Substituted pyrazolopiperidine carboxylic acids

Abstract

The present invention relates to substituted pyrazolopiperidine carboxylic acids, their salts, and processes for their preparation, as well as their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF and HFpEF), hypertension (HTN), peripheral arterial disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic and diabetic kidney disease (CKD, DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), wound healing disorders such as diabetic foot ulcers (DFU).

Description

[Technical Field]

[0001] The present invention relates to substituted pyrazolopiperidinecarboxylic acids, salts thereof, and methods for producing them, and further relates to their use in the manufacture of pharmaceuticals for the treatment and / or prevention of diseases, particularly cardiovascular and cardiac diseases, preferably heart failure with reduced and maintained ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic and diabetic nephropathy (CKD, DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrous diseases, systemic sclerosis (SSc), sickle cell disease (SCD), diabetic foot ulcers (DFU), and other wound healing disorders. [Background technology]

[0002] Furthermore, the same pathophysiological mechanisms described above are also effective when transfusions are performed on patients who are candidates for transfusion (for example, by storing blood in a state where the free Hb concentration is elevated).

[0003] Furthermore, it is expected that in the future, the combination of sGC activators and synthetic Hb-based oxygen carriers will reduce the side effects observed so far [Weiskopf, Anaesthesia & Analgesia, 110:3; 659-661, 2010] caused by reduced NO utilization, making clinical application possible.

[0004] One of the most important cell signaling systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Released from the endothelium, it forms the NO / cGMP system with nitric oxide (NO), which transmits hormonal and mechanical signals. Guanylate cyclase catalyzes the biosynthesis of cGMP from guanosine triphosphate (GTP). Representative members of this family disclosed to date can be classified, according to their structural characteristics and ligand type, into particulate guanylate cyclases that can be stimulated by natriuretic peptides and soluble guanylate cyclases that can be stimulated by NO. Soluble guanylate cyclase consists of two subunits, possibly containing one heme molecule per heterodimer, which is part of the regulatory site. The latter plays a central role in the activation mechanism. NO can significantly enhance enzyme activity by binding to the iron atom of heme. On the other hand, heme-free formulations cannot be stimulated by NO. Carbon monoxide (CO) can also bind to the central iron atom of heme, but stimulation by CO is significantly less than stimulation by NO.

[0005] Through cGMP production and the subsequent regulation of phosphodiesterases, ion channels, and protein kinases, guanylate cyclase plays a crucial role in various physiological processes, particularly smooth muscle cell relaxation and proliferation, platelet aggregation and adhesion, and neuronal signaling, as well as disorders caused by impairments in these processes. Under pathophysiological conditions, the NO / cGMP system can be suppressed, potentially leading to conditions such as hypertension, platelet activation, increased cell proliferation and fibrosis, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, thrombosis, stroke, and myocardial infarction.

[0006] A possible therapeutic approach for such disorders that targets the in vivo cGMP signaling pathway, independent of NO, is a promising approach because it is expected to be highly efficient and have few side effects. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Weiskopf, Anaesthesia & Analgesia, 110:3; 659-661, 2010 [Overview of the project] [Problems that the invention aims to solve]

[0008] Compounds such as organonitrates, whose effects are based on NO, have historically been used primarily for the therapeutic stimulation of soluble guanylate cyclase. NO is produced by biotransformation and activates soluble guanylate cyclase by binding to the central iron atom of heme. In addition to side effects, the development of tolerance is one of the critical drawbacks of this mode of treatment [OV Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

[0009] In recent years, substances that directly stimulate soluble guanylate cyclase, i.e., substances that do not release NO beforehand, have been identified. The indazole derivative YC-1 was the first to be reported as an NO-independent but heme-dependent sGC stimulant [Evgenov et al., ibid.]. Based on YC-1, further substances were discovered that are more potent than YC-1 and do not exhibit associated inhibition of phosphodiesterase (PDE). This led to the identification of the pyrazolopyridine derivatives BAY41-2272, BAY41-8543, BAY63-2521, and BAY102-1189. Along with the recently published structurally different substances CMF-1571 and A-350619, these compounds form a new class of sGC stimulants [Evgenov et al., ibid.]. A common characteristic of this class of substances is the NO-independent and selective activation of heme-containing sGCs. Furthermore, combining this sGC stimulant with NO results in a synergistic effect on sGC activation based on the stabilization of the nitrosyl-heme complex. The precise binding site of the sGC stimulant in sGC is still under discussion. Even after removing the heme group from soluble guanylate cyclase, the enzyme still possesses detectable basal catalytic activity, i.e., cGMP is still formed. The residual basal catalytic activity of the heme-free enzyme cannot be stimulated by any of the stimulants mentioned above [Evgenov et al., ibid.].

[0010] Furthermore, NO and heme-independent sGC activators, with BAY58-2667 as the prototype of this class, have been identified. Common characteristics of these substances are that, when combined with NO, they only have an additive effect on enzyme activation, and that the activation of oxidized or heme-free enzymes is significantly higher than the activation of heme-containing enzymes [Evgenov et al., ibid.; JP Stasch et al., Br. J. Pharmacol. 136 (2002), 773; JP Stasch et al., J. Clin. Invest. 116 (2006), 2552]. Spectroscopic studies have revealed that BAY58-2667 substitutes weakly bound heme oxide groups on sGC as a result of weakening the iron-histidine bond. Furthermore, the characteristic sGC heme-binding motif, Tyr-x-Ser-x-Arg, has been shown to be absolutely essential for both the interaction of the heme group with the negatively charged propionic acid and the action of BAY58-2667. Given this background, it is hypothesized that the binding site of BAY58-2667 in sGC is identical to the binding site of the heme group [JP Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0011] The sGC activator lancaciguat (Hahn et al., Drugs Future 43 (2018), 738, WO 2012 / 139888) is currently in clinical development by Bayer (https: / / www.clinicaltrials.gov / NCT044507061). Our understanding of the redox equilibrium of sGC in health and disease is limited. Therefore, the therapeutic capacity of sGC activators is not yet fully understood. However, since oxidative stress may cause sGC enzymes to become heme-free, sGC activators may have a broader range of therapeutic capabilities, which still need to be identified and demonstrated in the future.

[0012] The compounds described in this invention can now similarly activate soluble guanylate cyclase in heme-free forms. This is confirmed by the fact that these novel activators, firstly, do not synergize with NO in heme-containing enzymes, and secondly, their effects cannot be blocked by 1H-1,2,4-oxadiazolo[4,3-a]quinoxarin-1-one (ODQ), a heme-dependent inhibitor of soluble guanylate cyclase, and are even enhanced by this inhibitor [see OV Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755; JP Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0013] WO2012 / 058132 discloses substituted pyrazolopyridine carboxylic acids as sGC activators. In contrast to the compounds according to the present invention, these compounds have a heteroaromatic pyridine moiety that links the pyrazole carboxylic acid to the rest of the molecule. Furthermore, the pyridine nitrogen is located at a different position from the piperidine nitrogen in the compounds according to the present invention. However, these compounds exhibit only ordinary pharmacokinetic properties in preclinical pharmacokinetic models, such as moderate clearance (CL) and moderate half-life and mean residence time (MRT) after intravenous (iv) administration.

[0014] Therefore, the object of the present invention is to provide novel sGC activator compounds for the treatment and / or prevention of diseases in humans and animals, particularly cardiovascular diseases and heart diseases, preferably heart failure with reduced and maintained ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic and diabetic nephropathy (CKD, DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrous diseases, systemic sclerosis (SSc), sickle cell disease (SCD), diabetic foot ulcers (DFU), and other wound healing disorders, which exhibit good pharmacokinetic behavior with a good pharmacological activity profile and beneficial physicochemical properties (e.g., solubility). [Means for solving the problem]

[0015] Surprisingly, certain substituted pyrazolopiperidinecarboxylic acids and their corresponding salts were found to represent very potent sGC activators with favorable pharmacological activity profiles, good pharmacokinetic behavior, and beneficial physicochemical properties (e.g., solubility).

[0016] The present invention provides compounds of formula (I), as well as salts thereof, solvates thereof, and solvates of salts thereof. [ka] During the ceremony, R 1 This represents hydrogen or halogen, R 2 This represents hydrogen or halogen, R 3 This represents chloro or trifluoromethyl, R 4 This represents hydrogen or C1-C4-alkyl, R 5 This represents C1-C6-alkyl, X1 represents nitrogen or carbon. X2 represents nitrogen or carbon. [Modes for carrying out the invention]

[0017] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by those selected from the specified group, but not exceeding the normal valency of the specified atom under current circumstances. Combinations of substituents and / or variable elements are permitted.

[0018] As used herein, the term "one or more" means, for example, in the definition of substituents of the compounds of general formula (I) of the present invention, "one, two, three, four or five, particularly one, two, three or four, more specifically one, two or three, and even more specifically one or two."

