X 1 represents chloro or bromo, in the presence of a base.
  • the reaction [G1] is generally carried out in inert solvents, preferably in a temperature range from 0°C up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4- dimethylaminopyridine or diisopropylethylamin, or pyridine, or other bases such as sodium hydride, or lithium diisopropylamide; preference is given to triethylamine.
  • alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4- dimethylaminopyridine or diisopropylethylamin, or pyridine, or other bases such as sodium hydride, or lithium diisopropylamide; preference is given to triethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide, acetonitrile, acetone or pyridine, or mixtures of solvents, or mixtures of solvents with water; preference is given to acetone.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane
  • ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxyethane, dioxan
  • the compounds of the formula (XI) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds of the formula (X) are known or can be prepared
  • X 1 represents chloro or bromo, in the presence of a base.
  • reaction [G2] is generally carried out as described for reaction [G1].
  • the compounds of the formula (XI) are known or can be synthesized from the corresponding starting compounds by known processes.
  • R 2 is as defined above and
  • X 2 represents hydroxy, in the presence of a dehydrating agent.
  • reaction [H1] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0°C to 50°C at atmospheric pressure.
  • reaction [H1] can also be carried out without a solvent only in one base if the base is a liquid at room temperature.
  • Suitable dehydrating agents are, for example, carbodiimides such as L/,L/’-diethyl-, N,N’- dipropyl-, L/,L/’-diisopropyl-, /V,/V-dicyclohexylcarbodiimide, A/-(3-dimethylaminoisopropyl)-/V- ethylcarbodiimide hydrochloride (EDCI) (optionally in the presence of pentafluorophenol (PFP)), /V-cyclohexylcarbodiimide-/V-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1,2-oxazolium compounds such as 2-ethyl-5- phenyl-1,2-oxazolium 3-sulphate or 2-te/f-butyl-5-methyl-isoxazolium perchlor
  • Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or /V-methylmorpholine.
  • alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or /V-methylmorpholine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-methylpyrrolidone or acetonitrile, or mixtures of the solvents; preference is given to dimethylformamide.
  • halogenated hydrocarbons such as dichloromethane or trichloromethane
  • hydrocarbons such as benzene or toluene
  • other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-
  • the compounds of the formula (XII) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds of the formula (X) are known or can also be prepared
  • X 2 represents hydroxy, in the presence of a dehydrating agent.
  • reaction [H2] is generally carried out as described for reaction [H1]
  • the compounds of the formula (XII) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the reaction [I] is generally carried out in inert solvents, preferably in a temperature range from 0°C up to reflux of the solvents in a sealed vessel.
  • Inert solvents are, for example, alcohols such as methanol, ethanol or iso-propanol, ethers such as diethyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, /V-methyl-pyrrolidone, dimethylacetamide, acetonitrile, or mixtures of solvents; preference is given to methanol.
  • R 2 , R 3 and R 4 are each as defined above,
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl
  • R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with an ammonia equivalent in the presence of a base, an oxidant and a phase transfer catalyst.
  • the reaction [J] is generally carried out in biphasic mixtures of aqueous and organic solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Ammonia equivalents are, for example, ammonium chloride, ammonium hydroxide and ammonium acetate; preference is given to ammonium chloride and ammonium hydroxide.
  • Bases are, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide or alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate; preference is given to sodium hydroxide.
  • Oxidants are, for example, sodium hypochlorite.
  • Phase transfer catalyst for example, tetraalkyl ammonium salts such as methyltrioctylammonium chloride, tetrabutylammonium chloride, benzyltributylammonium chloride and tetrahexylammonium chloride; preference is given to methyltrioctylammonium chloride.
  • Organic solvents are, for example, ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, dioxane or tetrahydrofuran; preference is given to methyl tert- butyl ether.
  • reaction [K] by reacting compounds of the formula (XIII) with an (aminooxy)(diphenyl)phosphine oxide in the presence of a base.
  • the reaction [K] is generally carried out in inert solvents, preferably in a temperature range from 0°C up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, alkali metal hydrides such as sodium hydride or potassium potassium, alkali metal amides such as lithium diisopropylamide of potassium bis(trimethylsilyl)amide; preference is given to sodium hydride.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, N- methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to dimethylformamide.
  • the compounds of the formula (XIII) are known or can be prepared
  • R 4 is as defined above and
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with compounds of the formula (XV) in which R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, in the presence of a copper(ll) sorce and a ligand.
  • the reaction [L] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Copper(ll) sorces are, for example, copper(ll)chloride, copper(ll)bromide, copper(ll)iodide or copper(ll)oxide; preference is given to copper(ll)oxide.
  • Ligands are, for example, 1,10-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline or pathophenanthroline; preference is given to 1,10-phenanthroline.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, /V-methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to 1,4-dioxane.
  • ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, /V-methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to 1,4-dioxane.
  • R 4 is as defined above, with 2 equivalents of compounds of the formular (XV) in the presents of a base.
  • the reaction [M] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, 1,8-diazabicyclo[5.4.0]undec-7-en, 1,5-diayabicyclo [4.3.0] nonene-5, 1,1,3,3-tetramethylguanidine, 1,4-diazabicyclo(2.2.2)octane, triethylamine or N,N- diisopropylethylamine, preference is given to 1,8-diazabicyclo[5.4.0]undec-7-en.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to tetrahydrofuran.
  • ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, 1,4-dioxane or tetrahydrofuran
  • other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to tetrahydrofuran.
  • the compounds of the formula (XVI) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds of the formula (XIII) are known or can also be prepared
  • R 3 and R 4 are each as defined above,
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with a base.
  • the reaction [N] is generally carried out in inert solvents, preferably in a temperature range from 0°C up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, alkali metal tert- butoxides, such as sodium tert- butoxide or potassium tert- butoxide or alkali metal hydrides such as sodium hydride or potassium hydride, or alkali metal amides such as lithium diisopropylamide or potassium bis(trimethylsilyl)amide; preference is given to potassium ferf-butoxide.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, iso-propanol, ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as toluene, dimethylformamide, N-methyl-pyrrolidone or dimethylacetamide, or mixtures of solvents; preference is given to a mixture of ethanol, toluene and tetrahydrofuran.
  • alcohols such as methanol, ethanol, iso-propanol
  • ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxyethane, dioxane or tetrahydrofuran
  • other solvents such as toluene, dimethylformamide, N-methyl-pyrrolidone or dimethylacetamide, or mixture
  • R 3 and R 4 are each as defined above,
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 15 represents methyl or ethyl, with a compound of the formula (XIX) in which R 14 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl.
