Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present application relates to novel substituted fused pyrimidines and triazines, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular Treatment and / or prophylaxis of cardiovascular diseases.
• cyclic guanosine monophosphate cGMP
• NO nitric oxide
• the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
• GTP guanosine triphosphate
• the previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO.
• the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.
• CO carbon monoxide
• guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
• the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
• a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
• the dual principle is met for the purposes of the present invention, when the compounds of the invention show an effect on recombinant guanylate cyclase reporter cell lines according to the investigation under B-2 as a minimal effective concentration (MEC) of ⁇ 3 ⁇ and inhibition of human phosphodiesterase 5 (PDE5 ) according to the study under B-6 as IC50 ⁇ 100 nM.
• MEC minimal effective concentration
• PDE5 human phosphodiesterase 5
• Phosphodiesterase-5 is the name given to one of the enzymes that cleaves the phosphoric acid ester bond in cGMP to give 5'-guanosine monophosphate (5'-GMP).
• phosphodiesterase-5 occurs predominantly in the smooth muscle of the penile erectile tissue (corpus cavernosum penis) and the pulmonary arteries.
• Blocking of cGMP degradation by inhibition of PDE5 leads to increased signals of the relaxation signal pathways and especially to increased blood supply to the penile erectile tissue and pressure reduction in the blood vessels of the lung. They are used to treat erectile dysfunction and pulmonary arterial hypertension.
• WO 2004/009590 describes Pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS diseases.
• WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines as sGC activators.
• the sGC stimulators described in WO 2012/004259 are fused aminopyrimidines and in WO 2012/004258, WO 2012/143510 and WO 2012/152629 fused pyrimidines and triazines.
• WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for the treatment of cardiovascular diseases.
• the object of the present invention was to provide new substances which act as stimulators of soluble guanylate cyclase and as stimulators of soluble guanylate cyclase and phosphodiesterase-5 inhibitors (dual principle) and have a similar or improved therapeutic profile compared to the compounds known from the prior art , such as for their in vivo properties, such as their pharmacokinetic and pharmacodynamic behavior and / or their metabolism profile and / or their dose-response relationship.
• the present invention relates to compounds of the general formula (I)
• Pv 5 is hydrogen, deuterium, halogen, difluoromethyl, trifluoromethyl, (G-C4) -alkyl,
• # l is the point of attachment to the carbonyl group, the point of attachment to the pyrimidine or triazine ring is, m is a number 0, 1 or 2,
• R 6A is hydrogen, fluorine, (C 1 -C 4) -alkyl, hydroxyl or amino, in which (C 1 -C 4) -alkyl having 1 to 3 substituents independently of one another selected from the group fluorine, trifluoromethyl, hydroxy, (C 1 -C 4) Alkoxy, Ffydroxycarbonyl, (C 1 -C 4) alkoxycarbonyl and amino may be substituted,
• R 6B represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 6) -alkyl, cyano, (C 3 -C 7) -cycloalkyl, difluoromethoxy, trifluoromethoxy or a group of the formula -MR 12 , where (C 1 -C 6) -alkyl may be substituted with 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl, (C3-C7) -cycloalkyl, difluoromethoxy and trifluoromethoxy, and wherein
• M is a bond or (C 1 -C 4) -alkanediyl
• R 8 and R 9 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle in turn is independently selected with 1 or 2 substituents 10 from the group cyano, trifluoromethyl, (G-C6) -alkyl,
• R 9 and R 10 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn has 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (C 1 -C 6) -alkyl, 20 hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, (GG) -
• Alkoxycarbonyl, amino, mono- (Ci-C6) -alkylamino and di- (Ci-C6) -alkylamino may be substituted
• R 11 is (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, or
• R 8 and R 11 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn has 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (G-C6) -alkyl, 30 hydroxy, oxo, (GG) -alkoxy, trifluoromethoxy, (GG) - Alkoxycarbonyl, amino, mono- (C 1 -C 6) -alkylamino and di- (C 1 -C 6) -alkylamino, and wherein 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl in turn with 1 to 3 substituents independently of one another selected from the group halogen, cyano, difluoromethyl, trifluoromethyl, (C 1 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, hydroxy
• R 6A and R 6B together with the carbon atom to which they are attached, a
• R 7A is hydrogen, fluorine, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxycarbonyl or hydroxyl,
• R is hydrogen, fluorine, (C 1 -C 4 ) -alkyl or trifluoromethyl, represents hydrogen, cyano, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, difluoromethyl, (C 3 -C 6) - Cycloalkyl or halogen, is benzyl, where benzyl is substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C 1 -C 4) -alkyl, cyclopropyl or (C 1 -C 4) -alkoxy,
• R 3 is hydrogen, cyano, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, difluoromethyl or (C 3 -C 6 ) -cycloalkyl,
• R 4 is hydrogen, cyano, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, difluoromethyl or (C 3 -C 6 ) -cycloalkyl, and also their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• the present invention relates to compounds of the general formula (I)
• A is nitrogen or CR 5 ,
• (C 1 -C 6) -alkyl may be substituted by a group -NR 13 R 14 , in which
• R 13 is hydrogen, methyl or ethyl, in which
• (Ci-C4) -alkyl may be substituted by 1 to 3 substituents fluorine, and wherein
• R 15 is (C 1 -C 4 ) -alkyl or (C 3 -C 5 ) -cycloalkyl
• R 16 is (C 1 -C 4 ) -alkyl or (C 3 -C 5 ) -cycloalkyl, or
• Form 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C4) alkyl, hydroxy and oxo, wherein
• R 21 is hydrogen or (C 1 -C 4 ) -alkyl
• R 22 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may in each case in each case be substituted by hydroxyl or fluorine, or
• R 21 and R 22 together with the atom to which they are respectively attached, form a 4- to 7-membered heterocycle, for a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2; in which
• # l is the point of attachment to the carbonyl group, the point of attachment to the pyrimidine or triazine ring is, m is a number 0, 1 or 2,
• R 6A is hydrogen, fluorine, (C 1 -C 4) -alkyl, hydroxyl or amino, in which (C 1 -C 4) -alkyl having 1 to 3 substituents independently of one another selected from the group fluorine, trifluoromethyl, hydroxy, (C 1 -C 4) Alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl and amino may be substituted,
• R 6B is hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, cyano, (C 3 -C 7 ) -cycloalkyl, difluoromethoxy, trifluoromethoxy or a group of the formula -MR 12 , wherein (Ci-C6) alkyl having 1 to 3 substituents independently of one another selected from the group (Ci-C4) alkoxy, fluoro, cyano, trifluoromethyl, (C3-C7) cycloalkyl, difluoromethoxy and trifluoromethoxy may be substituted in which (C 1 -C 4) -alkoxy may be substituted by phenyl, and in which
• M is a bond or (C 1 -C 4) -alkanediyl
• R 8 , R 9 and R 10 are each independently hydrogen
• R 8 and R 9 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle in turn is independently selected with 1 or 2 substituents from the group consisting of cyano, trifluoromethyl, (Ci-Ce) alkyl, hydroxy, oxo, (Ci-Ce) alkoxy, trifluoromethoxy, (CI-C ⁇ ) - alkoxycarbonyl, amino, mono- (Ci-C6) alkylamino and Di (Ci-C6) alkylamino may be substituted, or
• R 9 and R 10 together with the atom (s) to which they are respectively attached, form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn is independently selected with 1 or 2 substituents from the group consisting of cyano, trifluoromethyl, (Ci-Ce) alkyl, hydroxy, oxo, (Ci-Ce) alkoxy, trifluoromethoxy, (CI-C ⁇ ) - alkoxycarbonyl, amino, mono- (Ci-C6) alkylamino and Di- (Ci-C6) -alkylamino may be substituted,
• R 11 is (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, or
• R 8 and R 11 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle in turn having 1 or 2 substituents independently selected from the group cyano, trifluoromethyl, (G-CeJ-alkyl, hydroxy, oxo, (Ci-Ce) alkoxy, trifluoromethoxy, (G-C ⁇ ) - alkoxycarbonyl, amino, mono- (Ci-C6) -alkylamino and di- (Ci-C6) -alkylamino, and wherein 4-7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl in turn with 1 to 3 substituents independently of one another are selected from the group consisting of halogen, cyano, difluoromethyl, trifluoromethyl, (C 1 -C 6) -alkyl, (C 3 -C 7) -cycloalkyl,
• R TM is hydrogen, fluorine, (C 1 -C 4 ) -alkyl or trifluoromethyl
• R 1 is hydrogen, fluorine, cyano, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, trifluoromethyl, difluoromethyl, (C 3 -C 6) -cycloalkyl or halogen
• R 2 is benzyl, 3,3,3 Trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl or 3,3,4,4,4-pentafluorobut-1-yl, wherein benzyl having 1 to 3 substituents independently selected from the group fluorine , Chlorine, (C 1 -C 4) -alkyl, cyclopropyl or (C 1 -C 4) -alkoxy,
• R 3 is hydrogen, cyano, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, difluoromethyl or (C 3 -C 6 ) -cycloalkyl,
• R 4 is hydrogen, cyano, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy, trifluoromethyl, difluoromethyl or (C 3 -C 6 ) -cycloalkyl, and also their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
• Physiologically acceptable salts of the compounds 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, formic 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 customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
• solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
• the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
• the present invention encompasses all tautomeric forms.