[0019] In the context of this invention, unless otherwise specified, substituents are defined as follows:

[0020] The term "halogen" or "halogeno" in combinations such as halogenoalkyl means fluorine, chlorine, bromine, or iodine atoms, in particular fluorine, chlorine, or bromine atoms, and more specifically fluorine or chlorine.

[0021] The terms "C1-C4-alkyl," "C1-C5-alkyl," and "C1-C6-alkyl" refer to linear or branched saturated monovalent hydrocarbon groups having 1, 2, 3, or 4 carbon atoms, 1, 2, 3, 4, or 5 carbon atoms, and 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, or 1,3-dimethylbutyl groups, or their isomers. In particular, the group has 1, 2, 3, or 4 carbon atoms ("C1-C4-alkyl") and is, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butylisobutyl, or tert-butyl group, and more specifically, has 1, 2, or 3 carbon atoms ("C1-C3-alkyl") and is, for example, a methyl, ethyl, n-propyl, or isopropyl group.

[0022] The terms "C1-C6-halogenoalkyl," "C2-C6-halogenoalkyl," "C1-C4-halogenoalkyl," "C2-C4-halogenoalkyl," "C1-C3-halogenoalkyl," and "C1-C2-halogenoalkyl" refer to a linear or branched saturated monovalent hydrocarbon group in which the term "alkyl" is defined as above, and one or more hydrogen atoms are replaced by halogen atoms, either identical or different. In particular, the halogen atom is a fluorine atom. The C1-C6 halogenoalkyl groups include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropan-1-yl, 1,1,1-trifluoropropan-2-yl, 1,3-difluoropropan-2-yl, 3-fluoropropan-1-yl, 1,1,1-trifluorobutan-2-yl, and 3,3,3-trifluoro-1-methyl-propan-1-yl.

[0023] The terms "C1-C4-halogenoalkoxy" and "C1-C3-halogenoalkoxy" refer to a linear or branched saturated, monovalent C1-C4-alkoxy or C1-C3-alkoxy group in which one or more hydrogen atoms are replaced by the same or different halogen atoms. Alkoxy This represents a linear or branched saturated monovalent alkoxy group having 1 to 4 or 1 to 3 carbon atoms, for example, and preferably methoxy, ethoxy, n-propoxy, or isopropoxy. In particular, the halogen atom is a fluorine atom. The C1-C3-halogenoalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or pentafluoroethoxy.

[0024] The term "C3-C6-cycloalkyl" refers to a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms. The C3-C6-cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0025] The compounds according to the present invention are the compounds of formula (I), and salts, solvates and solvates of salts thereof, as well as the compounds encompassed by formula (I) and described hereinafter as working examples, and salts, solvates and solvates of salts thereof, insofar as the compounds encompassed by formula (I) and described hereinafter are not already salts, solvates and solvates of salts.

[0026] Depending on their structure, the compounds of the present invention may exist in different stereoisomeric forms, i.e., in the form of configurational isomers or, where appropriate, in the form of conformational isomers (such as in the case of enantiomers and / or diastereomers, e.g., rotamers and atropisomers). Accordingly, the present invention encompasses enantiomers and diastereomers and individual mixtures thereof. Stereoisomerically uniform components can be isolated from such mixtures of enantiomers and / or diastereomers by known methods. Chromatographic processes are preferably used for this purpose, in particular HPLC chromatography on an achiral or chiral phase.

[0027] The present invention includes all possible tautomers of the compounds of the present invention, either as a single tautomer or as a mixture of said tautomers in any ratio.

[0028] In the context of the present invention, the term "enantiomerically pure" is to be understood as meaning that the subject compound is present in an enantiomeric excess of more than 95%, preferably more than 97%, relative to the absolute configuration of the chiral center. The enantiomeric excess (ee value) is in this case calculated by evaluation of the corresponding HPLC chromatogram on a chiral phase using the following formula: ee = [E A (area %) - E B (area %)] × 100% / [E A (area %) + E B (area %)]] (E A : excess enantiomer, E B : deficient enantiomer).

[0029] The present invention also encompasses all preferred isotopic forms of the compounds according to the present invention. In this specification, isotopic forms of the compounds of the present invention are understood to mean compounds in which at least one atom in the compound of the present invention has the same atomic number but is replaced by another atom having a different atomic mass than the atomic mass that is normally or dominant in nature. Examples of isotopes that can be incorporated into the compounds according to the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example. 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 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. Specific isotopic forms of the compounds according to the present invention, particularly those incorporating one or more radioactive isotopes, may be useful, for example, for testing the mechanism of action or the distribution of active ingredients in the body. Because they are relatively easy to manufacture and detect, they are particularly useful in this regard. 3 H or 14 Compounds labeled with 1C isotopes are suitable for this purpose. Furthermore, incorporating an isotope, such as deuterium, can increase the metabolic stability of the compound, which can be particularly therapeutically effective by, for example, increasing its half-life in the body and reducing the required dose of the active ingredient. Thus, such modifications of the compounds of the present invention may also constitute preferred embodiments of the present invention. The isotopic forms of the compounds according to the present invention can be produced by methods known to those skilled in the art, for example, by the procedures further described below in the Method and Examples, using the corresponding isotopic modifications of the individual reagents and / or starting compounds.

[0030] In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the present invention. However, the present invention also includes salts that are not suitable for pharmaceutical use themselves but can be used, for example, for the isolation or purification of the compounds according to the present invention.

[0031] Physiologically acceptable salts of the compounds according to the present invention include acid addition salts of mineral acids, carboxylic acids, and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid salts.

[0032] Physiologically acceptable salts of the compounds according to the present invention further include salts of ordinary bases, for example preferably alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example preferably salts of ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, and choline.

[0033] The present invention comprises all possible salts of the compounds of the present invention, either as a single salt or as a mixture of said salts in any proportion.

[0034] In the context of the present invention solvateThis is described as a form of the compound of the present invention that forms a complex in a solid or liquid state by coordination with solvent molecules. The compounds of the present invention may contain polar solvents, particularly water, methanol, or ethanol, as structural elements of the crystal lattice of the compound. A hydrate is a specific form of a solvate whose coordination is by water. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, for example, hydrate, hemi, (semi), mono, sesqui, di, tri, tetra, penta, etc., are possible, respectively. The present invention includes all such hydrates or solvates.

[0035] Furthermore, the compounds according to the present invention can exist as N-oxides, which are defined as at least one nitrogen atom of the compound of the present invention being oxidized in a known manner. The present invention includes all such possible N-oxides.

[0036] The present invention further encompasses prodrugs of the compounds of the present invention. The term “prodrug” in this context includes compounds that may be biologically active or inactive but are converted to the compounds of the present invention during their residence time in the body (e.g., by metabolism or hydrolysis).

[0037] R 1 However, these represent hydrogen and fluorine. R 2 However, these represent hydrogen and fluorine. R 3 However, it represents chloro or trifluoromethyl, R 4 However, it represents hydrogen or methyl, R 5 However, it represents C1-C5-alkyl, X1 represents nitrogen or carbon, X2 represents nitrogen or carbon. Compounds of formula (I), as well as their salts, solvates thereof, and solvates of their salts are preferred.

[0038] R 1 However, these represent hydrogen and fluorine. R2 However, these represent hydrogen and fluorine. R 3 However, it represents chloro or trifluoromethyl, R 4 However, it represents hydrogen or methyl, R 5 However, these represent methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, and isobutyl. X1 represents nitrogen or carbon, X2 represents nitrogen or carbon. Compounds of formula (I), as well as their salts, solvates thereof, and solvates of their salts are also preferred.

[0039] R 1 However, it represents hydrogen, R 2 However, it represents hydrogen, R 3 However, it represents chloro or trifluoromethyl, R 4 However, it represents hydrogen or methyl, R 5 However, these represent methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, and isobutyl. X1 represents carbon or CF, X2 represents carbon. Compounds of formula (I), as well as their salts, solvates thereof, and solvates of their salts are also preferred.

[0040] R 1 However, it represents hydrogen, R 2 However, it represents hydrogen, R 3 However, it represents chloro or trifluoromethyl, R 4 However, it represents hydrogen, R 5 However, these represent methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, and isobutyl. X1 represents carbon, X2 represents carbon. Compounds of formula (I), as well as their salts, solvates thereof, and solvates of their salts are also preferred.

[0041] R 1 However, it represents hydrogen, R 2 However, it represents hydrogen, R 3 However, it represents chloro, R 4 However, it represents hydrogen, R 5 However, it represents isobutyl, X1 represents carbon, X2 represents carbon. Compounds of formula (I), as well as their salts, solvates thereof, and solvates of their salts are also preferred.