  • the reaction [O] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, iso-propanol, ethers such as diethyl ether, methyl tert- butyl ether, 1 ,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, N-methyl-pyrrolidone, dimethylacetamide or acetonitrile; preference is given to ethanol.
  • the compounds of the formula (XIX) are known or can be synthesized from the corresponding starting compounds by known processes.
  • R 4 is as defined above, with compounds of the formula (XXI) (xxi), in which
  • R 3 is as defined above
  • R 13 represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and
  • R 15 represents methyl or ethyl, with pivaloyl chloride and a base.
  • the reaction [P] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.
  • Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N- methylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamin, or pyridine; preference is given to triethylamine.
  • organic bases such as trialkylamines, for example triethylamine, N- methylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamin, or pyridine; preference is given to triethylamine.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as toluene, dimethylformamide, N-methyl-pyrrolidone or dimethylacetamide; preference is given to toluene.
  • ethers such as diethyl ether, methyl tert- butyl ether, 1,2- dimethoxyethane, dioxane or tetrahydrofuran
  • solvents such as toluene, dimethylformamide, N-methyl-pyrrolidone or dimethylacetamide; preference is given to toluene.
  • R 3 and R 4 have the meaning given above and X 3 represents chlorine, bromine or iodine, are reacted with compounds of the formula (II) (II), in which
  • R 1 is as defined above, in the presence of a dehydrating agent.
  • reaction [Q] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0°C to 50°C at atmospheric pressure.
  • the reaction [Q] can also be carried out without a solvent only in one base if the base is a liquid at room temperature.
  • Suitable dehydrating agents are, for example, carbodiimides such as N,N ’-diethyl-, N,N’- dipro- pyl- N,N ’-diisopropyl-, A/,/ ⁇ /-dicydohexylcarbodiimide, A/-(3-dimethylaminoisopropyl)-/ ⁇ /'-ethylcarbo- diimide hydrochloride (EDCI) (optionally in the presence of pentafluorophenol (PFP)), /V-cyclohexyl- carbodiimide-/ ⁇ /-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1 ,2-oxazolium compounds such as 2-ethyl
  • Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or triethylamine.
  • alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine or triethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-methylpyrrolidone or acetonitrile, or mixtures of the solvents; preference is given to dimethylformamide or dichloromethane.
  • the compounds of the formula (II) are known or can be synthesized from the corresponding starting compounds by known processes.
  • the compounds of the formula (XXIV) are known, can be synthesized from the corresponding starting compounds by known processes or can be prepared analogously to the processes described in the Examples section.
  • the preparation of the starting compounds and of the compounds of the formula (I) can be illustrated by the synthesis schemes which follow.
  • the compounds of the invention have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention have an unforeseeable useful pharmacological activity spectrum and good pharmacokinetic behavior, in particular a sufficient exposure of such a compound in the blood above the minimal effective concentration within a given dosing interval after oral administration.
  • Such a profile results in an improved peak-to-trough ratio (quotient of maximum to minimum concentration) within a given dosing interval, which has the advantage that the compound can be administered less frequently and at a significantly lower dose to achieve an effect.
  • They are compounds that inhibit the activation of the EP3 receptor by its ligand Prostaglandin E2 (PGE2).
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral arterial occlusive disease , and/or diabetes, and/or ophthalmic disorders and/or urogenital disorders, in particular those associated with excess PGE2.
  • disorders in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral arterial occlusive disease , and/or diabetes, and/or ophthalmic disorders and/or urogenital disorders, in particular those associated with excess PGE2.
  • PGE2 concentrations have been measured in atherosclerotic vascular walls of mice and humans. Once released upon plaque rupture, PGE2 binds on four specific receptors EP1 , EP2, EP3 and EP4 on cell membranes. PGE2 has been shown to interfere with human and murine platelet function via EP3 and EP4 receptors. Stimulation of EP3 potentiates platelet activation and aggregation induced by primary agonists like collagen or ADP, whereas stimulation of EP4 inhibits platelet activation. This PGE2-dependent balance of platelet activation and inhibition can be tipped by modulation of EP3 or EP4 receptors.
  • the "thrombotic or thromboembolic disorders” include disorders which occur preferably in the arterial vasculature and which can be treated with the compounds according to the invention, in particular disorders leading to peripheral arterial occlusive disorders and in the coronary arteries of the heart, such as acute coronary syndrome (ACS), myocardial infarction with ST segment elevation (STEMI) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, but also thrombotic or thromboembolic disorders in cerebrovascular arteries, such as transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic strokes, such as strokes due to atrial fibrillation, non-cardioembolic strokes, such as lacunar stroke, strokes due to large or small artery diseases, or strokes due to undetermined cause,
  • ACS acute coronary
  • the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of disorders where, the pro-inflammatory component plays an essential role, including vasculitides like Kawasaki disease, Takayasu arteritis and Thrombangiitis obliterans (Buerger’s disease) as well as inflammatory disorders like myocarditis.
  • the pro-inflammatory component plays an essential role, including vasculitides like Kawasaki disease, Takayasu arteritis and Thrombangiitis obliterans (Buerger’s disease) as well as inflammatory disorders like myocarditis.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis of disorders of the urogenital tract like overactive bladder, interstitial cystitis and bladder pain syndrome.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis of diabetes mellitus including its end-organ manifestations like diabetic retinopathy and diabetic nephropathy. Furthermore, the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of neurological disorders like neuropathic pain, Alzheimer’s disease and Parkinson’s disease,
  • the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of pulmonologic disorders like chronic cough, asthma and COPD.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides for the use of the compounds according to the invention for production of a medicament for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.
  • the present invention further provides a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.
  • the present invention further provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.
  • the present invention provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of thrombotic or thromboembolic, in particular atherothrombotic disorders using a therapeutically effective amount of a compound according to the invention.
  • the present invention further provides medicaments comprising a compound according to the invention and one or more further active compounds.
  • the compounds according to the invention can also be used for preventing coagulation ex vivo, for example for the protection of organs to be transplanted against organ damage caused by formation of clots and for protecting the organ recipient against thromboemboli from the transplanted organ, for preserving blood and plasma products, for cleaning/pretreating catheters and other medical auxiliaries and instruments, for coating synthetic surfaces of medical auxiliaries and instruments used in vivo or ex vivo or for biological samples which may comprise factor Xla or plasma kallikrein.
  • the present invention furthermore provides a method for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples which may comprise factor Xla or plasma kallikrein or both enzymes, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.
  • the compounds of the invention can act systemically and/or locally.