• the present invention also includes all suitable isotopic variants of the compounds of the invention.
• An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
• isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
• Certain isotopic variants of a compound according to the invention such as in particular those in which one or more radioactive isotopes are incorporated, may be of use, for example for the investigation of the active compound.
• isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
• Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
• alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
• alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
• Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,1-diyl, propane-1,2-diyl, propane 2,2-diyl, butane-1,4-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl.
• Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having the particular number of carbon atoms indicated. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
• Alkynyl in the context of the invention represents an alkynyl radical having 2 to 4 carbon atoms with a triple bond. Examples which may be mentioned are ethynyl, propynyl and butynyl.
• Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
• Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy , 3-methylbutoxy and n-hexoxy.
• Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms.
• Alkoxycarbonyl in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. Examples which may be mentioned by way of example include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
• Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
• Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N - methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
• Heterocyclyl or heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms which contains one or two ring heteroatoms from the series ⁇ , O, S, SO and / or SO 2 and is linked via a ring carbon atom , Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and Dioxidothiomorpholinyl.
• C-linked 5- or 6-membered heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, up to three identical or different ring heteroatoms from the series N, O and / or S. contains and is linked via a ring carbon atom.
• Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
• Preference is given to pyrazol-3-yl, pyrazol-5-yl, pyrazol-5-yl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridyl and pyrimidinyl.
• 5- or 6-membered heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S. a ring carbon atom or optionally linked via a ring nitrogen atom.
• Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. Preference is given to pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
• Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine. Preference is given to bromine and iodine.
• An oxo group in the context of the invention is an oxygen atom which is bonded to a carbon atom via a double bond.
• a thiooxo group in the context of the invention represents a sulfur atom which is bonded via a double bond to a carbon atom.
• the end point of the line where the symbol # 1 , or * stands is not a carbon atom or a CH 2 group, but is part of the bond to the respectively designated atom to which L or R 2 is bonded.
• treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
• therapy is understood to be synonymous with the term “treatment”.
• prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
• the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
• A is nitrogen or CR 5 , where
• R 5 is hydrogen, deuterium, fluorine, iodine, difluoromethyl, trifluoromethyl, (C 1 -C 4) -alkyl, vinyl, allyl, ethynyl, cyclopropyl, cyclobutyl, hydroxy, phenyl, pyrazol-3-yl, pyrazol-4-yl, pyrazole -5-yl or pyridyl, wherein (Ci-C4) alkyl, vinyl, allyl, ethynyl, phenyl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl and pyridyl with 1 or 2 substituents independently selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl,
• L is a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where # l is the point of attachment to the carbonyl group,
• # is the point of attachment to the pyrimidine or triazine ring
• m is a number 0 or 1
• R 6A is hydrogen, fluorine, methyl, ethyl, hydroxy or amino
• R represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -MR 12 , where (C 1 -C 4 ) -alkyl having 1 to 3 substituents independently of one another selected from the group fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, Cyclopentyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy may be substituted, and wherein
• M is a bond, methylene, ethane-1, 2-diyl or propane-1, 3-diyl,
• R 8 and R 9 are each independently hydrogen, methyl
• Ethyl iso -propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl or pyridyl, wherein methyl, ethyl and iso-propyl are further independently 1 or 2 substituents selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and amino may be substituted,
• R 11 is methyl, ethyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, and wherein oxadiazolonyl, oxadiazolethionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl are themselves independent with 1 or 2 substituents from one another selected from the group consisting of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl, Cyclopropylmetyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy
• R 7A is hydrogen, fluorine, methyl, ethyl or hydroxy
• R TM is hydrogen, fluorine, methyl, ethyl or trifluoromethyl
• R 1 is hydrogen or fluorine
• R 2 is benzyl, where benzyl is substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, methyl or methoxy,
• R 3 is hydrogen or methyl
• R 4 is hydrogen
• R 13 is hydrogen, methyl or ethyl, in which
• (C 1 -C 4 ) -Alkyl may be substituted by 1 to 3 substituents fluorine, and wherein
• R 15 is (C 1 -C 4 ) -alkyl or (C 3 -C 5 ) -cycloalkyl
• R 16 is (C 1 -C 4 ) -alkyl or (C 3 -C 5 ) -cycloalkyl, or together with the Nitrogen atom to which they are attached, a
• 4- to 6-membered heterocycle form wherein the 4- to 6-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C4) alkyl and oxo, and wherein 2 1 is hydrogen or (C 1 -C 4 ) -alkyl,
• R 22 is hydrogen or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl may in each case in each case be substituted by hydroxyl or fluorine, or
• R 21 and R 22 together with the atom to which they are respectively attached, form a 4- to 7-membered heterocycle, for a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2; in which
• # 1 is the point of attachment to the carbonyl group, the point of attachment to the pyrimidine or triazine ring is, m is a number 0 or 1,
• R 6A is hydrogen, fluorine, methyl, ethyl, hydroxy or amino
• R 6B is hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, (C 2 -C 6 ) -
• -NR 8 - (C O) -OR n , -NR ⁇ C ⁇ -NR ⁇ 10 , oxadiazolonyl, oxadiazolothionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl or pyrazinyl, wherein r the number 0 or 1 means
• R 8 and R 9 are each independently hydrogen
• R 11 is methyl, ethyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, and wherein oxadiazolonyl, oxadiazolethionyl, phenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl and pyrazinyl are themselves independent with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl, Cyclobutyl, cyclopropylmetyl, cyclobutylmethyl, hydroxy, methoxy and ethoxy, or
• R 6A and R 6B together with the carbon atom to which they are attached, a
• Form pyrrolidinyl or tetrahydropyranyl ring in which the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl and tetrahydropyranyl ring may be substituted with 1 or 2 substituents independently selected from the group of fluorine and methyl,
• R 7A is hydrogen, fluorine, methyl, ethyl or hydroxy
• R TM is hydrogen, fluorine, methyl, ethyl, trifluoromethyl or (C 1 -C 4) -alkoxycarbonyl
• R 1 is hydrogen or fluorine
• R 2 is benzyl, 3,3,3-trifluoroprop-1-yl, 4,4,4-trifluorobut-1-yl or 3,3,4,4,4-pentafluorobutyl yl, where benzyl is substituted by 1 to 3 substituents independently of one another selected from the group fluorine, methyl or methoxy,
• R 3 is hydrogen, methyl or trifluoromethyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• # l represents the point of attachment to the carbonyl group
• # 2 represents the point of attachment to the pyrimidine or triazine ring
• m is a number
• R 6A is hydrogen, fluorine, methyl, ethyl, hydroxy or amino
• R 6B is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -MR 12 , wherein methyl and ethyl having 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl , Cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy, and wherein
• R 8 and R 9 are each independently hydrogen or
• Cyclopropyl and in which phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl, in turn, having 1 or 2 substituents selected independently of one another from the group fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, 1,1, 2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmetyl and cyclobutylmethyl may be substituted, or