[0042] Compounds of the following formula, as well as their salts, solvates thereof, or solvates of their salts, are also preferred. [ka]

[0043] Compounds of the following formula are particularly preferred. [ka]

[0044] The present invention further provides a method for producing a compound of formula (I), or a salt thereof, a solvate thereof, or a solvate of a salt thereof, In the first stage [B], the compound of formula (IV) below: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 X1 and X2 are defined as above. ] is a compound of the following formula (III): [ka] [In the formula, R 5arepresents a C1-C3 alkyl group, preferably isopropyl. Reacting with a reducing agent, a suitable solvent, and a base yields a compound of formula (II): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 And X1 and X2 are defined as above. ] obtained, In the second stage [A], When the compound of formula (II) is reacted with a base, the compound of formula (I) is obtained: [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 And X1 and X2 are defined as above. ] obtained; Optionally, Stage 3 [A] * Then, in the presence of a suitable acid and in a suitable solvent, the compound of formula (I) is dissolved in the corresponding salt of formula (Ia): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 And X1 and X2 are defined as above. Convert to ].

[0045] Reaction [A] * (Salt formation) Reaction [A] * This process is generally carried out in an inert solvent, in the presence of an acid, preferably at a temperature range of 0°C to 60°C, and at atmospheric pressure.

[0046] Acids suitable for salt formation are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, and water may be optionally added. Hydrogen chloride, hydrogen bromide, toluenesulfonic acid, methanesulfonic acid, or sulfuric acid are preferred.

[0047] Suitable inert solvents for salt formation include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether, or other solvents such as acetone, ethyl acetate, ethanol, n-propanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylpropylene urea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of the aforementioned solvents can also be used. Diethyl ether, dioxane, tetrahydrofuran, or mixtures thereof are preferred.

[0048] Reaction [A] (ester hydrolysis) The hydrolysis of the ester group in the compound of formula II is carried out by conventional methods, by treating the ester with an acid or base in an inert solvent, in the latter form, by treating the initially formed salt with an acid to convert it to a free carboxylic acid. In the case of tert-butyl esters, ester hydrolysis is preferably carried out with an acid.

[0049] Suitable inert solvents for these reactions are water or organic solvents commonly used for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane; or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide, or dimethyl sulfoxide. Mixtures of these solvents can also be used. For basic ester hydrolysis, a mixed solvent of water and dioxane, tetrahydrofuran, methanol, ethanol, and / or dimethylformamide, or a mixed solvent of tetrahydrofuran and methanol or ethanol, is preferred. For reactions with trifluoroacetic acid, dichloromethane is preferred, and for reactions with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water is preferred.

[0050] Suitable bases are conventional inorganic bases. These include alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, or calcium carbonate. Lithium hydroxide, sodium hydroxide, or potassium hydroxide are preferred.

[0051] Suitable acids for ester hydrolysis are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, with the optional addition of water. For tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and for methyl esters, hydrochloric acid is preferred.

[0052] Ester hydrolysis is generally carried out within a temperature range of -20°C to +120°C, preferably 0°C to +80°C.

[0053] Compounds of the following formula (II):

Chemical

Chemical

Chemical

Chemical

[0054] Reaction [B] (reductive amination) The reaction of step [B] is generally carried out in an inert solvent in the presence of a reducing agent, optionally in the presence of a base and / or a dehydrating agent, preferably at atmospheric pressure and in a temperature range of 0°C to 60°C.

[0055] Reducing agents suitable for reductive amination are conventional alkali metal hydrides for such purposes, including sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; it is preferred to use sodium triacetoxyborohydride.

[0056] In these reactions, the addition of an acid such as in particular acetic acid and / or a dehydrating agent, for example molecular sieves or trimethyl orthoformate or triethyl orthoformate, may be advantageous.

[0057] The base is an organic base, for example a trialkylamine such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine, or pyridine. Bases, especially N,N-diisopropylethylamine and triethylamine, may be advantageous in these reactions.

[0058] Suitable solvents for these reactions are in particular alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF), or mixtures of such solvents; it is preferred to use tetrahydrofuran.

[0059] The reaction is generally carried out within a temperature range of 0°C to +60°C.

[0060] Aldehydes of formula (III) are commercially available, known, or can be synthesized from known starting materials by known methods.

[0061] Compounds of formula (IV):

Chemical Formula

[0062] The compound of formula (IV) is derived from the corresponding compound of formula (V) below. [C] Compounds of the following formula (V): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 X1 and X2 are defined as described above. These can be synthesized by reacting them in the presence of a suitable acid and a suitable solvent.

[0063] Reaction [C] (deprotection) The reaction [C] is generally carried out in an inert solvent, in the presence of a suitable acid, preferably at a temperature range of 0°C to 60°C, and at atmospheric pressure.

[0064] The acid is an organic or inorganic acid such as sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or a mixture thereof, with water optionally added. Hydrogen chloride or trifluoroacetic acid is preferred.

[0065] Suitable solvents for these reactions include, in particular, alcohols such as methanol, ethanol, n-propanol or isopropanol; ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane; polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF); and mixtures of such solvents; however, tetrahydrofuran is preferred.

[0066] The reaction generally takes place within a temperature range of 0°C to +60°C.

[0067] Compound of formula (V): [ka] [In the formula, R 1 , R 2 , R 3 , R 4 X1 and X2 are defined as described above. ] is new.

[0068] The compound of formula (V) is derived from the corresponding compound of formula (VIII). [D] Compounds of the following formula (VIII): [ka] [In the formula, R 1 , R 2 and R 3 It is defined as above. In the presence of a suitable palladium catalyst, a base, and a suitable solvent, Compounds of the following formula (VI): [ka] It can be synthesized by reacting it with [another substance].

[0069] Reaction [D] (Suzuki coupling) Reaction [D] is generally carried out in an inert solvent, in the presence of a suitable palladium catalyst and a suitable base, preferably at a temperature range from room temperature to reflux of the solvent, and at atmospheric pressure.

[0070] The inert solvent for reaction step [D] is, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether; hydrocarbons such as benzene, xylol, toluene, hexane, cyclohexane, or petroleum; or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile, or water. Mixtures of the above solvents can also be used. Preferably, mixtures of dimethylformamide / water and toluene / ethanol are used.

[0071] Suitable bases for the reaction steps are conventional inorganic bases. These include alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide; alkali metal hydrogen carbonates, such as sodium bicarbonate or potassium bicarbonate; alkali metal or alkaline earth metal carbonates, such as lithium carbonate, sodium, potassium, calcium, or cesium; or alkali hydrogen phosphates, such as disodium hydrogen phosphate or dipotassium hydrogen phosphate. Preferably, the base used is sodium carbonate or potassium carbonate.

[0072] Examples of palladium catalysts suitable for the reaction step ["Suzuki coupling"] include, for example, palladium / activated carbon, palladium(II) acetate, tetrakis-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II)-chloride, bis-(acetonitrile)-palladium(II)-chloride, and [1,1′-bis(diphenylphospino)ferrocene]dichloropalladium(II)-dichloromethane complex [e.g., Hassan J. et al, Chem. Rev.]. 102 See 1359-1469 (2002).

[0073] These reaction steps are generally carried out within a temperature range of +20°C to +150°C, preferably +50°C to +100°C.

[0074] The compound of formula (VI) is novel, commercially available, or obtainable by known means. Compounds of the following formula (VIII): [ka] [In the formula, R 1 , R 2 and R 3 It is defined as described above. ] is new.

[0075] The compound of formula (VIII) is [E] Compounds of the following formula (IX): [ka] [In the formula, R 1 , R 2 and R 3 It is defined as above. It can be produced by reacting it with triphytic anhydride in the presence of a base and an inert solvent.

[0076] Reaction [E] (Triflation) The reaction [E] is generally carried out in an inert solvent, preferably at atmospheric pressure in a temperature range from room temperature to reflux of the solvent.

[0077] The base is, for example, an organic base such as alkali amines or pyridines, or an inorganic base such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, or an alkali metal carbonate such as cesium carbonate, sodium carbonate, or potassium carbonate, or an alkoxide such as potassium tert-butoxide or sodium tert-butoxide, or a pyridine such as pyridine or 2,6-lutidine, or an alkali amine such as triethylamine or N,N-diisopropylethylamine; triethylamine is preferred.

[0078] The inert solvent is, for example, an ether such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, or tetrahydrofuran, or another solvent such as dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, or pyridine, or a mixture thereof; dichloromethane is preferred.

[0079] Compounds of formula (IX): [ka] [In the formula, R 1 , R 2 and R 3 It is defined as described above. ] is new.

[0080] The compound of formula (IX) is [F] Compounds of the following formula (X): [ka] [In the formula, R 1 , R 2 and R 3 This is defined as above. It can be produced by reacting it with an acid in an inert solvent of any choice.