  • they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Suitable for extraocular (topic) administration are administration forms which operate in accordance with the prior art, which release the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in crystalline and/or amorphized and/or dissolved form such as, for example, eye drops, sprays and lotions (e.g. solutions, suspensions, vesicular/colloidal systems, emulsions, aerosols), powders for eye drops, sprays and lotions (e.g. ground active compound, mixtures, lyophilisates, precipitated active compound), semisolid eye preparations (e.g. hydrogels, in-situ hydrogels, creams and ointments), eye inserts (solid and semisolid preparations, e.g. bioadhesives, films/wafers, tablets, contact lenses).
  • eye drops e.g. solutions, suspensions, vesicular/colloidal systems, emulsions, aerosols
  • powders for eye drops, sprays and lotions
  • Intraocular administration includes, for example, intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar and subtenon administration.
  • Suitable for intraocular administration are administration forms which operate in accordance with the prior art, which release the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in crystalline and/or amorphized and/or dissolved form such as, for example, preparations for injection and concentrates for preparations for injection (e.g. solutions, suspensions, vesicular/colloidal systems, emulsions), powders for preparations for injection (e.g.
  • gels for preparations for injection semisolid preparations, e.g. hydrogels, in-situ hydrogels
  • implants solid preparations, e.g. biodegradable and nonbiodegradable implants, implantable pumps. Preference is given to oral administration or, in the case of ophthalmologic disorders, extraocular and intraocular administration.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • the compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia,
  • fillers and carriers for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )),
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),
  • buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),
  • capsule materials for example gelatine, hydroxypropylmethylcellulose
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • antioxidants for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore relates to a pharmaceutical composition which comprises at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • An embodiment of the invention are pharmaceutical compositions comprising at least one compound of formula (I) according to the invention, preferably together with at least one inert, non toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the above cited purposes.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • inventive compounds can be employed alone or, if required, in combination with other active ingredients.
  • present invention further provides medicaments comprising at least one of the inventive compounds and one or more further active ingredients, especially for treatment and/or prophylaxis of the aforementioned disorders.
  • suitable active ingredient combinations include:
  • organic nitrates and NO donors for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • hypotensive active ingredients by way of example and with preference from the group of the calcium antagonists, angiotensin All antagonists, ACE inhibitors, NEP-inhibitors, vasopeptidase-inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase-inhibitors and the diuretics;
  • antiarrhythmic agents by way of example and with preference from the group of sodium channel blocker, beta-receptor blocker, potassium channel blocker, calcium antagonists, If- channel blocker, digitalis, parasympatholytics (vagoliytics), sympathomimetics and other antiarrhythmics as adenosin, adenosine receptor agonists as well as vernakalant;
  • positive-inotrop agents by way of example cardiac glycoside (Dogoxin), beta-adrenergic and dopaminergic agonists, such as isoprenalin, adrenalin, noradrenalin, dopamin or dobutamin;
  • Dogoxin cardiac glycoside
  • beta-adrenergic and dopaminergic agonists such as isoprenalin, adrenalin, noradrenalin, dopamin or dobutamin
  • vasopressin-receptor-antagonists by way of example and with preference from the group of conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050, as well as the compounds described in WO 2010/105770, WO2011/104322 and WO 2016/071212;
  • active ingredients which alter lipid metabolism for example and with preference from the group of the thyroid receptor agonists, cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.
  • cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid
  • bronchodilatory agents for example and with preference from the group of the beta-adrenergic rezeptor-agonists, such as, by way of example and preferably, albuterol, isoproterenol, metaproterenol, terbutalin, formoterol or salmeterol, or from the group of the anticholinergics, such as, by way of example and preferably, ipratropiumbromid;
  • anti-inflammatory agents for example and with preference from the group of the gluco corticoids, such as, by way of example and preferably, prednison, prednisolon, methylprednisolon, triamcinolon, dexamethason, beclomethason, betamethason, flunisolid, budesonid or fluticason as well as the non-steroidal anti-inflammatory agents (NSAIDs), by way of example and preferably, acetyl salicylic acid (aspirin), ibuprofen and naproxen, 5-amino salicylic acid-derivates, leukotriene-antagonists, TNF-alpha-inhibitors and chemokin-receptor antagonists, such as CCR1, 2 and/or 5 inhibitors;
  • NSAIDs non-steroidal anti-inflammatory agents
  • agents modulating the immune system for example immunoglobulins
  • agents that inhibit the signal transductions cascade for example and with preference from the group of the kinase inhibitors, byway of example and preferably, from the group of the tyrosine kinase- and/or serine/threonine kinase inhibitors;
  • agents that inhibit the degradation and modification of the extracellular matrix, for example and with preference from the group of the inhibitors of the matrix-metalloproteases (MMPs), by way of example and preferably, inhibitors of chymasee, stromelysine, collagenases, gelatinases and aggrecanases (with preference from the group of MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) as well as of the metallo-elastase (MMP-12) and neutrophil-elastase (HNE), as for example sivelestat or DX-890;
  • MMPs matrix-metalloproteases
  • agents that block the Kunststoff of serotonin to its receptor, for example and with preference antagonists of the 5-HT2b-receptor;
  • organic nitrates and NO-donators for example and with preference sodium nitroprussid, nitro glycerine, isosorbid mononitrate, isosorbid dinitrate, molsidomine or SIN-1, as well as inhaled NO;
  • agents that stimulates the synthesis of cGMP, wiessen sGC Modulatoren, for example and with preference riociguat, cinaciguat, vericiguat or BAY 1101042;
  • prostacyclin-analogs for example and with preference iloprost, beraprost, treprostinil or epoprostenol;
  • agents that inhibit soulble epoxidhydrolase (sEH), for example and with preference N,N'-Di- cyclohexyl urea, 12-(3-Adamantan-1-yl-ureido)-dodecanic acid or 1-Adamantan-1-yl-3- ⁇ 5-[2- (2-ethoxyethoxy)ethoxy]pentyl ⁇ -urea;
  • SEH soulble epoxidhydrolase
  • agents that interact with glucose metabolism for example and with preference insuline, biguanide, thiazolidinedione, sulfonyl urea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors;
  • natriuretic peptides for example and with preference atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, Nesiritid) natriuretic peptide type C (CNP) or urodilatin;
  • ABP atrial natriuretic peptide
  • BNP natriuretic peptide type B
  • CNP natriuretic peptide type C
  • urodilatin urodilatin
  • agents that affect the energy metabolism of the heart for example and with preference etomoxir, dichloroacetat, ranolazine or trimetazidine, full or partial adenosine A1 receptor agonists such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate; agents that affect the heart rate, for example and with preference ivabradin; cyclooxygenase inhibitors such as, for example, bromfenac and nepafenac; inhibitors of the kallikrein-kinin system such as, for example, safotibant and ecallantide; inhibitors of the sphingosine 1-phosphate signal paths such as, for example, sonepcizumab; inhibitors of the complement-C5a receptor such as, for example, eculizumab; plasminogen activators (thrombolytics/fibrinolytics)