• R 13 is fluorine
• R 14 is hydrogen, fluorine, methyl or methoxy
• R 15 is hydrogen or fluorine
• R 3 is hydrogen or methyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• R 21 is hydrogen or (C 1 -C 4 ) -alkyl
• R 22 is hydrogen or (C 1 -C 4 ) -alkyl, or a group -CH 2 -NR 13 R 14 or -CH 2 -CH 2 - NR 13 R 14 is in which
• R 13 is hydrogen, methyl or ethyl
• Ethyl may be substituted by 1 to 3 substituents fluorine, and in which
• R 15 is methyl, ethyl or cyclopropyl
• R 16 is methyl, ethyl or cyclopropyl
• Form a 5- or 6-membered heterocycle, wherein the 5- or 6-membered heterocycle in turn may be substituted with oxo, is a group # 1 -CR 6A R 6B - (CR 7A R 7B ) m - # 2 , wherein
• # l represents the point of attachment to the carbonyl group, the point of attachment to the pyrimidine or triazine ring is, m is a number 0,
• R 6A is hydrogen, methyl, ethyl, hydroxy or amino
• R 6B represents hydrogen, fluorine, difluoromethyl, trifluoromethyl, 1,1,2,2,2-pentafluoroeth-1-yl, methyl, ethyl, allyl, but-3-en-1-yl, or a group of the formula -MR 12 , wherein methyl and ethyl may be substituted with 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy, wherein methoxy and ethoxy may be substituted with phenyl, and wherein
• R 8 and R 9 are each independently hydrogen or
• Cyclopropyl, and wherein l, 3,4-thiadiazol-5-yl may be substituted with 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, methyl or ethyl, or
• R 17 , R 18 , R 19 and R 20 independently represent hydrogen, fluorine, methyl or
• R 2 is 3,3,3-trifluoroprop-1-yl or 3,3,4,4,4-pentafluorobut-1-yl
• R 3 is hydrogen, methyl or trifluoromethyl
• R 4 is hydrogen, and theirs Salts, solvates and solvates of salts.
• R 13 is hydrogen or methyl
• Ethyl may be substituted with 1 to 3 substituents fluorine, wherein
• R 15 is methyl, ethyl or cyclopropyl
• R 16 is methyl, ethyl or cyclopropyl
• R 6A is hydrogen, methyl, ethyl, hydroxy or amino
• R 6B is hydrogen, trifluoromethyl, 1,1,2,2,2-pentafluoroeth-1-yl, methyl, ethyl, allyl, but-3-en-1-yl or a group of the formula -MR 12 wherein methyl and ethyl having 1 to 2 substituents independently selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, methoxy and ethoxy, in which methoxy and ethoxy may be substituted with phenyl, and wherein
• M is a bond
• R 8 and R 9 are each independently hydrogen or
• Cyclobutyl or cyclopentyl ring form represents hydrogen or fluorine, a group of the formula
• R 17 , R 18 , R 19 and R 20 independently of one another are hydrogen, fluorine, methyl or methoxy, with the proviso that at least one of the radicals R 17 , R 18 , R 19 or R 20 is different from hydrogen, with the In that at least one of the radicals R 17 , R 18 , R 19 or R 20 is hydrogen, and with the proviso that only one of the radicals R 17 , R 18 , R 19 or R 20 is methyl or methoxy, or
• R 2 is 3,3,3-trifluoroprop-1-yl or 3,3,4,4,4-pentafluorobut-1-yl,
• R 3 is hydrogen, methyl or trifluoromethyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• A is nitrogen or CR 5 , where
• R 5 is methyl or pyrazol-5-yl, wherein methyl is substituted with a group -NR R, wherein
• R ] 13 is hydrogen
• R ] 14 is hydrogen, methyl, ethyl or -S (O) 2 -R 16 wherein Ethyl may be substituted with 1 to 3 substituents fluorine, and wherein
• R 16 is methyl or cyclopropyl
• 5-membered heterocycle form in which the 5-membered heterocycle may in turn be substituted with oxo
• L is a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where
• R 6A is methyl
• R 6B is methyl, R 1 is hydrogen or fluorine, R 2 is a group of the formula
• R 17 , R 18 , R 19 and R 20 independently of one another are hydrogen, fluorine, methyl or methoxy, with the proviso that at least one of the radicals R 17 , R 18 , R 19 or R 20 is different from hydrogen, with the In that at least one of the radicals R 17 , R 18 , R 19 or R 20 is hydrogen, and with the proviso that in each case only one of the radicals R 17 , R 18 , R 19 or R 20 is methyl or methoxy,
• R 3 is hydrogen, methyl or trifluoromethyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• A is nitrogen or CR 5 , where
• R 5 L stands for hydrogen, for a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where
• # 1 represents the point of attachment to the carbonyl group, the point of attachment being to the pyrimidine or triazine ring, m is a number 0, R 6A is amino,
• R 6B is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -MR 12 , wherein methyl and ethyl may be substituted with 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy, and wherein
• R 8 and R 9 are each independently hydrogen or
• Cyclopropyl and in which phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl themselves with 1 or 2 substituents independently of one another selected from the group fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, iso-propyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmetyl and cyclobutylmethyl, is hydrogen or fluorine, a group of the formula
• R 13 is fluorine
• R 14 is hydrogen, fluorine, methyl or methoxy
• R 15 is hydrogen or fluorine
• R 3 is hydrogen or methyl
• R 4 is hydrogen
• A is nitrogen or CR 5 , where
• R 5 L stands for hydrogen, for a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where
• # ! represents the point of attachment to the carbonyl group
• # is the point of attachment to the pyrimidine or triazine ring
• m is a number 0
• R 6A is methyl or hydroxy
• R 6B is pentafluoroethyl or cyclopropylmethyl, R 1 is hydrogen or fluorine, R 2 is a group of the formula stands, where
• Pv 14 is hydrogen, fluorine, methyl or methoxy
• Pv 15 is hydrogen or fluorine
• P 3 is hydrogen or methyl
• R 4 is hydrogen
• A is nitrogen or CR 5 , where
• R 5 L stands for hydrogen, for a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where
• # is the point of attachment to the pyrimidine or triazine ring
• m is a number
• R 6A stands for amino, R is hydrogen, fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl or a group of the formula -MR 12 , where methyl and ethyl having 1 to 3 substituents independently of one another selected from the group fluorine, cyano, trifluoromethyl, Cyclopropyl, cyclobutyl, difluoromethoxy, trifluoromethoxy, methoxy and ethoxy may be substituted, and wherein
• R 8 and R 9 are each independently hydrogen or
• Cyclopropyl and in which phenyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and pyrimidinyl themselves with 1 or 2 substituents independently of one another selected from the group fluorine, difluoromethyl, trifluoromethyl, methyl, ethyl, iso-propyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmetyl and cyclobutylmethyl, is hydrogen or fluorine, a group of the formula
• Pv 17 , R 18 , R 19 and R 20 are independently hydrogen, fluoro, methyl or
• R 20 are different from hydrogen, with the proviso that at least one of R 17 , R 18 , R 19 or R 20 is hydrogen, and with the proviso that in each case only one of R 17 , R 18 , R 19 or
• R 20 is methyl or methoxy
• R 3 is hydrogen or methyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• A is nitrogen or CR 5 , where
• R 5 L is hydrogen, a group -CR 6A R 6B # I - (CR 7A R 7B) m - # 2, where
• # ! is the point of attachment to the carbonyl group, for the attachment point to the to the pyrimidine or triazine ring, m is a number 0, R 6A is hydroxy,
• R 6B is 2,2,2-trifluoroethyl, pentafluoroethyl or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl having 1 substituent selected from the group consisting of (C 3 -C 7) -cycloalkyl, difluoromethoxy, trifluoromethoxy and (C 1 -C 4) -alkoxy, R 1 is hydrogen or fluorine, a group of the formula
• R 13 is fluorine
• R 14 is hydrogen, fluorine, methyl or methoxy
• R 15 is hydrogen or fluorine
• R 3 is hydrogen or methyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• A is nitrogen or CR 5 , where R 5 is hydrogen
• L is a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, in which
• # is the point of attachment to the pyrimidine or triazine ring
• m is a number
• R 6A is hydroxyl
• R 6B is 2,2,2-trifluoroethyl, pentafluoroethyl or (C 1 -C 4 ) -alkyl, in which (C 1 -C 4 ) -alkyl having 1 substituent selected from the group consisting of (C 3 -C 7) -cycloalkyl, difluoromethoxy, trifluoromethoxy and (C 1 -C 4) -alkoxy is substituted,
• R 1 is hydrogen or fluorine
• R 2 is a group of the formula
• R 17 , R 18 , R 19 and R 20 are independently hydrogen, fluoro, methyl or
• radicals R 17 , R 18 , R 19 or R 20 are different from hydrogen, with the proviso that at least one of R 17 , R 18 , R 19 or R 20 is hydrogen , and with the proviso that in each case only one of the radicals R 17 , R 18 , R 19 or R 20 is methyl or methoxy,
• R 3 is hydrogen or methyl
• R 4 is hydrogen, and their salts, solvates and solvates of the salts.