[0081] Reaction [F] (acidic deprotection) The reaction [F] is generally carried out in an inert solvent or without a solvent, preferably at atmospheric pressure, in a temperature range from 0°C to reflux of the solvent.

[0082] Examples of inert solvents include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, or 1,2-dichloroethane; alcohols such as methanol or ethanol; ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, or tetrahydrofuran; or other solvents or mixtures of solvents such as dimethylformamide, dimethoxyethane, N-methylpyrrolidone, dimethylacetamide, acetonitrile, acetone, or pyridine; dichloromethane or dioxane are preferred.

[0083] Suitable acids for acidic deprotection are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, with the optional addition of water. Hydrogen chloride or trifluoroacetic acid are preferred.

[0084] Compound of formula (X): [ka] [In the formula, R 1 , R 2 and R 3 [This is defined as above.] is new.

[0085] The compound of formula (X) is [G] Compounds of the following formula (XII): [ka] [In the formula, R 1 and R 2 The above definition applies. ] In the presence of a palladium source, a suitable ligand, and a base, the compound of formula (XI) below: [ka] [In the formula, R 3 It is defined as above. It can be manufactured by reacting it with ].

[0086] Reaction [G] (Buchwald-Hartwig coupling) The reaction [G] is generally carried out at atmospheric pressure in an inert solvent, preferably in a temperature range from room temperature to reflux of the solvent, in the presence of a palladium source, a suitable ligand, and a base.

[0087] Suitable palladium sources and ligands include, for example, palladium / activated carbon, palladium(II) acetate, tris(dibenzylideneacetone)palladium(O), tetrakis-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II) chloride, bis-(acetonitrile)-palladium(II) chloride, [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and corresponding dichloromethane complexes, such as 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) and (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl (2-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos-PD-G3, CAS number: 1445085-55-1), (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2′,4′,6′-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos, CAS number: 564483-18-7), bis(2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis(diphenylphospino)-9,9-dimethylxanthene (Xantphos: CAS number: 161265-03-8) [e.g., Hassan J. et al, Chem. Rev. 2002, 102, See 1359-1469, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos, CAS No.: 1070663-78-3), 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (SPhos, CAS No.: 657408-07-6), 2-dicyclohexylphosphine-2′,6′-diisopropoxy It may also be used in combination with additional phosphan ligands such as cibiphenyl (RuPhos, CAS number: 787618-22-8), 2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (RockPhos), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tert-ButylXPhos).In addition, a corresponding pre-catalyst such as chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos pre-catalyst) can be used [see, for example, SL Buchwald et al, Chem. Sci. 2013, 4, 916], and optionally, additional phosphine ligands such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos) can be used in combination.

[0088] Preferred combinations include 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tris(dibenzylideneacetone)palladium (0), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) or dicyclohexyl[2′,4′,6′-tris(1-methylethyl)biphenyl-2-yl]phosphane (XPhos).

[0089] Suitable inorganic or organic bases include, for example, alkali or alkaline earth metal carbonates such as lithium carbonate, sodium, potassium, calcium, or cesium; alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate; alkali metal or alkaline earth hydroxides such as sodium hydroxide, barium, or potassium; alkali metal or alkaline earth phosphates such as potassium phosphate; alkali metal alcoholates such as sodium or potassium tert-butyrate and sodium methanelate; alkali metal phenolates such as sodium phenolate; amides such as potassium acetate, sodium amide, lithium-, sodium-, or potassium-bis(trimethylsilyl)amide or lithium diisopropylamide; or organic amines such as 1,5-diazabicyclo[4·3·0]non-5-ene (DBN) and 1,8-diazabicyclo[5·4·0]unde-7-ene (DBU). Cesium carbonate, sodium carbonate, potassium carbonate, or sodium bicarbonate are preferred.

[0090] Examples of inert solvents include ethers such as dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, di-n-butyl ether, cyclopentyl methyl ether, glycol dimethyl ether, or diethylene glycol dimethyl ether; alcohols such as tert-butanol or amyl alcohol; or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene, or acetonitrile; or mixtures thereof. Preferred solvents include tert-butanol, 1,4-dioxane, and toluene.

[0091] Compounds of formula (XI) are known or can be synthesized by known methods from corresponding commercially available starting compounds.

[0092] Compound of formula (XII): [ka] [In the formula, R1 and R 2 [This is defined as above.] is new.

[0093] The compound of formula (XII) is [H] Compounds of the following formula (XIII): [ka] [In the formula, R 1 and R 2 It is defined as above. It can be produced by reacting it with an acid in an inert solvent.

[0094] Reaction [H] (debocylation) The reaction [H] is generally carried out in an inert solvent, in the presence of a suitable acid, preferably at atmospheric pressure, in a temperature range of 0°C to 60°C.

[0095] The acid is an organic or inorganic acid such as sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or a mixture thereof, with water optionally added. Hydrogen chloride or trifluoroacetic acid are preferred.

[0096] The inert solvent is an alcohol such as methanol, ethanol, or isopropanol; an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane; a polar aprotic solvent such as dichloromethane, acetonitrile, or N,N-dimethylformamide (DMF); or a mixture of such solvents; the use of 1,4-dioxane is preferred.

[0097] Compounds of the following formula (XIII): [ka] [In the formula, R 1 and R 2 [This is defined as above.] is new.

[0098] The compound of formula (XIII) is [I] Compounds of the following formula (XV): [ka] [In the formula, R 1 and R 2 The definition is as described above. ] in a solvent, a compound of the following formula (XIV): [ka] It can be manufactured by reacting it with [another substance].

[0099] Reaction [I] (pyrazole formation) Reaction [I] generally takes place in a solvent at temperatures ranging from room temperature to reflux.

[0100] Suitable solvents include alcohols such as methanol, ethanol, or isopropanol; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane; polar aprotic solvents such as dichloromethane, acetonitrile, or N,N-dimethylformamide (DMF); or mixtures of such solvents; the use of ethanol is preferred.

[0101] Compounds of formula (XIV) are known, commercially available, or can be synthesized from corresponding starting compounds by known methods.

[0102] Compound of formula (XV): [ka] [In the formula, R 1 and R 2 [This is defined as above.] is new.

[0103] The compound of formula (XV) is [J] Compounds of the following formula (XVI): [ka] [In the formula, R 1 and R 2 It is defined as above. It can be produced by reacting it with hydrogen in a suitable solvent in the presence of palladium / activated carbon.

[0104] Reaction [J] (Z deprotection) The reaction [J] is generally carried out in a suitable solvent in the presence of palladium / activated carbon, at room temperature to reflux temperature, preferably at 1 bar.

[0105] Suitable solvents include alcohols such as methanol, ethanol, or isopropanol; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane; aprotic solvents such as dichloromethane, acetonitrile, N,N-dimethylformamide (DMF), NMP, acetic acid, or water; or mixtures of such solvents; ethanol / acetic acid is preferred.

[0106] Compound of formula (XVI): [ka] [In the formula, R 1 and R 2 [This is defined as above.] is new.

[0107] The compound of formula (XVI) is [K] Compounds of the following formula (XVII): [ka] [In the formula, R 1 and R 2 The above definition applies. ] is prepared in the presence of a reducing agent and a suitable solvent, and the compound of the following formula (XVIII): [ka] It can be manufactured by reacting it with [another substance].

[0108] Reaction [K] (reductive hydrazine reaction) The reaction [K] is generally carried out at atmospheric pressure in the presence of a reducing agent and a suitable solvent, at temperatures ranging from room temperature to reflux of the solvent.

[0109] Suitable solvents include alcohols such as methanol, ethanol, n-propanol, or isopropanol; ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane; polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF); or mixtures of such solvents; the use of tetrahydrofuran / methanol is preferred.

[0110] Suitable reducing agents are alkali metal hydrides such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; the use of sodium borohydride is preferred.

[0111] Compounds of formula (XVIII) are either publicly known and commercially available, or can be synthesized from corresponding starting compounds by known methods.

[0112] The compound of formula (XVII) is either publicly known and commercially available, or can be synthesized from a corresponding starting compound by a known method.

[0113] The preparation of the starting compound and the compound of formula (I) can be explained by the following synthesis diagrams 1 to 3.

[0114] Figure 1 [ka] Diagram 2 [ka] Diagram 3 [ka]

[0115] The compounds of the present invention possess valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0116] The compounds according to the present invention are potent activators of soluble guanylate cyclase. These result in vasodilation, inhibition of platelet aggregation, a decrease in blood pressure, and increased coronary and renal blood flow. These effects are mediated by the direct, heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP.

[0117] Furthermore, the compounds according to the present invention have advantageous pharmacokinetic properties, particularly with respect to bioavailability and / or duration of action after intravenous or oral administration.