  • anticoagulatory substances such as, for example, heparin (UFH), low- molecular-weight heparins (LMW), for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675/ORG42675;
  • anticoagulants such as, for example, heparin (UFH), low- molecular-weight heparins (LMW), for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675/ORG42675;
  • DTI direct thrombin inhibitors
  • Pradaxa diabigatran
  • atecegatran AZD- 0837
  • DP-4088 phosphatidylcholine
  • SSR-182289A argatroban
  • argatroban argatroban
  • bivalirudin and tanogitran BIBT-986 and prodrug BIBT-1011
  • hirudin thrombin inhibitors
  • direct factor Xa inhibitors such as, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/R PR- 130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux;
  • direct factor Xa inhibitors such as, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/R PR- 130673), letaxaban (TAK-442), razax
  • inhibitors of coagulation factor XI and Xla such as, for example, FXI ASO-LICA, BAY 121- 3790, MAA868, BMS986177, EP-7041 and AB-022;
  • platelet aggregation inhibitors substances which inhibit the aggregation of platelets
  • thrombocyte aggregation inhibitors such as, for example, acetylsalicylic acid (such as, for example, aspirin), P2Y12 antagonists such as, for example, ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor and elinogrel, and PAR-1 antagonists such as, for example, vorapaxar, and PAR-4 antagonists;
  • platelet adhesion inhibitors such as GPVI and/or GPIb antagonists such as, for example, Revacept or caplacizumab; ⁇ fibrinogen receptor antagonists (g lycoprotei n- 11 b/l 11 a antagonists) such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;
  • recombinant human activated protein C such as, for example, Xigris or recombinant thrombomodulin.
  • Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances.
  • the inventive compounds are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidin or dipyridamole.
  • a platelet aggregation inhibitor by way of example and with preference aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidin or dipyridamole.
  • the inventive compounds are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, dabigatran, melagatran, bivalirudin or clexane.
  • the inventive compounds are administered in combination with a GPIIb/llla antagonist such as, by way of example and with preference, tirofiban or abciximab.
  • a GPIIb/llla antagonist such as, by way of example and with preference, tirofiban or abciximab.
  • the inventive compounds are administered in combination with a factor Xa inhibitor, by way of example and with preference rivaroxaban (BAY 59- 7939), DU-176b, apixaban, betrixaban, otamixaban, fidexaban, razaxaban, letaxaban, eribaxaban, fondaparinux, idraparinux, PMD-3112, darexaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • rivaroxaban BA
  • the inventive compounds are administered in combination with a factor XI or factor Xla inhibitor, by way of example and with preference FXI ASO- LICA, BAY 121-3790, MAA868, BMS986177, EP-7041 or AB-022.
  • the inventive compounds are administered in combination with heparin or with a low molecular weight (LM W) heparin derivative.
  • the inventive compounds are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.
  • Hypotensive agents are preferably understood to mean compounds from the group of the calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and the diuretics.
  • the inventive compounds are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • the inventive compounds are administered in combination with an alpha- 1 -receptor blocker, by way of example and with preference prazosin.
  • the inventive compounds are administered in combination with a beta-receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker by way of example and with preference propranolol, atenolol, timolol, pindolol
  • the inventive compounds are administered in combination with an angiotensin All antagonist, by way of example and with preference losartan, candesartan, valsartan, telmisartan or embusartan or a dual angiotensin All antagonist/neprilysin- inhibitor, by way of example and with preference LCZ696 (valsartan/sacubitril).
  • the inventive compounds are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an endothelin antagonist by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.
  • the inventive compounds are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.
  • the inventive compounds are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone or eplerenone.
  • the inventive compounds are administered in combination with a loop diuretic, for example furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics, for example amiloride and triamterene, with aldosterone antagonists, for example spironolactone, potassium canrenoate and eplerenone, and also thiazide diuretics, for example hydrochlorothiazide, chlorthalidone, xipamide and indapamide.
  • a loop diuretic for example furosemide, torasemide, bumetanide and piretanide
  • potassium-sparing diuretics for example amiloride and triamterene
  • aldosterone antagonists for example spironolactone
  • potassium canrenoate and eplerenone potassium canrenoate and eplerenone
  • thiazide diuretics for example hydrochlorothiazide, chlorthalidone,
  • Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reduc tase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.
  • the CETP inhibitors such as HMG-CoA reduc tase inhibitors or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reduc tase inhibitors or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-gamma and/or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric
  • the inventive compounds are administered in combination with a CETP inhibitor, by way of example and with preference dalcetrapib.anacetrapib, torcetrapib (CP- 529414), JJT-705 or CETP vaccine (Avant).
  • a CETP inhibitor by way of example and with preference dalcetrapib.anacetrapib, torcetrapib (CP- 529414), JJT-705 or CETP vaccine (Avant).
  • the inventive compounds are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist by way of example and with preference D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the inventive compounds are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the inventive compounds are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS- 188494 or TAK-475.
  • the inventive compounds are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SM P-797.
  • an ACAT inhibitor by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SM P-797.
  • the inventive compounds are administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R- 103757 or JTT-130.
  • the inventive compounds are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.
  • the inventive compounds are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042.
  • the inventive compounds are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.
  • the inventive compounds are administered in combination with a lipase inhibitor, a preferred example being orlistat.
  • the inventive compounds are administered in combination with a polymeric bile acid adsorbent, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • the inventive compounds are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • the inventive compounds are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • the inventive compounds are administered in combination with sGC modulators, by way of example and with preference, riociguat, cinaciguat or vericiguat.
  • the inventive compounds are administered in combination with an agent affecting the glucose metabolism, by way of example and with preference, insuline, a sulfonyl urea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors.
  • an agent affecting the glucose metabolism by way of example and with preference, insuline, a sulfonyl urea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors.
  • the compounds according to the invention are administered in combination with a TGFbeta antagonist, by way of example and with preference pirfenidone or fresolimumab.
  • the compounds according to the invention are administered in combination with a CCR2 antagonist, by way of example and with preference CCX- 140.
  • the compounds according to the invention are administered in combination with a TNFalpha antagonist, by way of example and with preference adalimumab.
  • the compounds according to the invention are administered in combination with a galectin-3 inhibitor, by way of example and with preference GCS- 100.