• A is CR 5 , where
• R 5 is (C 1 -C 4 ) -alkyl, (C 2 -C 4 ) -alkenyl, (C 2 -C 4 ) -alkynyl, cyclopropyl, cyclobutyl, phenyl or C-linked 5- or 6-membered heteroaryl, wherein (Ci-C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, phenyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently selected from the group with fluorine, difluoromethyl, trifluoromethyl, (GC 4 ) alkyl, difluoromethoxy, trifluoromethoxy, (Ci-C 4 ) alkoxy, (Ci-C 4 ) alkoxycarbonyl, cyclopropyl and cyclobutyl are substituted, and their salts, solvates and solvates of salts.
• A is nitrogen
• L is a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, which is the point of attachment to the carbonyl group is the point of attachment to the triazine ring, represents a number 0, represents amino , is hydrogen, fluorine, difluoromethyl, trifluoromethyl, (C 1 -C 6) -alkyl, cyano, (C 3 -C 7) -cycloalkyl, difluoromethoxy, trifluoromethoxy or a group of the formula -MR 12 , wherein (Ci-Ce) alkyl having 1 to 3 substituents independently selected from the group of fluorine, cyano, trifluoromethyl, (C3-C7) -cycloalkyl, difluoromethoxy and trifluoromethoxy may be substituted, and wherein
• M is a bond or (C 1 -C 4) -alkanediyl
• R 8 , R 9 and R 10 are each independently hydrogen
• R 8 and R 9 together with the AtonV (s) to which they are respectively attached form a 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle is in turn selected from 1 or 2 substituents independently the group cyano, trifluoromethyl, (G-C6) alkyl, hydroxy, oxo, (Ci-Ce) alkoxy, trifluoromethoxy, (CI-C ⁇ ) - alkoxycarbonyl, amino, mono- (Ci-C6) -alkylamino and di - (Ci-C6) -alkylamino, or
• R 9 and R 10 together with the atom (s) to which they are respectively attached form a 4- to 7-membered heterocycle, in which the 4- to 7-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group cyano, trifluoromethyl, (G-CeJ-alkyl, hydroxy, oxo, (Ci-Ce) -alkoxy, trifluoromethoxy, (GC ⁇ ) Alkoxycarbonyl, amino, mono- (C 1 -C 6) -alkylamino and di- (C 1 -C 6) -alkylamino may be substituted,
• R 11 is (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, or
• R 8 and R 11 together with the AtonV (s) to which they are respectively attached, form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle is in turn selected from 1 or 2 substituents independently the group cyano, trifluoromethyl, (G-CeJ-alkyl, hydroxy, oxo, (Ci-Ce) alkoxy, trifluoromethoxy, (GC ⁇ ) - alkoxycarbonyl, amino, mono- (Ci-C6) alkylamino and di- (Ci -C6) -alkylamino, and wherein 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl in turn having 1 to 3 substituents independently selected from the group halogen, cyano, difluoromethyl, trifluoromethyl, (Ci -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, hydroxy, ox
• L is a group # 1 -CR 6A R 6B - (CR 7A R 7B) m - # 2, where
• # ' represents the point of attachment to the carbonyl group, for the attachment site to the triazine ring, m is a number 0,
• R 6A stands for amino
• R 6B is difluoromethyl, trifluoromethyl or (C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl having 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 3 -C 7) -cycloalkyl, difluoromethoxy, Trifluoromethoxy and (C 1 -C 4) -alkoxy may be substituted,
• R 1 , R 2 , R 3 and R 4 each have the meanings given above, and their salts, solvates and solvates of the salts.
• R 2 is 2-fluoro-3-methylbenzyl, 2-fluoro-4-methylbenzyl, 2-fluoro-3-methoxybenzyl or 4-methoxybenzyl, and their salts, solvates and solvates of the salts.
• L represents a group * -CR 6A R 6B - (CR 7A R 7B ) p - #, where
• # represents the point of attachment to the pyrimidine or triazine ring
• p stands for a number
• R 6A stands for amino
• R 6B is pentafluoroethyl, ethoxyethyl, methoxycarbonyl, ethoxycarbonyl, (benzyloxy) methyl or cyclopropylmethyl, and their salts, solvates and solvates of the salts.
• * represents the point of attachment to the pyrimidine or triazine ring
• p stands for a number
• R 6A is methyl
• R 6B is pentafluoroethyl, ethoxyethyl, methoxycarbonyl, ethoxycarbonyl, benzyloxy) methyl or cyclopropylmethyl, and their salts, solvates and solvates of the salts.
• R 6B is pentafluoroethyl, ethoxyethyl, methoxycarbonyl, ethoxycarbonyl, benzyloxy) methyl or cyclopropylmethyl, and their salts, solvates and solvates of the salts.
• T formula (T) in which
• L represents a group * -CR 6A R 6B - (CR 7A R 7B ) p - #, where
• * represents the point of attachment to the carbonyl group
• # represents the point of attachment to the pyrimidine or triazine ring
• p stands for a number
• R 6A is methyl
• R 6B is methyl, and their salts, solvates and solvates of the salts.
• R 6B is methyl, and their salts, solvates and solvates of the salts.
• particular preference is also given to compounds of the formula (I) in which
• A is nitrogen
• L represents a group * -CR 6A R 6B - (CR 7A R 7B ) p - #, in which
• # represents the point of attachment to the pyrimidine or triazine ring
• R ⁇ 6A is methyl
• R 6B is methyl, and their salts, solvates and solvates of the salts.
• R 21 is hydrogen or (C 1 -C 4) -alkyl
• R 22 is hydrogen or (C 1 -C 4) -alkyl, and wherein methyl and ethyl may be substituted with a group -NR 13 R 14 , wherein
• R 13 is hydrogen or methyl
• Ethyl may be substituted with 1 to 5 substituents fluorine, and wherein
• R 15 is methyl, ethyl or cyclopropyl
• R 16 is methyl, ethyl or cyclopropyl
• R 13 and R 14 together with the nitrogen atom to which they are attached form a 5-membered heterocycle in which the 5-membered heterocycle may in turn be substituted by oxo, and their salts, solvates and solvates of the salts.