[0118] The compounds according to the present invention exhibit superior pharmacokinetic (PK) properties compared to compounds disclosed in the prior art (WO2012 / 058132) (see Experimental Section, Tables 3-6). For example, Example 2 of the present invention showed lower plasma clearance (CL) in rats and dogs compared to the prior art compound disclosed as Example 174 in WO2012 / 058132. plasma Example 2 also shows a much higher exposure (AUC) (up to 10 times), and therefore a much higher exposure. Example 2 also shows a long half-life and mean residence time (MRT) in all tested animal species after po (oral) administration. Example 2 shows remarkably low plasma clearance and very high exposure (AUC) with good bioavailability after po administration in all tested animal species. norm Based on exposure and area under the normalized curve, the inventors observe a clear superiority in pharmacokinetic (PK) properties compared to Example 174 disclosed in WO2012 / 058132.

[0119] The compounds according to the present invention have an unpredictable and useful pharmacological activity spectrum and good pharmacokinetic behavior, particularly sufficient exposure of such compounds in the blood above a minimum effective concentration within a given dosing interval after oral administration. Such a profile results in an improved peak-to-trough ratio (quotient of maximum concentration / minimum concentration) within a given dosing interval, which has the advantage of allowing the compound to be administered at a lower frequency and significantly lower dose to achieve the desired effect. These are compounds that activate soluble guanylate cyclase.

[0120] In the context of the present invention, “treatment” or “to treat” includes inhibiting, delaying, suppressing, alleviating, reducing, limiting, reducing, suppressing, counteracting, or curing a disease, condition, disorder, injury, or health problem, or the development, course, or progression of such condition and / or symptoms. The term “therapy” is understood herein to be synonymous with the term “treatment.”

[0121] In the context of the present invention, the terms “prevention,” “prevention,” and “inhibition” are used synonymously and refer to the risk of suffering, experiencing, contracting, or having a disease, condition, disability, injury, or health problem, or the avoidance or mitigation of the development or progression of such condition and / or symptoms of such condition.

[0122] Treatment or prevention of disease, condition, disability, injury, or health problem may be partial or complete.

[0123] Furthermore, the compounds according to the present invention have additional advantageous properties, particularly with respect to their pulmonary selective action (as opposed to systemic action), their retention time in the lungs after intrapulmonary administration, and / or their duration of action.

[0124] The compounds according to the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiac diseases, cardiorenal and renal diseases, cardiopulmonary and pulmonary diseases, neurodegenerative diseases, thromboembolic diseases, fibrotic disorders, and wound healing disorders.

[0125] The compounds according to the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), heart-renal and kidney diseases, preferably chronic and diabetic kidney disease (CKD and DKD), cardiopulmonary and lung diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrous diseases, systemic sclerosis (SSc), sickle cell disease (SCD), diabetic foot ulcers (DFU), and other wound healing disorders.

[0126] Therefore, the compounds according to the present invention are used, for example, to treat high blood pressure (hypertension), heart failure, coronary heart disease, stable and unstable angina, pulmonary hypertension (PAH) and secondary pulmonary hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal, renal vascular and treatment-resistant hypertension, peripheral and cardiovascular disorders, arrhythmias, atrial and ventricular arrhythmias and conduction disorders, such as grade I-III atrioventricular block, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de Pointes tachycardia, atrial and ventricular premature contractions, atrioventricular junctional premature contractions, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), and autoimmune heart diseases (pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy). It can be used in the treatment and / or prevention of cardiovascular, cardiopulmonary, and cardiorenal disorders such as boxer cardiomyopathy, aneurysms, cardiogenic shock, septic shock, anaphylactic shock, and other types of shock; as well as in the treatment and / or prevention of ischemia such as thromboembolism and myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, pre-eclampsia, inflammatory cardiovascular disorders, coronary and peripheral artery spasms, pulmonary edema, cerebral edema, renal edema or heart failure-induced edema, peripheral perfusion impairment, reperfusion injury, arterial and venous thrombosis, microalbuminuria, heart failure, endothelial dysfunction, microvascular and macrovascular injury (vasculitis); and in pharmaceuticals for the prevention of restenosis after, for example, thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, and bypass surgery.

[0127] In the context of this invention, the term "pulmonary hypertension" encompasses both its primary and secondary subforms, as defined below according to the Dana Point classification based on their respective etiologies [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3]. rd See edition, Hodder Arnold Publ., 2011, pp. 197-206; MM Hoeper et al., J.Am. Coll. Cardiol. 2009, 54 (1), S85-S96. These include, in particular, group 1 pulmonary hypertension (PAH), which specifically includes idiopathic and familial types (IPAH and FPAH, respectively). Furthermore, PAH also encompasses persistent pulmonary hypertension in neonates, as well as pulmonary hypertension (APAH) associated with collagenosis, congenital systemic pulmonary shunt lesions, portal hypertension, HIV infection, ingestion of certain drugs and medications (e.g., appetite suppressants), pulmonary hypertension (APAH) associated with disorders having significant venous / capillary components such as pulmonary veno-occlusive disorders and pulmonary capillary hemangiomatosis, or pulmonary hypertension (APAH) associated with other disorders such as thyroid disorders, glycogen storage disease, Gaucher disease, hereditary telangiectasia, abnormal hemoglobinopathy, myeloproliferative disorders and splenectomy. Group 2 of the Dana Point classification includes PH patients with left heart disorders causing ventricular, atrial, or valvular disorders. Group 3 includes forms of pulmonary hypertension associated with lung damage, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF), and / or hypoxemia (e.g., sleep apnea syndrome, alveolar hypoventilation, chronic high-altitude disease, hereditary malformations). Group 4 includes PH patients with chronic thrombotic and / or embolic damage, such as thromboembolic occlusion of the proximal and distal pulmonary arteries (CTEPH) or non-thromboembolic events (e.g., as a result of tumor damage, parasites, or foreign bodies). Patients with less common forms of pulmonary hypertension, such as sarcoidosis, histiocytosis X, or lymphangiomatosis, are grouped into Group 5.

[0128] In the context of the present invention, the term “heart failure” includes both acute and chronic heart failure, as well as specific or related types of diseases, such as acute decompensated heart failure, right heart failure, left heart failure, total heart failure, and even diastolic and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmEF), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects and cardiomyopathy, heart valve defects, heart valve defect-related heart failure, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, compound heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, and cardiac storage disorders.

[0129] Furthermore, the compounds according to the present invention can also be used for the treatment and / or prevention of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, combined hyperlipoproteinemia, hypercholesterolemia, abetalipoproteinemia, sitosterolemia, xanthomatous disease, Tanzier's disease, steatosis, obesity, and metabolic syndrome.

[0130] Furthermore, the compounds according to the present invention can be used for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, hearing impairment, tinnitus, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic ulcers and gangrene of the limbs, CREST syndrome, erythema, onychomycosis, and rheumatic disorders.

[0131] Furthermore, the compound according to the present invention can be used not only for the treatment of sickle cell disease (SCD), sickle cell anemia, and other SCD-related disease symptoms (e.g., end-organ damage affecting the lung, brain, kidney or heart), but also for the treatment of vaso-occlusive events or pain crises, achalasia, hemolysis-induced vascular disorders in the treatment of malaria, thalassemia, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemia or rhabdomyolysis. Furthermore, even when a patient with an indication for transfusion receives a blood transfusion (e.g., storage under conditions where the free Hb concentration is increased), the above-mentioned similar pathophysiological mechanism is valid, so it is considered that the present compound can be used for patients receiving blood transfusions. Finally, in the future, the combination of an sGC activator and a synthetic Hb-based oxygen carrier can alleviate the previously observed side effects caused by reduced NO bioavailability [Weiskopf, Anaesthesia & Analgesia, 110:3; 659-661, 2010], thus enabling further clinical applications.

[0132] The compound according to the present invention can also be used for preventing ischemia- and / or reperfusion-related damage to organs or tissues, and in particular as an additive for perfusion and preservation solutions for human or animal-derived organs, organ parts, tissues or tissue parts in the field of surgical intervention or transplantation medicine.

[0133] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of renal disorders, particularly renal insufficiency and renal failure. In the context of the present invention, the terms renal insufficiency and renal failure include both their acute and chronic symptoms (chronic kidney disease; CKD), as well as underlying or related kidney diseases, such as nephropathy, including renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, glomerulopathy, glomerulonephritis, acute glomerulonephrosis, glomerulosclerosis, tubulointerstitial disease, primary and congenital kidney disease, immune-mediated kidney diseases such as nephritis, kidney graft rejection and immune complex-induced nephropathy, toxic nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, and diabetic nephropathy (D This includes KD, pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized by, for example, an abnormal decrease in creatinine and / or water excretion, an abnormal increase in blood concentrations of urea, nitrogen, potassium and / or creatine, changes in the activity of renal enzymes such as glutamyl synthase, changes in urine osmolality or urine volume, increased microalbuminuria, overt albuminuria, lesions of the glomeruli and arterioles, tubular dilation, hyperphosphatemia and / or the need for dialysis. The present invention also includes the use of compounds according to the present invention for the treatment and / or prevention of complications of renal failure, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (e.g., hypercalcemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

[0134] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of urinary tract diseases, such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic hyperplasia (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), incontinence, such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC), as well as erectile dysfunction and female sexual dysfunction.