  • the compounds according to the invention are administered in combination with a Nrf-2 inhibitor, by way of example and with preference bardoxolone
  • the compounds according to the invention are administered in combination with a BMP-7 agonist, by way of example and with preference THR- 184.
  • the compounds according to the invention are administered in combination with a NOX1/4 inhibitor, by way of example and with preference GKT- 137831.
  • the compounds according to the invention are administered in combination with a medicament which affects the vitamin D metabolism, by way of example and with preference calcitriol, alfacalcidol, doxercalciferol, maxacalcitol, paricalcitol, cholecalciferol or paracalcitol.
  • the compounds according to the invention are administered in combination with a cytostatic agent, by way of example and with preference cyclophosphamide.
  • the compounds according to the invention are administered in combination with an immunosuppressive agent, by way of example and with preference ciclosporin.
  • the compounds according to the invention are administered in combination with a phosphate binder, by way of example and with preference colestilan, sevelamer hydrochloride and sevelamer carbonate, Lanthanum and lanthanum carbonate.
  • the compounds according to the invention are administered in combination with renal proximal tubule sodium-phosphate co-transporter, by way of example and with preference, niacin or nicotinamide.
  • the compounds according to the invention are administered in combination with a calcimimetic for therapy of hyperparathyroidism.
  • the compounds according to the invention are administered in combination with agents for iron deficit therapy, by way of example and with preference iron products.
  • the compounds according to the invention are administered in combination with agents for the therapy of hyperurikaemia, by way of example and with preference allopurinol or rasburicase.
  • the compounds according to the invention are administered in combination with glycoprotein hormone for the therapy of anaemia, by way of example and with preference erythropoietin.
  • the compounds according to the invention are administered in combination with biologies for immune therapy, by way of example and with preference abatacept, rituximab, eculizumab or belimumab.
  • the compounds according to the invention are administered in combination with vasopressin antagonists (group of the vaptanes) for the treatment of heart failure, by way of example and with preference tolvaptan, conivaptan, lixivaptan, mozavaptan, satavaptan or relcovaptan.
  • vasopressin antagonists group of the vaptanes
  • the compounds according to the invention are administered in combination with Jak inhibitors, by way of example and with preference ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) or TG101348.
  • the compounds according to the invention are administered in combination with prostacyclin analogs for therapy of microthrombi.
  • the compounds according to the invention are administered in combination with an alkali therapy, by way of example and with preference sodium bicarbonate.
  • the compounds according to the invention are administered in combination with an mTOR inhibitor, by way of example and with preference everolimus or rapamycin.
  • the compounds according to the invention are administered in combination with an NHE3 inhibitor, by way of example and with preference AZD1722 or tenapanor.
  • the compounds according to the invention are administered in combination with an eNOS modulator, by way of example and with preference sapropterin.
  • the compounds according to the invention are administered in combination with a CTGF inhibitor, by way of example and with preference FG-3019.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day, and more preferably from about 0.01 mg/kg to about 10 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of formula (I) according to the invention are administered orally once or twice or three times a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once a day. For the oral administration, a rapid release or a modified release dosage form may be used.
  • NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered.
  • the 1 H-NMR data of selected compounds are listed in the form of 1 H-NMR peaklists. For each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), 6 2 (intensity 2 ), ... , d, (intensity,), ... , d h (intensity n ).
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H-NMR interpretation.
  • Method 1 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B ⁇ 1.2 min 100% B ® 2.0 min 100% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 2 Column: Kinetex EVO-C18 (Phenomenex), 2.6 pm, 3.0 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 10% B ® 1.1 min 100% B -> 1.7 min 100% B; column oven: 40°C; flow rate: 1.0 ml/min.
  • Method 3 Column: Shim-pack XR-ODS (Shimadzu), 2.2 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 1.1 min 100% B ® 1.7 min 100% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 4 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B ⁇ 1.2 min 100% B ® 1.6 min 100% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 5 Column: Ascentis Express C18 (Supelco), 2.7 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 2.0 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.
  • Method 6 MS instrument: Thermo Scientific FT-MS; instrument UHPLC+: Thermo Scientific Ulti- Mate 3000; column: Waters HSS T3, 2.1 c 75 mm, C18 1.8 pm; eluent A: 1 L water + 0.01% formic acid, eluent B: 1 L 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 rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.
  • Method 7 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B ® 2.0 min 95% B ® 2.6 min 95% B; column oven: 40°C; flow rate: 0.8 ml/min.
  • Method 8 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 30% B ® 3.5 min 95% B ® 4.1 min 95% B; column oven: 40°C; flow rate: 0.8 ml/min.
  • Method 9 Column: XSELECT CSH C18, 2.5 pm, 3.0 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B ® 2.0 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 10 Column: Shim-pack XR-ODS (Shimadzu), 2.2 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 2.9 min
  • Method 12 Column: XSELECT CSH C18, 2.5 pm, 3.0 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B -> 1.1 min 100% B ® 1.7 min 100% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 13 Column: Ascentis Express C18 (Supelco), 2.7 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 1.1 min 95% B ® 1.8 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.
  • Method 14 Column: Ascentis Express C18 (Supelco), 2.7 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B -> 2.1 min 100% B ® 2.8 min 100% B; column oven: 40°C; flow rate: 1.5 ml/min.
  • Method 15 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; gradient: 0.0 min 5% B ® 3.7 min 70% B ® 4.2 min 95% B ® 4.7 min 95% B; column oven: 40°C; flow rate: 0.8 ml/min.
  • Method 16 Column: CORTECS C18 (Waters), 2.7 pm, 2.1 c 50 mm; mobile phase A: 0.05% formic acid in water, mobile phase B: 0.05% formic acid in acetonitrile; gradient: 0.0 min 5% B ® 1.1 min 100% B -> 1.8 min 100% B; column oven: 40°C; flow rate: 1.0 ml/min.
  • Method 17 Column: Kinetex EVO-C18 100A (Phenomenex), 2.6 pm, 3.0 c 50 mm; mobile phase A: 5mM ammonium hydrogencarbonate in water, mobile phase B: acetonitrile; gradient: 0.0 min 10% B ® 2.1 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.2 ml/min.
  • Method 18 Column: Shim-pack XR-ODS (Shimadzu), 2.2 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 2.0 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.
  • Method 19 Column: Ascentis Express C18 (Supelco), 2.7 pm, 3.0 c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 1.7 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.
  • Method 20 MS instrument: Waters Single Quad MS System; Waters UPLC Acquity; column: Waters BEH C18, 1.7 pm, 50 c 2.1 mm; eluent A: 1 L water + 1.0 ml aq. ammonium hydroxide solution (25% ammonia), eluent B: 1 L acetonitrile; gradient: 0.0 min 92% A -> 0.1 min 92% A ® 1.8 min 5% A ® 3.5 min 5% A; column oven: 50°C; flow rate: 0.45 ml/min; UV detection: 210 nm (208-400 nm).
  • Method 21 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 pm 50 x 1 mm; eluent A: 1 L water + 0.25 ml 99% formic acid, eluent B: 1 L acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A 1.2 min 5% A 2.0 min 5% A; oven: 50°C; flow rate: 0.40 ml/min; UV-Detection: 210 nm.