• A is CR 5 , where
• R 5 is methyl or pyrazol-5-yl, wherein methyl is substituted with a group -NR 13 R 14 , wherein
• R 13 and R 14 independently of one another represent hydrogen, methyl, ethyl or -S (O) 2 -R 16 , wherein
• Ethyl may be substituted with 1 to 3 substituents fluorine, and wherein
• R ] 16 is methyl or cyclopropyl, or
• R 13 and R] 14 together with the nitrogen atom to which they are attached form a 5-membered heterocycle wherein 5-membered heterocycle can in turn be substituted with oxo, and their salts, solvates and solvates of the salts.
• radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
• the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)
• T 1 is (C 1 -C 4 ) -alkyl, to give a compound of the formula (IV)
• T 3 is (C 1 -C 4 ) -alkyl
• T 4 is (C 1 -C 4 ) -alkyl
• R 5A in (XV-A) is (C 2 -C 4 ) -alkenyl or (C 2 -C 4 ) -alkynyl,
• X 3 is bromine or iodine, to give a compound of formula (ID)
• n, L, R 1 , R 2 , R 3 , R 4 and R 5A each have the meanings given above,
• Y is chlorine, in an inert solvent in the presence of a suitable base to give a compound of the formula (XVII)
• R 5A in (XV-A) is (C 2 -C 4 ) -alkenyl or (C 2 -C 4 ) -alkynyl,
• R and R independently of one another represent cyano or (C 1 -C 4) -alkoxycarbonyl, and in the following the protective group R is split off as described in [E], whereby compound (1-E) is formed by hydrolysis and decarboxylation,
• Inert solvents for process step (II) + (III) - (IV) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (II), pyridine, Acetonitrile, sulfolane or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to
• Suitable bases for process step (II) + (III) - (IV) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium hydrogen carbonate, Alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to potassium tert-butoxide or sodium methoxide.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
• alkali hydrogen carbonates such as sodium
• the reaction (II) + (III) - (IV) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 75 ° C to + 100 ° C, optionally in a microwave.
• the Reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
• halogen sources in the reaction (IV) - (V) are diiodomethane, a mixture of cesium iodide, iodine and copper (I) iodide or copper (II) bromide.
• the process step (IV) - (V) is carried out in the case of diiodomethane as the halogen source with a molar ratio of 10 to 30 moles of isopentyl nitrite and 10 to 30 moles of the iodine equivalent based on 1 mole of the compound of formula (IV).
• the process step (IV) - (V) is carried out with or without solvent.
• Suitable solvents are all organic solvents which are inert under the reaction conditions.
• Preferred solvent is dimethoxyethane.
• the reaction (IV) - (V) is generally carried out in a temperature range of + 20 ° C to + 100 ° C, preferably in the range of + 50 ° C to + 100 ° C, optionally in a microwave.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• Inert solvents for process step (V) - (IA) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.
• the reduction (V) - (I-A) is carried out with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• the reaction (V) - (I-A) is generally carried out in a temperature range of + 20 ° C to + 50 ° C.
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• Inert solvents for process step (II) + (VI) - (VII) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.
• Suitable bases for process step (II) + (VI) - (VII) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, Alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN).
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
• alkali hydrogen carbonates such as sodium or potassium bicarbonate
• Alkali alcoholates such as sodium or potassium meth
• reaction (II) + (VI) - (VII) is generally carried out in a temperature range from + 50 ° C to + 120 ° C, preferably from + 50 ° C to + 100 ° C, optionally in a microwave.
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the reactions (VII) - (VTII) and (XII) - (XIII) can be carried out in a solvent which is inert under the reaction conditions or without solvent.
• Preferred solvent is sulfolane.
• the reactions (VII) - (VIII) and (XII) - ( ⁇ ) are generally carried out in a temperature range from + 70 ° C to + 150 ° C, preferably from + 80 ° C to + 130 ° C, optionally in a microwave ,
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the reaction takes place (XII) - (XIII) without solvent in a temperature range from 0 ° C to + 50 ° C at atmospheric pressure.
• the process step (VIII) - (IX) is carried out by reaction with sodium azide with intermediate formation of the azide derivatives, which are further reduced directly to the corresponding amines.
• Inert solvents for the azide formation are, for example, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN '-Dimethylpropylen- urea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane.
• ethers such as diethyl ether, dioxane, dimethoxye
• the azide is generally formed in a temperature range from + 50 ° C to + 100 ° C, preferably from + 60 ° C to + 80 ° C, at atmospheric pressure.
• the reduction is carried out in an inert solvent such as, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanedi
• the reduction takes place at + 10 ° C to + 30 ° C with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or without hydrogen with stannous chloride and hydrochloric acid.
• transition metal catalysts such as palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or without hydrogen with stannous chloride and hydrochloric acid.
• reaction (VIII) - (IX) can also be carried out in a step analogous to process step (XIII) - (XIV).
• Process (XIII) - (XIV) takes place in a solvent which is inert under the reaction conditions.
• Suitable solvents are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or else Water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile.
• the reaction (XIII) - (XIV) is generally carried out in a temperature range from + 20 ° C to + 100 ° C, preferably from + 40 ° C to + 70 ° C, optionally in a microwave.
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the cyclizations ( ⁇ ) - (IB) and (XIV) - (IC) are carried out in a reaction inert solvent such as alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as Diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea ( DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane.
• a reaction inert solvent such
• Suitable bases for process steps (IX) - (IB) and (XIV) - (IC) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or Potassium bicarbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to potassium tert-butoxide.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
• the reactions (DQ - (IB) and (XIV) - (IC) are generally carried out in a temperature range from 0 ° C to + 50 ° C, preferably from + 10 ° C to + 30 ° C, optionally in a microwave Reaction can be carried out at normal or elevated pressure (eg in the range of 0.5 to 5 bar) . Generally, one works at atmospheric pressure.
• the cyclization to (I-B) or (I-C) directly in the reduction of the azide to the corresponding amine (IX) or in the reaction ( ⁇ ) - (XIV) without addition of other reagents.
• Inert solvents for process step (X) + (XI) - (XII) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.
• the reaction (X) + (XI) - (XII) is generally carried out in a temperature range from + 50 ° C to + 120 ° C, preferably from + 50 ° C to + 100 ° C, optionally in a microwave.
• the reaction can be carried out at normal or elevated pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.
• Inert solvents for process step (II) - (X) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, Dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is ethanol.
• Suitable bases for process step (II) - (X) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [ 4.3.0] non-5-en (DBN).
• DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
• DBN 1,5-diazabicyclo [ 4.3.0] non-5-en
• triethylamine Preferably triethylamine.
• the reaction (II) - (X) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably from + 10 ° C to + 30 ° C.
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• Process step (V) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (I-D) takes place in a solvent which is inert under the reaction conditions.
• Suitable solvents are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (II), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile, dioxane and tetrahydrofuran.
• the reaction (V) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (ID) can be carried out in the presence of a suitable palladium and / or copper catalyst.
• a suitable palladium and / or copper catalyst is, for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphospliin) palladium (II) chloride, bis (acetonitrile) - palladium (II ) -chloride, [l, l'-bis (diphenylphospliino) ferrocene] dichloropalladium (n) and corresponding dichloromethane complex, optionally in combination with additional phosphane ligands such as (2-biphenyl) di-tert-butylphosphine, dicyclohexyl [
• Suitable copper catalysts are, for example, copper bronze, copper (I) oxide, copper (I) iodide or copper (I) bromide.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4- diazabicyclo [2.2.2] octane (DABCO ®).
• DBN 1,5-diazabicyclo
• the reaction (V) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (ID) is generally in a temperature range of 0 ° C to + 200 ° C, preferably carried out at + 10 ° C to + 150 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
• radical R 5A is unsaturated, this can then be completely or partially saturated.
• the reduction is carried out with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• the reduction is generally carried out in a temperature range from + 20 ° C to + 50 ° C.
• the reaction can be carried out at normal or elevated pressure (for example in the range from 1 to 150 bar). In general, it works at 1 to 3 bar.
• the process step (V) + (R 25 -Y) - (XVII) takes place in a solvent which is inert under the reaction conditions.