[0135] The compounds according to the present invention are also suitable for the treatment and / or prevention of asthmatic diseases, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), α-1 antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (e.g. pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).

[0136] The compounds described in the present invention are also active compounds for the inhibition of central nervous system disorders characterized by impairments of the NO / cGMP pathway. They are particularly suitable for improving perception, concentration, learning or memory after cognitive impairments that occur in association with conditions / diseases / syndromes such as mild cognitive impairment, age-related learning and memory impairment, age-related memory impairment, vascular dementia, craniocerebral trauma, stroke, dementia occurring after stroke (post-stroke dementia), traumatic craniocerebral injury, generalized concentration impairment, concentration impairment in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia associated with frontal lobe degeneration such as Pick's syndrome, Parkinson's disease, progressive supranuclear palsy, dementia associated with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jakob dementia, HIV dementia, schizophrenia with dementia or Korsakoff psychosis. They are also suitable for the treatment and / or prevention of central nervous system disorders such as anxiety, tension and depression, CNS-related dysfunction and sleep disorders, and for the inhibition of pathological disorders of the intake of food, stimulants and addictive substances.

[0137] Furthermore, the compounds according to the present invention are also suitable for regulating cerebral blood flow, and are therefore effective agents for inhibiting migraine. They are also suitably used for the prevention and management of sequelae of cerebral infarction (Apoplexia cerebri) such as stroke, cerebral ischemia and craniocerebral trauma. The compounds according to the present invention can likewise be used for inhibiting pain conditions.

[0138] Furthermore, the compounds according to the present invention have anti-inflammatory properties and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic enteritis (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatic disorders, inflammatory skin disorders, and inflammatory eye disorders.

[0139] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of fibrotic disorders of internal organs, such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatofibrosis and fibrous eye disorders. In the context of the present invention, the term “fibrotic disorders” particularly includes disorders such as hepatic fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, endocardial cardiomyopathy, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic disorders resulting from diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, systemic sclerosis, morphea, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (e.g., sarcoidosis). The compounds according to the present invention can also be used to promote wound healing, including the healing of finger ulcers and diabetic foot ulcers, to suppress postoperative scarring resulting from, for example, glaucoma surgery, and cosmetically for aging and keratinized skin.

[0140] Due to its activity profile, the compounds according to the present invention are particularly suitable for the treatment and / or prevention of cardiovascular diseases and heart and cardiopulmonary disorders such as primary and secondary pulmonary hypertension, heart failure, angina pectoris and hypertension, as well as for the treatment and / or prevention of thromboembolic disorders, ischemia, vascular disorders, microcirculatory disorders, renal failure, fibrous disorders and arteriosclerosis.

[0141] The present invention further provides the use of compounds according to the present invention for the treatment and / or prevention of disorders, in particular the above-mentioned disorders.

[0142] The present invention further provides the use of compounds according to the present invention for the manufacture of pharmaceuticals for the treatment and / or prevention of disorders, in particular the above-mentioned disorders. The present invention further provides a pharmaceutical product comprising at least one of the compounds according to the present invention for the treatment and / or prevention of disorders, particularly the above-mentioned disorders.

[0143] The present invention further provides the use of compounds according to the present invention in methods for treating and / or preventing disorders, particularly those described above.

[0144] The present invention further provides a method for treating and / or preventing a disorder, in particular the above-mentioned disorder, using an effective amount of at least one of the compounds according to the present invention.

[0145] Therefore, these are suitable for use as pharmaceuticals for the treatment and / or prevention of diseases in humans and animals.

[0146] The present invention further provides the use of compounds according to the present invention for the treatment and / or prevention of disorders, particularly cardiovascular disorders, preferably thrombotic or thromboembolic disorders and / or thrombotic or thromboembolic complications such as acute coronary syndrome, myocardial infarction, ischemic stroke, or peripheral artery occlusive disease, and / or diabetes and / or genitourinary disorders, particularly disorders related thereto.

[0147] In relation to the present invention, "thrombotic or thromboembolic disorders" preferably occur in the arterial vascular system and are treatable with the compounds of the present invention, particularly disorders leading to peripheral artery occlusive disorders and disorders in the coronary arteries of the heart, such as acute coronary syndrome (ACS), myocardial infarction with ST segment elevation (STEMI) and myocardial infarction without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, angioplasty, stent implantation or aortic coronary artery bypass, etc. This includes not only reocclusion and restenosis after coronary intervention, but also thrombotic or thromboembolic disorders of the cerebrovascular arteries such as transient ischemic attacks (TIAs), ischemic strokes such as cardiac embolic strokes such as stroke due to atrial fibrillation, non-cardiac embolic strokes such as lacunar infarction, strokes due to arteriosclerosis or arteriosclerosis, or strokes of unknown cause, latent strokes, embolic strokes, embolic strokes of unknown cause, or thrombotic and / or thromboembolic events leading to stroke or TIA.

[0148] Furthermore, the compounds according to the present invention are particularly suitable for the treatment and / or prevention of disorders in which pro-inflammatory components play a very important role, including vasculitides such as Kawasaki disease, Takayasu arteritis and thromboangiitis obliterans (Buerger's disease), as well as inflammatory disorders such as myocarditis.

[0149] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of disorders of the urogenital system such as overactive bladder, interstitial cystitis and bladder pain syndrome.

[0150] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of diabetes including its end-organ manifestations such as diabetic retinopathy and diabetic nephropathy.

[0151] Furthermore, the compounds according to the present invention are particularly suitable for the treatment and / or prevention of neurological disorders such as neuropathic pain, neurodegenerative disorders, and dementia including vascular dementia or Alzheimer's disease and Parkinson's disease.

[0152] Furthermore, the compounds according to the present invention are particularly suitable for the treatment and / or prevention of pulmonary diseases such as chronic cough, asthma and COPD.

[0153] The present invention further provides the use of a compound according to the present invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0154] The present invention further provides the use of a compound according to the present invention for the manufacture of a medicament for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[0155] The present invention further provides a method for the treatment and / or prevention of disorders, in particular the disorders mentioned above, using a therapeutically effective amount of a compound according to the present invention.

[0156] The present invention further provides a compound according to the present invention for use in a method for the treatment and / or prevention of disorders, in particular the disorders mentioned above, wherein a therapeutically effective amount of the compound according to the present invention is used.

[0157] In particular, the present invention provides compounds for use in methods for treating and / or preventing thrombotic or thromboembolic, especially atherothrombotic, disorders, using therapeutically effective amounts of the compounds according to the present invention.

[0158] The present invention further provides a pharmaceutical product comprising the compound according to the present invention and one or more further active compounds.

[0159] Furthermore, the compounds according to the present invention may also be used to prevent coagulation ex vivo, for example, to protect transplanted organs from organ damage caused by thrombus formation, and to protect organ transplant recipients from thromboembolism from transplanted organs, for the preservation of blood and plasma products, for cleaning / pretreatment of catheters and other medical aids and instruments, for coating synthetic surfaces of medical aids and instruments used in vivo or ex vivo, or for biological samples that may contain factor XIa or plasma kallikrein.

[0160] The present invention further provides a method for preventing blood coagulation in vitro, particularly in stored blood or biological samples that may contain the enzymes factor XIa or plasma kallikrein or both, characterized in that an anticoagulantly effective amount of the compound according to the present invention is added.

[0161] The compounds of the present invention can act systemically and / or locally. In this regard, these compounds can be administered by suitable methods, for example, orally, parenterally, through the lungs, nasally, sublingually, on the tongue, in the oral cavity, rectally, through the skin, percutaneously, conjunctiva, or via the ear route, or as implants or stents.

[0162] With regard to these administration routes, the compounds according to the present invention can be administered in a suitable dosage form.

[0163] With regard to oral administration, the compounds according to the present invention can be formulated into known dosage forms in the industry that deliver the compounds of the present invention in a rapid and / or modified form, such as tablets (uncoated or coated tablets having enteric or sustained-release coatings that dissolve slowly or are insoluble), orally disintegrating tablets, films / wafers, films / lyophilized products, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols, or liquids. The compounds according to the present invention can be incorporated into the above dosage forms in crystalline and / or amorphous and / or soluble forms.

[0164] Parenteral administration can be carried out by avoiding the absorption stage (e.g., intravenous, arterial, intracardiac, intraspinal, or intralumbar) or by including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Preferred forms of administration for parenteral administration are injectable and infusion formulations in the form of liquids, suspensions, emulsions, lyophilized products, or sterile powders.