  • Method 22 Instrument: Agilent MS Quad 6150;HPLC: Agilent 1290; column: Waters Acquity UPLC HSS T3 1.8 pm 50 x 2.1 mm; eluent A: 1 L water + 0.25 ml 99% formic acid, eluent B: 1 L acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 90% A 0.3 min 90% A 1.7 min 5% A 3.0 min 5% A; oven: 50°C; flow rate: 1.20 ml/min; UV-Detection: 205 - 305 nm.
  • Method 23 Instrument MS: Waters SQD; Instrument HPLC: Waters UPLC; column: Zorbax SB- Aq (Agilent), 1.8 pm 50 mm x 2.1 mm; eluent A: water + 0.025% formic acid, eluent B: acetonitrile (ULC) + 0.025% formic acid; gradient: 0.0 min 98%A 0.9 min 25%A 1.0 min 5%A 1.4 min 5%A - 1.41 min 98%A - 1.5 min 98%A; oven: 40°C; flow rate: 0.60 ml/min; UV-detection: DAD; 210 nm.
  • Method 24 System MS: Waters TOF instrument; System UPLC: Waters Acquity l-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 pm 50 x 1 mm; eluent A: 1 L water + 0.100 ml 99% formic acid, eluent B: 1 L acetonitrile + 0.100 ml 99% formic acid; Gradient: 0.0 min 90% A 1.2 min 5% A 2.0 min 5% A; oven: 50°C; flow rate: 0.40 ml/min; UV-Detection: 210 nm.
  • Method P1 Instrument: Waters Prep LC/MS System; column: XBridge C18 5 pm, 100 c 30 mm; eluent A: water, eluent B: acetonitrile; flow rate: 80 ml/min plus 5.0 ml of aq. ammonia (2% ammonia in water); at-column injection; gradient: 0.0-2.0 min 0% B, 2.0-10 min 0% B ® 100% B, 10-12 min 100%; column oven: RT; UV detection: 200-400 nm.
  • Method P3 Column: Phenomenex Gemini C18 250 x 50mm x 10 urn; eluent A: water + 0.05% of ammonia; eluent B: acetonitrile; gradient: 0-28 min 10% B ® 35% B.
  • Method P4 Column: Chromatorex C18, 10pm, 205 c 50 mm; eluent A: water + 0.1% of formic acid; eluent B: acetonitrile; gradient: 0.0-5.0 min 10% B, 5.0-17.5 min 10% B to 95% B, 17.5-21.0 min 95% B; flow rate: 150 ml/min, UV-Detection: 210 nm.
  • Method P5 Column: Reprosil C18, 10pm, 205 c 50 mm; eluent A: water + 0.1% of formic acid; eluent B: acetonitrile; gradient: 0.0-5.0 min 10% B, 5.0-17.5 min 10% B to 95% B, 17.5-21.0 min 95% B; flow rate: 150 ml/min, UV-Detection: 210 nm.
  • Method P6 Instrument: Waters Prep LC/MS System; column: XBridge C18 5pm 100x30 mm; eluent A : water, eluent B: acetonitrile, flow rate: 65 ml/min plus 5.0 ml of aqueous ammonia (2% ammonia in water); column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0- 2.0 min 10% B, 2.0-2.2 min 10% B to 20% B, 2.2-7.0 min 20% B to 60% B, 7.0- 7.5 min 60% B to 92% B, 7.5-9.0 min 92% B.
  • Method P7 Column: Chromatorex C- 18, 125 c 30 mm; eluent A: water + 0.1% formic acid, eluent B: aceto-nitrile; gradient: 90:10 5:95; flow rate: 75 ml/min; UV detection: 210 nm.
  • Method P9 Instrument: Waters Prep LC/MS System; column: Phenomenex Kinetex C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 63 ml, eluent B 7 ml, 2.0-10 min eluent A from 63-39 ml, eluent B from 7-31 ml, 10-12 min eluent B 70 ml. Eluent C and D at a constant flow 5 ml/min over the whole run.
  • Method P10 Instrument: Waters Prep LC/MS System; column: Phenomenex Kinetex C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 55 ml, eluent B 15 ml, 2.0-10 min eluent A from 55-31 ml, eluent B from 15-39 ml, 10-12 min eluent B 70 ml. Eluent C and D at a constant flow 5 ml/min over the whole run.
  • Method P11 Instrument: Waters Prep LC/MS System; column: Phenomenex Kinetex C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 47 ml, eluent B 23 ml, 2.0-10 min eluent A from 47-23 ml, eluent B from 23-47 ml, 10-12 min eluent B 70 ml. Eluent C and D at a constant flow 5 ml/min over the whole run.
  • Method P12 Instrument: Waters Prep LC/MS System; column: Phenomenex Kinetex C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 39 ml, eluent B 31 ml, 2.0-10 min eluent A from 39-15 ml, eluent B from 31-55 ml, 10-12 min eluent B 70 ml.
  • Method P14 Instrument: Waters Prep LC/MS System; column: XBridge C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% ammonia, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 55 ml, eluent B 15 ml, 2.0-10 min eluent A from 55-31 ml, eluent B from 15-39 ml, 10-12 min eluent B 70 ml. Eluent C and D at a constant flow 5 ml/min over the whole run.
  • Method P15 Instrument: Waters Prep LC/MS System; column: XBridge C18 5pm 100x30 mm; eluent A: water, eluent B: acetonitrile, eluent C: 2% ammonia, eluent D: acetonitrile/water (80vol%/20vol%), flow rate: 80 ml/min, column oven: RT; wavelength: 200-400 nm; At-Column injection; gradient: 0.0-2.0 min eluent A 63 ml, eluent B 7 ml, 2.0-10 min eluent A from 63-39 ml, eluent B from 7-31 ml, 10-12 min eluent B 70 ml. Eluent C and D at a constant flow 5 ml/min over the whole run.
  • Method P16 Column: Chromatorex C18, 10pm, 250 c 50 mm; eluent A: water + 0.1% of trifluoroacetic acid; eluent B: acetonitrile; gradient: 0.0-38 min 10% B to 95% B.
  • Microwave Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit.
  • the reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.
  • the compounds according to the invention may be obtained 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 to the corresponding free base or acid by various methods known to the person skilled in the art.
  • any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process.
  • names and structural formulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCI”, “x CF 3 COOH”, “x Na + " should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein.
  • the reaction was heated at 100°C for 3 h under an atmosphere of nitrogen, then the reaction solution was poured into water (400 ml). The precipitate was collected by filtration, washed with water (400 ml x 2) and dried under reduced pressure. The residue was stirred in methanol/dichloromethane (200 ml of a 1:10 mixture) for 30 min, then the solid was collected by filtration and dried to give 10.4 g (85% of theory, 94% purity) of a mixture of the title compounds.
  • reaction mixture was then diluted with water (20 ml), concentrated under reduced pressure to remove the ethanol and the pH was adjusted to 4 with hydrochloric acid (4.0 N). The precipitate was collected by filtration, washed with water and dried to afford 1.04 g (52% of theory, 94% purity) of the title compound.
  • reaction mixture was then diluted with water (5 ml), concentrated under reduced pressure to remove the ethanol and extracted with MTBE.
  • the pH of aqueous phase was adjusted to 1 with hydrochloric acid (2.0 N) and the precipitate was collected by filtration, washed with water and dried to afford 331 mg (26% of theory, 85% purity) of the title compound.
  • Methylmagnesium bromide (13 ml of a 1.0 M solution in THF, 13 mmol) was added slowly to a solution of methyl (2S)-amino(4-fluorophenyl)ethanoate hydrochloride (485 mg, 2.21 mmol) in THF (9.7 ml). After complete addition, the reaction mixture was slowly warmed to RT and stirred at this temperature overnight. Hydrochloric acid solution (1.0 M aqueous solution) was then added, and the mixture was washed with MTBE. The layers were separated and the organic layer was discarded. The aqueous layer was brought to basic pH by addition of sodium hydroxide (1.0 M aqueous solution) and was extracted with ethyl acetate.
  • aqueous sodium hydroxide (4.0 ml of a 1.0 M aqueous solution, 4.0 mmol) was added and stirring was continued at RT for two days. After this time, solid sodium hydroxide (346 mg, 8.65 mmol) was added and the mixture was stirred for three days at RT. The ethanol was removed and the aqueous layer was acidified by addition of hydrochloric acid (1.0 M aqueous solution) and the precipitate was collected by filtration and dried. The solid was redissolved in ethanol (3.5 ml) and sodium hydroxide (3.5 ml of a 1.0 M aqueous solution, 3.5 mmol) was added and the mixture was stired at 60°C overnight. After cooling to RT, the mixture was poured into water and acidified by addition of hydrochloric acid (1.0 M aqueous solution). The precipitate was collected by filtration and dried to afford 402 mg (61% of theory, 92% purity) of the title compound.
  • 7.554 (1.01), 7.565 (2.32), 7.568 (2.49), 7.585 (3.83), 7.598 (1.54), 7.706 (3.15), 7.708 (3.14), 7.987 (4.72), 12.019 (0.49).
  • the aqueous layer was extracted with ethyl acetate (100 x 3 ml) and then acidified to pH 3 with hydrochloric acid (1.0 M in water). The resulting precipitate was filtered and the filter cake was washed with water (2 x 300 ml). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with acetonitrile (300 ml) and ethyl acetate (300 ml) to afford the title compound. Yield 5.10 g (57% of theory).