• Inert solvents for process step (V) + (R 25 -Y) - (XVII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene , Toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, N, N-dimethylacet
• alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or cesium carbonate, Alkali hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine , l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [2.2.2] octane (DABCO)
• the reaction (V) + (R 25 -Y) - (XVII) is generally carried out in a temperature range of -20 ° C to + 200 ° C, preferably at + 10 ° C to + 100 ° C.
• the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
• Process step (XVII) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (XVIII) takes place in a solvent which is inert under the reaction conditions.
• Suitable solvents are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (II), toluene , Acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferred are dioxane and tetrahydrofuran.
• reaction (XVII) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (XVTII) can be carried out in the presence of a suitable palladium and / or copper catalyst.
• Suitable palladium catalysts are palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II ) -chloride, [l, l'-bis (diphenylphospliino) ferrocene] dichloropalladium (n) and corresponding dichloromethane complex, optionally in combination with additional phosphane ligands such as (2-biphenyl) di-tert-butylphosphine, dicyclohexyl [2 ' , 4 ', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis (dipheny
• Suitable copper catalysts are, for example, copper bronze, copper (I) oxide, copper (I) iodide or copper (I) bromide.
• the reaction (XVII) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (XVIII) takes place in the presence of a suitable base.
• Suitable bases for this reaction are the usual inorganic or organic bases.
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3 .0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4-diazabicyclo [2.2.2] octane (DABCO ®).
• triethylamine or sodium bicarbonate is used.
• the reaction (XVII) + (XV-A) or (XV-B) or (XV-C) or (XV-D) - (XVIII) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably carried out at + 10 ° C to + 150 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
• the process step (XVIII) - (ID) is carried out in the case of PMB by reaction with a mixture of trifluoromethanesulfonic anhydride and trifluoroacetic acid or trifluoroacetic acid and trifluoromethanesulfonic acid or cerium (IV) ammonium nitrate in suitable solvents such as acetonitrile, DMF or NMP and in the case of SEM as a protective group by reaction first with trifluoroacetic acid in suitable solvents we dichloromethane and then with aqueous mineral acid in suitable solvents such as ethanol, THF or dioxane.
• suitable solvents such as acetonitrile, DMF or NMP
• SEM as a protective group
• the reaction (XVIII) - (I-D) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably at + 10 ° C to + 150 ° C, optionally in the microwave.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 20 bar). In general, it works at 0.5 to 10 bar.
• Suitable solvents are, for example, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF.
• Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, Calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, Calcium or cesium carbonate
• the reaction (XVIII) + (XIX) - (XX) is generally carried out in a temperature range from 0 ° C to + 200 ° C, preferably at + 20 ° C to + 100 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
• Process step (V) + copper cyanide - (XXI) takes place in a solvent which is inert under the reaction conditions.
• suitable solvents are, for example, ethers, such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane.
• ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glyco
• reaction (V) + Kupfercaynid- (XXI) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably at + 40 ° C to + 180 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
• the reduction (XXI) - (I-F) is carried out with hydrogen in conjunction with transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• transition metal catalysts such as palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
• the reaction (XXI) - (IF) is generally carried out in a temperature range of + 20 ° C to + 100 ° C.
• the reaction can be carried out at normal or elevated pressure (for example in the range from 0.5 to 100 bar). In general, it works at 1 to 3 bar.
• Process step (IF) + (XXII) - (IG) takes place in a solvent which is inert under the reaction conditions.
• Suitable solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichlorethylene or chlorobenzene, ethers such as Diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU ), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or sulfolane. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMF or a mixture of DMF and dichloromethane
• Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium , Amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, pyridine, $ -dimethylamino-pyridine, 1.5 - diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
• the reaction (I-F) + (XXII) - (I-G) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably at + 10 ° C to + 50 ° C.
• the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure
• the preparation of the compounds of the formula (I) according to the invention can be carried out by reversing the reaction steps using protective group chemistry, as shown by way of example in the following synthesis scheme (Scheme 9):
• transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, Grignard reactions, eliminations, alkylation, acylation, amination, esterification, ester cleavage, etherification, Ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
• reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, Grignard reactions, eliminations, alkylation, acylation, amination, esterification, ester cleavage, etherification, Ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.
• reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, Grignard reactions, eliminations
• the compounds of the formula (II) are known from the literature (see, for example, WO 2011/147809, WO 03/095451, Example 6A) or can be prepared in analogy to processes known from the literature.
• the compounds of the formula (VI), (XI), (XV-A), (XV-B), (XV-C), (XV-D), (XVI), (XIX) and (XXII) are commercially available , known from the literature or can be prepared in analogy to known literature.
• the compounds of the invention act as potent stimulators of soluble guanylate cyclase and inhibitors of phosphodiesterase-5, have valuable pharmacological properties, and have an improved therapeutic profile, such as their in vivo properties and / or their pharmacokinetic behavior and / or metabolic profile. They are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.
• the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and intracellular cGMP increase.
• the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, for example, endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
• EDRF endothelium-derived relaxing factor
• NO donors NO donors
• protoporphyrin IX arachidonic acid or phenylhydrazine derivatives.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
• the compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and the ventricles as well as conduction disorders such as atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles , AV junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aor
• cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
• Cardiac insufficiency in cardiac valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, dystolic heart failure and systolic heart failure and acute phase n worsening of existing chronic heart failure.
• the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome.
• the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, erythematosis, onychomycosis
• the compounds according to the invention are also suitable for the treatment of muscular dystrophy, such as the muscular dystrophy Becker-Kiener (BMD) and Duchenne muscular dystrophy (DMD).
• the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the Urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urgency, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant diseases the organs of the male and female urogenital system.
• BPS benign prostatic syndrome
• BPH benign prostatic hyperplasia
• BPE benign prostate enlargement
• BOO bladder emptying disorder
• LUTS lower urinary tract syndromes
• FUS lower urinary tract syndromes
• UI incontinence
• MUI mixed, urgency, stress, or overflow incontinence
• MUI UUI, SUI, OUI
• kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
• renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hyperten
• the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).
• PAH pulmonary arterial hypertension
• PH pulmonary hypertension
• COPD chronic obstructive pulmonary disease
• ARDS acute respiratory tract syndrome
• ALI acute lung injury
• AATD alpha-1-antitrypsin deficiency
• CF
• the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
• they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis.
• the compounds according to the invention are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, pleasure and addiction.
• the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.
• the compounds according to the invention have antiinflammatory activity and can therefore be used as antiinflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic intestinal inflammation (IBD, Crohn's Disease, UC). , Pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
• SIRS sepsis
• MODS multiple organ failure
• IBD chronic intestinal inflammation
• UC chronic intestinal inflammation
• Pancreatitis peritonitis
• rheumatoid diseases inflammatory skin diseases and inflammatory ocular diseases.
• the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
• fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
• the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
• the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
• the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
• the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.
• Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
• the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
• the compounds of the invention may be used alone or as needed in combination with other agents.
• Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
• suitable combination active ingredients may be mentioned by way of example and preferably:
• organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• cGMP cyclic guanosine monophosphate
• PDE phosphodiesterases
• Antithrombotic agents by way of example and preferably from the group of thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;
• Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics; and / or ⁇ fat metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, as exemplified and preferably HMG co-eductase or squalene synthesis inhibitors, 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.
• Antithrombotic agents are preferably understood as meaning compounds from
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
• the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
• a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
• the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA -1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC
• the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
• LMW low molecular weight
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
• antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.
• the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
• the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
• the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably 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 such as by way of example and preferably propranolol, atenolol, timolol
• the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
• an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
• the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
• a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
• the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
• a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
• the compounds of the invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and Eplerenone and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide administered.
• a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
• potassium sparing diuretics such as amiloride and triamterene
• aldosterone antagonists such as spironolactone, potassium canrenoate and Eplerenone and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide administered.
• lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA eduktase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors, and lipoprotein (a) antagonists.
• CETP inhibitors such as HMG-CoA eduktase or squalene synthesis inhibitors
• ACAT inhibitors such as HMG-CoA eduktase or squalene synthesis inhibitors
• MTP inhibitors MTP inhibitors
• PPAR-alpha PPAR-alpha
• PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
• the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
• a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
• the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• T3 3,5,3'-triiodothyronine
• CGS 23425 CGS 23425
• axitirome CGS 26214
• the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastat
• the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
• the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
• an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
• the compounds of the invention are administered in combination with a PPAR gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• the compounds according to the invention are administered in combination with a PPA-delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
• a lipase inhibitor such as, for example and preferably, orlistat.
• the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds according to the invention quickly and / or modified donating application forms, the Compounds according to the invention in crystalline and / or amorphised and / or dissolved form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
• absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
• parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicaments including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or eye preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered powders, implants or stents.
• compositions according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• adjuvants include, among others.
• Excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers For example, antioxidants such as ascorbic acid
• dyes eg, inorganic pigments such as iron oxides
• flavor and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example, antioxidants such as
• the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg kg of body weight.
• Device Type MS Waters ZQ
• Device Type HPLC Agilent 1100 Series
• UV DAD Column: Thermo Hypersil GOLD 3 ⁇ 20 mm x 4 mm
• Eluent A 1 l of water + 0.5 ml of 50% formic acid
• eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
• UV detection 210 nm.
• Instrument Thermo DFS, Trace GC Ultra; Column: Restek RTX-35, 15 m x 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 1.20 ml / min; Oven: 60 ° C; Inlet: 220 ° C; Gradient: 60 ° C, 30 ° C / min 300 ° C (hold for 3.33 min).
• Method 9 Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 ⁇ 50 x 1 mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 95% A 6.0 min 5% A 7.5 min 5% A Oven: 50 ° C; Flow: 0.35 ml / min; UV detection: 210 - 400 nm.
• Method 10 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 mx 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).
• Instrument Micromass GCT, GC6890; Column: Restek RTX-35, 15 mx 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).
• Example 1A Example 1A
• Example 3A 55.00 g (135 mmol) of Example 3A were initially charged in sulfolane (220 ml) and admixed with 41.40 g (270 mmol) of phosphoryl chloride. Thereafter, it was heated to 120 ° C for 1 h. After cooling, it was added to warm water (1500 ml) and then neutralized with solid sodium bicarbonate. The precipitate which formed was filtered off with suction and washed with water. Thereafter, it was further purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 3: 2). After drying under high vacuum, 43.0 g of the title compound were obtained (73% of theory).
• Example 4A 10.00 g (23,482 mmol) of Example 4A were initially charged in DMF (200 ml) and treated with 2,290 g (35,223 mmol) of sodium azide. Thereafter, it was heated to 60 ° C for 1 h. After cooling, the reaction mixture was added to water and extracted three times with ethyl acetate. The organic phases were combined and washed once with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. The residue was used without further purification in the next step.
• Example 6A Ethyl ⁇ 4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrirnidin-5-yl ⁇ acetate
• Example 7A 2.00 g (5.550 mmol) of Example 7A were initially charged in dioxane (200 ml) and treated with 3.079 g (27.751 mmol) of selenium dioxide and heated to reflux for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). 890 mg of the title compound were obtained (42% of theory).
• Example 12A 1.45 g (about 4.950 mmol) of Example 12A were initially charged in ethanol (20 ml), treated dropwise with a suspension of 1.37 g (about 3.300 mmol) Example 11 A in 20 ml of ethanol and then heated to reflux overnight. After cooling, it was filtered from a precipitate and washed with ethanol. The filtrate was concentrated and the residue treated with diethyl ether. It was again filtered from a precipitate and the filtrate was concentrated and then purified by preparative HPLC (methanol: water gradient). There were obtained 297 mg of the title compound (18% of theory).
• Example 3 337 mg (0.682 mmol) of Example 3 were reacted in analogy to Example 10A. There were obtained 236 mg of the title compound (67% of theory).
• the diazonium salt thus prepared was added in portions to a 0 ° C cold solution of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml) and the mixture stirred for 30 min at RT.
• the reaction mixture was added to ice water (1.8 L) and extracted twice with ethyl acetate (487 mL each).
• the collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. 12.1 g (86% purity, 60% of theory) of the title compound were obtained as a solid.
• the crude product was reacted without further purification.
• Example 21A 1.00 g (3.152 mmol) of Example 21A were stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. It was then concentrated in vacuo. 908 mg (99% of theory) of the title compound were obtained.
• the aqueous phase was separated and extracted twice more with ethyl acetate (200 ml each time).
• the combined organic Phases were washed twice with 10% aqueous sodium chloride solution (100 ml each), dried and concentrated in vacuo.
• the crude product was reacted without further purification.
• Variant B 900 mg (3.122 mmol) of the compound obtained under Example 22A were dissolved in THF (14 ml) and treated with 0.646 ml (7.993 mmol) of pyridine. Then, with stirring, 1.129 ml (7.993 mmol) of trifluoroacetic anhydride were slowly added dropwise and then stirred at RT overnight. Thereafter, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were extracted with saturated aqueous sodium bicarbonate solution and 1N hydrochloric acid and then washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. 850 mg (99% of theory) of the title compound were obtained.
• Example 24A 23,000 g (66.22 mmol) of Example 24A were dissolved in 322 ml of ethanol and treated at 0 ° C with 26,804 g (264.88 mmol) of triethylamine and 6.027 g (66.22 mmol) hydrazine hydrate (55% solution in water). The mixture was stirred overnight at rt and then added to 1.715 l of a 10% aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed with 10% aqueous sodium chloride solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified on silica gel (eluent: dichloromethane / methanol, 95: 5). There were obtained 15,000 g (75% of theory) of the title compound.
• Example 26A 1.272 g (about 4.962 mmol) of Example 26A were initially charged in 10 ml of ethanol and heated to reflux. For this purpose, a suspension of 1.00 g (3.308 mmol) of Example 25 A in 40 ml of ethanol was added dropwise. After heating overnight, an additional 2.24 g of Example 26A was added and refluxed for a further night. After cooling, a solid was filtered off with suction, washed with a little ethanol and the filtrate was concentrated. The residue was purified by preparative HPLC purified (acetonitrile: water gradient). 270 mg (16% of theory) of the title compound were obtained.
• Example 30A 1,143 g (4,962 mmol) of Example 30A were reacted in analogy to Example 27A. The residue was purified by preparative HPLC (acetonitrile: water (+ 1% trifluoroacetic acid) gradient). There were obtained 334 mg (21% of theory) of the title compound.
• Example 19A 10.00 g (38.021 mmol) of Example 19A were reacted with 4-methoxybenzyl chloride in analogy to the procedure of Example 20A. Chromatography on silica gel (eluent: cyclohexane-ethyl acetate mixture) gave 8.94 g (61% of theory) of the title compound.
• Example 32A 8.94 g (23.332 mmol) of Example 32A were reacted in analogy to the procedure under Example 23A, variant A. The resulting crude product was reacted without further purification.
• Example 33A 6.52 g (23,098 mmol) of Example 33A were reacted in analogy to the procedure in Example 24A. Yield: 6.16 g (74% of theory)
• Example 34 A 6.16 g (17.141 mmol) of Example 34 A were reacted in analogy to the procedure under Example 25A. A purification on silica gel was not carried out. There were obtained 4.90 g (90% of theory) of the title compound, which was reacted without further purification.
• Example 40A 0.150 g (0.349 mmol) of the compound from Example 40A were reacted in analogy to the procedure of Example 41A with 1- (bromomethyl) -2-fluoro-3-methylbenzene. After filtration, it was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 83 mg of the title compound (44% of theory) were obtained.