[0165] Suitable extraocular (topical) administration forms include those that function by prior art to rapidly and / or in a modified or controlled manner to release the active compound, and that contain the active compound in crystalline and / or amorphous and / or soluble forms, such as eye drops, sprays and lotions (e.g., liquids, suspensions, vesicles / colloids, emulsions, aerosols), eye drop powders, sprays and lotions (e.g., pulverized active compounds, mixtures, lyophilized products, precipitated active compounds), semi-solid ophthalmic preparations (e.g., hydrogels, in-site hydrogels, creams and ointments), and ophthalmic implants (solid and semi-solid preparations, e.g., bioadhesives, films / wafers, tablets, contact lenses).

[0166] Intraocular administration methods include, for example, intravitreous, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar, and subspheric administration. Suitable administration methods for intraocular administration are those that function by prior art to rapidly and / or modified or controlled release of the active compound, and that contain the active compound in crystalline and / or amorphous and / or soluble forms, such as injectable formulations and concentrates for injectable formulations (e.g., liquids, suspensions, vesicles / colloids, emulsions), injectable powders (e.g., pulverized active compounds, mixtures, lyophilized products, precipitated active compounds), injectable gels (semi-solid formulations, e.g., hydrogels, in-sites hydrogels), and implants (solid formulations, e.g., biodegradable and non-biodegradable implants, implantable pumps).

[0167] Oral administration is preferred.

[0168] Examples of other suitable routes of administration include pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal solutions, intranasal sprays; tablets / films / wafers / capsules for tongue, sublingual or oral administration; suppositories; eye drops, eye ointments, eye washes, eyeball inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, agitated solutions (mixturae agitandae)), lipophilic suspensions, emulsions, ointments, creams, transdermal treatment systems (e.g., patches), lotions, pastes, foams, powders, implants, or stents.

[0169] The compounds according to the present invention can be incorporated into specified dosage forms. This can be done by mixing with pharmaceutically suitable excipients using methods known to the present day. Examples of pharmaceutically suitable excipients include the following: • Fillers and carriers (e.g., cellulose, microcrystalline cellulose, e.g., Avicel®, etc., lactose, mannitol, starch, calcium phosphate, e.g., Di-Cafos®, etc.), • Ointment base (e.g., petrolatum, paraffin, triglycerides, waxes, wool wax, wool wax alcohol, lanolin, hydrophilic ointment, polyethylene glycol), • Suppository bases (e.g., polyethylene glycol, cocoa butter, hard fat) • Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oil, liquid polyethylene glycol, paraffin), • Surfactants, emulsifiers, dispersants or wetters (e.g., sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g., Lanette®), sorbitan fatty acid esters (e.g., Span®), polyoxyethylene sorbitan fatty acid esters (e.g., Tween®), polyoxyethylene fatty acid glycerides (e.g., Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g., Pluronic®), • Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine) • Isotonic agents (e.g., glucose, sodium chloride), • Adsorbent (e.g., highly dispersed silica), • Viscosity enhancers, gel-forming agents, thickeners and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomer, polyacrylic acid (e.g., Carbopol®), alginate, gelatin), • Disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g., Explotab®), cross-linked polyvinylpyrrolidone, sodium croscarmellose (e.g., AcDiSol®)), • Flow regulators, lubricants, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g., Aerosil®, etc.)), • Coating materials that dissolve rapidly or in modified forms (e.g., sugars, shellac) and film-forming agents for films or diffusion films (e.g., polyvinylpyrrolidone (e.g., Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose phthalate acetate, polyacrylate, polymethacrylate (e.g., Eudragit®)), • Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose), Synthetic polymers (e.g., polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g., Eudragit®), polyvinylpyrrolidone (e.g., Kollidon®), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol, and their copolymers and block copolymers), • Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), • Permeation enhancers, • Stabilizers (e.g., antioxidants, such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, etc.) • Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • Colorants (e.g., inorganic pigments, e.g., iron oxide, titanium dioxide, etc.) Flavorings, sweeteners, flavorings, and / or odor masking agents.

[0170] The present invention further relates to pharmaceutical compositions comprising at least one compound according to the present invention together with one or more pharmaceutically suitable excipients, as in the conventional method, and to the use thereof according to the present invention.

[0171] One embodiment of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) according to the present invention together with at least one inert and nontoxic pharmaceutically suitable adjuvant, and the use of such pharmaceutical compositions for the above-mentioned purposes.

[0172] In another aspect, the present invention encompasses pharmaceutical combinations, particularly pharmaceuticals, comprising at least one compound of the general formula (I) of the present invention and at least one further active ingredient, for the treatment and / or prevention of vascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, as well as genitourinary and ophthalmic disorders.

[0173] The term "combination" in this invention is used as is known to those skilled in the art, and the combination may be a fixed combination, a non-fixed combination, or a parts kit.

[0174] In the present invention, a “fixed combination” is defined as a combination, as known to those skilled in the art, in which a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and further active ingredients exist together in one unit dose or as a single entity. One example of a “fixed combination” is a pharmaceutical composition in which the first active ingredient and further active ingredients exist in a mixture for co-administration, for example, in a formulation. Another example of a “fixed combination” is a pharmaceutical combination in which the first active ingredient and further active ingredients exist in one unit without being mixed.

[0175] In this invention, a non-fixed combination or "component kit" is defined as a combination in which the first active ingredient and further active ingredients exist in multiple units, as is known to those skilled in the art. One example of a non-fixed combination or component kit is a combination in which the first active ingredient and further active ingredients exist separately. The manufacture of the non-fixed combination or component kit can be administered separately, sequentially, simultaneously, at the same time, or over time.