Landscapes

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

Abstract

L'invention concerne des dérivés de pyrrole triazine carboxamide substitués de formule (I) et des procédés pour leur préparation, ainsi que leur utilisation pour la préparation de médicaments pour le traitement et/ou la prophylaxie de maladies, en particulier de troubles cardiovasculaires, de préférence de troubles thrombotiques ou thromboemboliques, et du diabète, ainsi que de troubles urogénitaux et ophtalmiques.
PCT/EP2020/081248 2019-11-12 2020-11-06 Dérivés de pyrrolo triazine carboxamide substitués en tant qu'antagonistes du récepteur de la prostaglandine ep3 WO2021094209A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2019117536 2019-11-12
CNPCT/CN2019/117536 2019-11-12

Publications (1)

Publication Number Publication Date
WO2021094209A1 true WO2021094209A1 (fr) 2021-05-20

Family

ID=73172718

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/081248 WO2021094209A1 (fr) 2019-11-12 2020-11-06 Dérivés de pyrrolo triazine carboxamide substitués en tant qu'antagonistes du récepteur de la prostaglandine ep3

Country Status (1)

Country Link
WO (1) WO2021094209A1 (fr)

Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000071129A1 (fr) 1999-05-21 2000-11-30 Bristol-Myers Squibb Company Pyrrolotriazines inhibiteurs de kinases
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2004009601A1 (fr) 2002-07-19 2004-01-29 Bristol-Myers Squibb Company Inhibiteurs de l'azaindole kinase
WO2004013145A1 (fr) 2002-08-02 2004-02-12 Bristol-Myers Squibb Company Composes de pyrrolotriazine inhibiteurs de kinase
WO2006004724A2 (fr) 2004-06-30 2006-01-12 Bristol-Myers Squibb Company Procede de preparation de composes de pyrrolotriazine
US20060229449A1 (en) 2005-04-06 2006-10-12 Apurba Bhattacharya Method for preparing pyrrolotriazine compounds via in situ amination of pyrroles
WO2010105770A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft 2-acétamido-5-aryl-1,2,4-triazolones substitués et leur utilisation
WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2012069146A1 (fr) 2010-11-24 2012-05-31 Merck Patent Gmbh Quinazoline carboxamide azétidines
WO2014015523A1 (fr) 2012-07-27 2014-01-30 Hutchison Medipharma Limited Nouveaux composés hétéroaryliques et hétérocycliques et compositions et procédés s'y rapportant
US20150099782A1 (en) * 2013-10-09 2015-04-09 Pfizer Inc. Antagonists of prostaglandin ep3 receptor
WO2016071212A1 (fr) 2014-11-03 2016-05-12 Bayer Pharma Aktiengesellschaft Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
US20160176851A1 (en) * 2014-12-22 2016-06-23 Pfizer Inc. Antagonists of prostaglandin ep3 receptor
WO2017085056A1 (fr) 2015-11-16 2017-05-26 Topadur Pharma Ag Utilisation de dérivés 2-phényl-3,4-dihydropyrrolo[2,1 -f] [1,2,4]triazinone comme inhibiteurs de phosphodiestérase et leurs utilisations
WO2019219517A1 (fr) 2018-05-17 2019-11-21 Bayer Aktiengesellschaft Dérivés de dihydropyrazolo pyrazine carboxamide substitués
WO2020216701A1 (fr) * 2019-04-25 2020-10-29 Bayer Aktiengesellschaft Acylsulfonamides pour le traitement du cancer