• Example 44A 0.50 g (1.654 mmol) of the compound from Example 44A were reacted with 907 mg (3.308 mmol) of Example 25A in analogy to the procedure of Example 27A. 42 mg (5% of theory) of the title compound were obtained.
• Example 2A 5,887 g (19,256 mmol) of Example 2A were initially charged in tert-butanol (50 ml) and treated with 2,593 g (23.107 mmol) of potassium tert-butoxide. Subsequently, 3.2 g (19.256 mmol) of Example 1A in tert-butanol (25 ml) were added dropwise and the mixture heated to reflux overnight. The next day another 0.64 g (3.851 mmol) of Example 1 A was added and it was heated to reflux for a further day. After cooling, a precipitate was filtered off, which was washed with diethyl ether. It was then slurried in water and filtered once more and washed with diethyl ether. After drying under high vacuum, 6.65 g of the title compound were obtained (85% of theory).
• Example 46A 5.00 g (12.394 mmol) of Example 46A were initially charged in iso-pentyl nitrite (35.87 ml) and diiodomethane (1.16 mol, 93.71 ml) and heated to 85 ° C. for 12 h. After cooling, it was filtered off from solids, concentrated and then purified by chromatography on silica gel (mobile phase: first cyclohexane-dichloromethane gradient, then dichloromethane-methanol gradient). There were obtained 5.50 g of the title compound (67% of theory).
• Example 48A 28 g (168,513 mmol) of Example 48A were reacted in analogy to the procedure of Example 19A. After chromatography on silica gel (cyclohexane: ethyl acetate 9: 1), 14.9 g (31% of theory) of the title compound were obtained.
• Example 49A 13 g (46,925 mmol) of Example 49A were reacted in analogy to the procedure under Example 20A. Chromatography on silica gel (cyclohexane: ethyl acetate gradient) gave 8.4 g (43% of theory) of the title compound.
• Example 50A 9.3 g (24,146 mmol) of Example 50A were reacted in analogy to the procedure under Example 23A, variant A. After chromatography on silica gel (cyclohexane: ethyl acetate gradient), 5.7 g (80% of theory, 95% strength by weight) of the title compound were obtained.
• Example 51A were reacted in analogy to the procedure under Example 24A. This gave 6.6 g (96% of theory) of the title compound.
• Example 52A 500 mg (1.384 mmol) of Example 52A were reacted in analogy to the procedure under Example 25A. 365 mg (83% of theory) of the title compound were obtained.
• Example 53A 365 mg (1154 mmol) of Example 53A were reacted analogously to the procedure of Example 13A with 325 mg (1.731 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate. 589 mg (92% of theory, 82% purity) of the title compound were obtained.
• Example 52A 1g (2.767 mmol) of Example 52A were reacted in analogy to the procedure under Example 46A. 971 mg (80% of theory) of the title compound were obtained.
• Example 55A 960 mg (2,205 mmol) of Example 55A were reacted in analogy to the procedure under Example 47A. 749 mg (62% of theory, 84% strength) of the title compound were obtained.
• the filtrate was concentrated in vacuo.
• the residue was admixed with ethanol and the insoluble solid was filtered off and washed with ethanol. After drying under high vacuum, 0.61 g (9% of theory) of the title compound were obtained.
• the filtrate was concentrated in vacuo and the residue was dried under high vacuum. 3.14 g (43% of theory, 43% strength by weight) of the title compound were obtained.
• Example 63 A 100 mg (0.27 mmol) of Example 63 A in 3 ml of THF were initially taken under argon. At 0 ° C., 56 ⁇ l (0.32 mmol) of ⁇ , ⁇ -diisopropylethylamine were added, and 0.16 ml (0.32 mmol) of ammonia (2M in ethanol) were added dropwise. The mixture was then stirred at RT overnight. Now was partitioned between dichloromethane and IN aqueous hydrochloric acid, the aqueous phase with dichloromethane extracted, the combined organic phases dried over sodium sulfate and concentrated in vacuo.
• Example 65A 84.37 g (348.23 mmol) of Example 65A were initially charged in 1.10 l of ethanol. Under reflux, 55 g (0.174 mol, purity 90%) of Example I IA were added in portions and it was heated further at reflux overnight. Then, with a test batch starting from 11.1 g (35.1 mmol), Example 65 A was combined. It was then cooled to 5 ° C, the precipitated solid was filtered off and washed with tert-butyl methyl ether. The solid was discarded. The filtrate was concentrated in vacuo, the residue treated with 500 ml of tert-butyl methyl ether and stirred for 1 h at room temperature.
• Example 69A 100 mg (0.16 mmol) of Example 69A in 3.3 ml of a mixture of DMF, water and triethylamine (25: 4: 4) were initially charged under argon, with 170 ⁇ (1.55 mmol) of ethyl acrylate, 25 mg (0.03 mmol) of palladium (II). acetate and 115 mg (0.31 mmol) of tetra-n-butylammonium iodide and stirred at 60 ° C for 9 h.
• Example 2A Under an argon atmosphere, 4.69 g (15.32 mmol) of Example 2A in 120 ml of tert-butanol were initially charged and 3.07 g (30.66 mmol) of potassium bicarbonate and 4.2 g (17.63 mmol) of Example 74A were added at room temperature. It was stirred for 5 h at 85 ° C bath temperature. After cooling, water was added and stirred for 30 min at room temperature. The precipitated solid was filtered off and washed with water and diethyl ether. After drying under high vacuum, 6.2 g (88% of theory) of the title compound were obtained.
• Example 33 Under an argon atmosphere, 600 mg (0.77 mmol, purity 57%) of Example 33 were initially charged and 2.50 ml (64.12 mmol) of 80% hydrazine hydrate were added. It was stirred for 30 min at 80 ° C, cooled, concentrated by rotary evaporation and dried under high vacuum. 566 mg of the title compound were obtained as crude product.
• Example 76A To 55 mg (0.13 mmol) of Example 76A in 1 ml of acetonitrile was added 1 ml (26.88 mmol) of formic acid. It was stirred for 1.5 h at 80 ° C bath temperature, cooled and concentrated. The residue was combined with ethyl acetate and washed once each with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated. 29.7 mg (50% of theory) of the title compound were obtained.
• Example 78A Under argon atmosphere, 500 mg (1.36 mmol) of Example 78A in 10 ml of t-butanol were initially charged and treated with 272.6 mg (2.72 mmol) of potassium bicarbonate and 373 mg (1.57 mmol) Example 74A. After 5h stirring at 85 ° C was cooled and treated with water. After stirring for 30 minutes at room temperature, the precipitated solid was filtered off and washed with water and a little ether. After drying under high vacuum, 458 mg (63% of theory) of the title compound were obtained.
• Example 25A 4.12 g (13.62 mmol) of Example 25A were reacted in analogy to Example 66A. There were obtained 2.03 g (22% of theory, purity 70%) of the title compound.
• Etyl-5-amino-1- (2-fluorobenzyl) -4-formyl-1H-pyrazole-3-carboxylate was prepared analogously to compounds known from the literature from 2-fluorobenzyl bromide and sodium 1,4-diethoxy-1,4-dioxobutyl 2-en-2-olate (see Kelley et al J. Med Chem 1995, 38, 3884-3888, Toche et al J. Het Chem 2010, 47, 287-291 and Patent US4833246 , Column 24. a) Preparation of (2-fluorobenzyl) hydrazine:
• Example 90 A Emyl-3 2- [l 2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyrene
• Example 69A Under argon were added 500 mg (0.78 mmol) of Example 69A, 14.8 mg (0.08 mmol) of copper (T) iodide, 127 mg (1.51 mmol) of sodium bicarbonate, 0.31 ml (304.4 mg, 3.1 mmol) of ethyl propiolate and 54.6 mg (0.08 mmol) of dichlorobistriphenylphosphine Palladium (II) in 7 ml of DMF overnight at 60 ° C stirred. Aqueous ammonium chloride solution was added and the mixture extracted with ethyl acetate. The organic phases were dried, concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with cyclohexane / ethyl acetate.

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