Patent Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000006568A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2000071129A1 (fr) 1999-05-21 2000-11-30 Bristol-Myers Squibb Company Pyrrolotriazines inhibiteurs de kinases
WO2001019776A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
WO2001019778A1 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique a proprietes pharmaceutiques
WO2001019780A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
WO2001019355A2 (fr) 1999-09-13 2001-03-22 Bayer Aktiengesellschaft Derives d'acide dicarboxylique presentant de nouvelles proprietes pharmaceutiques
WO2002042301A1 (fr) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Nouveaux derives de pyrazolopyridine a substitution pyridine
WO2002070510A2 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
WO2002070462A1 (fr) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Derives d'acide aminodicarboxylique
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
WO2004009601A1 (fr) 2002-07-19 2004-01-29 Bristol-Myers Squibb Company Inhibiteurs de l'azaindole kinase
WO2004013145A1 (fr) 2002-08-02 2004-02-12 Bristol-Myers Squibb Company Composes de pyrrolotriazine inhibiteurs de kinase
WO2006004724A2 (fr) 2004-06-30 2006-01-12 Bristol-Myers Squibb Company Procede de preparation de composes de pyrrolotriazine
US20060229449A1 (en) 2005-04-06 2006-10-12 Apurba Bhattacharya Method for preparing pyrrolotriazine compounds via in situ amination of pyrroles
WO2010105770A1 (fr) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft 2-acétamido-5-aryl-1,2,4-triazolones substitués et leur utilisation
WO2011104322A1 (fr) 2010-02-27 2011-09-01 Bayer Pharma Aktiengesellschaft Aryltriazolone liée à un bis-aryle et son utilisation
WO2011147809A1 (fr) 2010-05-26 2011-12-01 Bayer Pharma Aktiengesellschaft 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
WO2012004258A1 (fr) 2010-07-09 2012-01-12 Bayer Pharma Aktiengesellschaft Pyrimidines et triazines annelées et leur utilisation pour traiter ou prévenir des affections du système cardio-vasculaire
WO2012028647A1 (fr) 2010-09-03 2012-03-08 Bayer Pharma Aktiengesellschaft Azahétérocycles bicycliques et leur utilisation
WO2012059549A1 (fr) 2010-11-04 2012-05-10 Bayer Pharma Aktiengesellschaft 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
WO2012069146A1 (fr) 2010-11-24 2012-05-31 Merck Patent Gmbh Quinazoline carboxamide azétidines
WO2014015523A1 (fr) 2012-07-27 2014-01-30 Hutchison Medipharma Limited Nouveaux composés hétéroaryliques et hétérocycliques et compositions et procédés s'y rapportant
WO2014015830A1 (fr) 2012-07-27 2014-01-30 Hutchison Medipharma Limited Nouveaux composés hétéroaryliques et hétérocycliques et compositions et procédés s'y rapportant
WO2014015675A1 (fr) 2012-07-27 2014-01-30 Hutchison Medipharma Limited Nouveaux composés hétéroaryle et hétérocycles, compositions et procédés
US20150099782A1 (en) * 2013-10-09 2015-04-09 Pfizer Inc. Antagonists of prostaglandin ep3 receptor
WO2015052610A1 (fr) 2013-10-09 2015-04-16 Pfizer Inc. Antagonistes de récepteur ep3 de prostaglandine
WO2016071212A1 (fr) 2014-11-03 2016-05-12 Bayer Pharma Aktiengesellschaft Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
US20160176851A1 (en) * 2014-12-22 2016-06-23 Pfizer Inc. Antagonists of prostaglandin ep3 receptor
WO2016103097A1 (fr) 2014-12-22 2016-06-30 Pfizer Inc. Antagonistes de récepteur ep3 de prostaglandine
WO2017085056A1 (fr) 2015-11-16 2017-05-26 Topadur Pharma Ag Utilisation de dérivés 2-phényl-3,4-dihydropyrrolo[2,1 -f] [1,2,4]triazinone comme inhibiteurs de phosphodiestérase et leurs utilisations
WO2019219517A1 (fr) 2018-05-17 2019-11-21 Bayer Aktiengesellschaft Dérivés de dihydropyrazolo pyrazine carboxamide substitués
WO2020216701A1 (fr) * 2019-04-25 2020-10-29 Bayer Aktiengesellschaft Acylsulfonamides pour le traitement du cancer

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
ACS MED. CHEM. LETT., vol. 1, 2010, pages 316 - 320
ARCH. INTERN. MED., vol. 162, 2002, pages 2405 - 2410
BIOORG. MED. CHEM. LETT., vol. 19, 2009, pages 4292 - 4295
CARDIOVASC. RES., vol. 101, 2014, pages 482 - 491
CAS, no. 1596379-00-8
CIRCULATION, vol. 104, 2001, pages 921 - 927
CITATION OF NMR PEAKLIST DATA WITHIN PATENT APPLICATIONS
DIABETES, vol. 62, 2013, pages 1904 - 1912
EMBO MOL MED, 2018, pages e8536
EUR. J. PHARMACOL., vol. 194, 1991, pages 63 - 70
IBID, vol. 21, 2011, pages 2806 - 2811
IBID, vol. 26, 2016, pages 2670 - 2675
IBID, vol. 361, 2009, pages 1045 - 1057
J. EXP. MED., vol. 204, 2007, pages 311 - 320
LANCET, vol. 377, 2011, pages 2193 - 2204
N. ENGL. J. MED., vol. 357, 2007, pages 2001 - 2015
N. ENGL. J. MED., vol. 377, 2017, pages 1319 - 1330
PLATELETS, vol. 21, 2010, pages 329 - 342
PROSTAGLANDINS & OTHER LIPID MEDIATORS, vol. 121, 2015, pages 4 - 16
R. A. RODRIGUEZ ET AL., J. AM. CHEM. SOC., vol. 136, 2014, pages 6908 - 6911
RESEARCH DISCLOSURE
RESEARCH DISCLOSURE, 1 August 2014 (2014-08-01), Retrieved from the Internet <URL:http://www.researchdisclosure.com/searching-disclosures>

Similar Documents

Publication Publication Date Title
TWI487702B (zh) Ｃ型肝炎病毒抑制劑
WO2019219517A1 (fr) Dérivés de dihydropyrazolo pyrazine carboxamide substitués
US11524944B2 (en) 2-phenylpyrimidine-4-carboxamides as AHR inhibitors
TW201211038A (en) Oxazine derivatives and their use in the treatment of neurological disorders
US9695131B2 (en) Substituted uracils as chymase inhibitors
US20230265072A1 (en) Substituted pyrazolo piperidine carboxylic acids
AU2018354785A1 (en) Substituted imidazopyridine amides and use thereof
US9751843B2 (en) Substituted uracils and use thereof
US20240051935A1 (en) Substituted pyrazolo piperidine carboxylic acids
WO2021094210A1 (fr) Dérivés de pyrazine carboxamide substitués utilisés en tant qu&#39;antagonistes du récepteur de la prostaglandine ep3
EP4259616A1 (fr) Acides pyrazolo pipéridine carboxyliques substitués
WO2021094209A1 (fr) Dérivés de pyrrolo triazine carboxamide substitués en tant qu&#39;antagonistes du récepteur de la prostaglandine ep3
US20240109864A1 (en) Substituted pyrazolyl piperidine carboxylic acids
WO2021094208A1 (fr) Antagonistes d&#39;imidazo pyrimidine ep3 substitués
KR20190138824A (ko) 치환된 n-아릴에틸-2-아릴퀴놀린-4-카르복스아미드 및 그의 용도

Legal Events

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

Ref document number: 20803528

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20803528

Country of ref document: EP

Kind code of ref document: A1