[0176] The compounds of the present invention can be used alone or, if necessary, in combination with other active ingredients. The present invention further provides a pharmaceutical comprising at least one compound of the present invention and one or more further active ingredients, particularly for the treatment and / or prevention of the above-mentioned disorders. Preferred examples of suitable active ingredient combinations include the following: • Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morcidomin, or SIN-1, and inhaled NO; • Cyclic guanosine monophosphate (cGMP), for example, inhibitors of phosphodiesterase (PDE) 1, 2, 5 and / or 9, especially PDE5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirofenafil, rodenafil or PF-00489791; Compounds that inhibit the degradation of cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 3 and 4, particularly cilostazol, milrinone, roflumilast, apremilast, or crisabolol: • Antihypertensive active ingredients, for example and preferably from the group consisting of calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, rho kinase inhibitors, and diuretics; • Antiarrhythmic agents, for example and preferably from the group of sodium channel blockers, β-receptor blockers, potassium channel blockers, calcium channel blockers, IF-channel blockers, digitalis, parasympathetic blockers (vagus nerve inhibitors), sympathomimetic agents and other antiarrhythmic agents as adenosine, adenosine receptor agonists and vernacarant; Positive inotropes, such as cardiac glycosides (dogoxin), β-adrenergic agonists, and dopamine agonists, such as isoprenaline, adrenaline, noradrenaline, dopamine, or dobutamine; Vasopressin receptor antagonists, for example and preferably from conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, pecavaptan, SR-121463, RWJ676070, or BAY86-8050, and from the group of compounds described in WO2010 / 105770, WO2011 / 104322, and WO2016 / 071212; • Active ingredients that alter lipid metabolism, for example and preferably from the group consisting of thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably from the group consisting of HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists; Bronchodilators, for example and preferably β-adrenergic receptor agonists, for example and preferably from the group consisting of albuterol, isoproterenol, metaproterenol, terbutaline, formoterol, or salmeterol; or anticholinergics, for example and preferably from the group consisting of ipratropium; • Anti-inflammatory agents, for example and preferably from the group of glucocorticoids, for example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone, and non-steroidal anti-inflammatory drugs (NSAIDs), for example and preferably acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminosalicylic acid derivatives, leukotriene antagonists, TNF-α inhibitors and chemokine receptor antagonists, for example CCR1, 2 and / or 5 inhibitors; • Drugs that modulate the immune system, such as immunoglobulins; - Agents that inhibit signal transduction cascades, for example and preferably from the group of kinase inhibitors, for example and preferably from the group of tyrosine kinase inhibitors and / or serine / threonine kinase inhibitors; • Agents that inhibit the degradation and alteration of the extracellular matrix, for example and preferably, inhibitors of matrix metalloproteinases (MMPs), for example and preferably, inhibitors of chymase, stromelysin, collagenases, gelatinases and aggrecanases (preferably from the group MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13), and inhibitors of metalloelastase (MMP-12) and neutrophil elastase (HNE), for example, from the group sivelestat or DX-890; • A drug that blocks the binding of serotonin to its receptor, for example, and preferably 5-HT 2b Receptor antagonists; • Organic nitrates and NO donors, for example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morcidomin or SIN-1, and inhaled NO; NO-independent but heme-dependent soluble guanylate cyclase stimulants, for example, the compounds described in particular in WO00 / 06568, WO00 / 06569, WO02 / 42301 and WO03 / 095451; • Organic nitrates and NO donors, for example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morcidomin or SIN-1, and inhaled NO; NO-independent but heme-dependent soluble guanylate cyclase stimulants, for example and preferably the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301, WO03 / 095451, WO2011 / 147809, WO2012 / 004258, WO2012 / 028647 and WO2012 / 059549; NO-dependent and heme-dependent soluble guanylate cyclase activators, for example and preferably the compounds described in WO01 / 19355, WO01 / 19776, WO01 / 19778, WO01 / 19780, WO02 / 070462 and WO02 / 070510; A drug that stimulates cGMP synthesis, for example, an sGC modulator, for example and preferably riociguat, synaciguat, belliciguat, or lancaciguat; Prostacyclin analogs, for example and preferably iloprost, beraprost, treprostinil, or epoprosterol; • Agents that inhibit soluble epoxide hydrolase (sEH), for example and preferably N,N'-dicyclohexylurea, 12-(3-adamantan-1-ylureido)dodecanoic acid, or 1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea; Drugs that interact with glucose metabolism, for example and preferably insulin, biguanides, diazolidinediones, sulfonylureas, acarbose, DPP4 inhibitors, GLP-1 analogs, or SGLT-2 inhibitors, such as empagliflozin, dapagliflozin, canagliflozin, and sotagliflozin; • Natriuretic peptides, for example and preferably atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, nesiritide), natriuretic peptide type C (CNP), or urodilatin; Cardiac myosin activators, for example and preferably omecumtive mecarbir (CK-1827452); • Calcium sensitizer, for example and preferably levocimendan; • Agents that affect the energy metabolism of the heart, for example and preferably etomoxyl, dichloroacetate, lanolazine or trimetazidine, complete or partial adenosine A1 receptor agonists, for example GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and BAY1067197; • Drugs that affect heart rate, for example, and preferably ivabradine; • Cyclooxygenase inhibitors, such as bromfenac and nepafenac; • Kallikrein-kinin inhibitors, e.g., safotivant, ecalantide; • Inhibitors of the sphingosine 1-phosphate signaling pathway, e.g., sonepcizumab; • Inhibitors of the complement-C5a receptor, e.g., eculizumab; • Plasminogen activators (thrombolytic agents / fibrinolytic agents) and compounds that promote thrombolysis / fibrinolysis, such as inhibitors of plasminogen activator inhibitors (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitors (TAFI inhibitors), such as tissue plasminogen activators (t-PA, e.g., Actilyse®), streptokinase, leteplase and urokinase, or plasminogen modifiers that increase plasmin formation; Anticoagulants, such as heparin (UFH), low molecular weight heparin (LMW), such as tinzaparin, sertoparin, pernaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semloparin (AVE5026), admiparin (M118), and EP-42675 / ORG42675; Direct thrombin inhibitors (DTIs), such as pradaxa (dabigatran), atesegatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudine, and tanogitran (BIBT-986 and the prodrug BIBT-1011), and hirudin; Direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-166, dalexaban (YM-150), otamixaban (FXV-673 / RPR-130673), retaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), hydraparinux, and fondaparinux; • Inhibitors of coagulation factors XI and XIa, e.g., FXI ASO-LICA, fesomarcene, BAY121-3790, MAA868, BMS986177, EP-7041, and AB-022; Substances that inhibit platelet aggregation (platelet aggregation inhibitors), such as acetylsalicylic acid (e.g., aspirin), P2Y12 antagonists, such as ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, and erinogrel, as well as PAR-1 antagonists, such as borapaxer, and PAR-4 antagonists; Platelet adhesion inhibitors such as GPVI and / or GPIb antagonists, e.g., rebacept or caplacizumab; • Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists), such as absiximab, eptifivatide, tyrofiban, lamifibane, refuradafiban, and fludafiban; • Recombinant human activated protein C, e.g., zygris or recombinant thrombomodulin.

[0177] Antithrombotic agents are preferably understood to mean compounds from the group consisting of platelet aggregation inhibitors, anticoagulants, or fibrinolytic agents.

[0178] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a platelet aggregation inhibitor, for example, and preferably, aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or dipyridamole.

[0179] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a thrombin inhibitor, for example, and preferably, ximelagatran, dabigatran, melagatran, bivalirudin, or clexane.

[0180] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a GPIIb / IIIa antagonist, for example, and preferably tirofiban or absiximab.

[0181] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with factor Xa inhibitors, for example, and preferably, rivaroxaban (BAY59-7939), DU-176b, apixaban, betrixaban, otamixaban, fidexaban, razakisaban, retaxaban, eribaxaban, fondaparinax, hydraparinax, PMD-3112, dalexaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV803, SSR-126512, or SSR-128428.

[0182] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with factor XI or factor XIa inhibitors, for example, and preferably FXI ASO-LICA, fesomersen, BAY121-3790, MAA868, BMS986177, EP-7041, or AB-022.

[0183] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0184] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a vitamin K antagonist, for example, and preferably coumarin.

[0185] Antihypertensive agents are preferably understood to mean compounds from the group consisting of calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, rho kinase inhibitors, and diuretics.

[0186] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a calcium channel blocker, for example, and preferably nifedipine, amlodipine, verapamil, or diltiazem.

[0187] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an α-1 receptor blocker, for example, and preferably prazosin.

[0188] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a β-receptor blocker, for example, and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutrol, bupranolol, metipranolol, nadolol, mepindolol, chalazarol, sotalol, metoprolol, betaxolol, ceriprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebibolol, epanolol, or bucindolol.

[0189] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with an angiotensin A II antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan, or embusartan, or a dual angiotensin A II antagonist / neprilysin inhibitor, for example and preferably LCZ696 (valsartan / sacubitril).

[0190] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with ACE inhibitors, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, hosinopril, quinopril, perindopril, or trandopril.

[0191] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an endothelin antagonist, for example, and preferably, bosentan, dalsentan, ambrisentan, or citaxsentan.

[0192] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a renin inhibitor, for example, and preferably, aliskiren, SPP-600, or SPP-800.

[0193] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a mineralocorticoid receptor antagonist, for example, and preferably, spironolactone, AZD9977, finerenone, or eplerenone.

[0194] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with loop diuretics, such as furosemide, torasemide, bumetanide, and pyretanide; 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.

[0195] Lipid metabolism modifiers are preferably understood to mean compounds from the group consisting of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0196] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a CETP inhibitor, for example, and preferably, darcetrapib, anacetrapib, torcetrapib (CP-529414), JJT-705, or a CETP vaccine (Avant).

[0197] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a thyroid receptor agonist, for example, and preferably, D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS23425, or axithyrom (CGS26214).

[0198] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an HMG-CoA reductase inhibitor from statins, for example, and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0199] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a squalene synthesis inhibitor, for example, and preferably BMS-188494 or TAK-475.

[0200] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with an ACAT inhibitor, for example, and preferably, abasimib, melinamide, pactimibe, eflusimibe, or SMP-797.

[0201] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an MTP inhibitor, for example, and preferably, impritapide, BMS-201038, R-103757, or JTT-130.

[0202] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a PPAR-γ agonist, for example, and preferably pioglitazone or rosiglitazone.

[0203] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a PPAR-δ agonist, for example, and preferably GW501516 or BAY68-5042.

[0204] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a cholesterol absorption inhibitor, for example, and preferably, ezetimibe, tiquesid, or pamaquesid.

[0205] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a lipase inhibitor, a preferred example being orlistat.

[0206] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a polymeric bile acid adsorbent, for example, and preferably, cholestyramine, colestipol, colesolvam, cholestaGel, or colestimide.

[0207] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a bile acid reabsorption inhibitor, for example, and preferably an ASBT (=IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435, or SC-635.

[0208] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a lipoprotein (a) antagonist, for example, and preferably gemcabene calcium (CI-1027) or nicotinic acid.

[0209] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a lipoprotein (a) antagonist, for example, and preferably gemcabene calcium (CI-1027) or nicotinic acid.

[0210] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an sGC modulator, for example, and preferably, riociguat, synaciguat, or beliciguat.

[0211] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with agents that affect glucose metabolism, for example, and preferably, insulin, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors, empagliflozin, dapagliflozin, canagliflozin, or sotagliflozin.

[0212] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a TGFβ antagonist, for example, and preferably, pirfenidone or fresolimmab.

[0213] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a CCR2 antagonist, for example, and preferably CCX-140.

[0214] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a TNFα antagonist, for example, and preferably adalimumab.

[0215] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a galectin-3 inhibitor, for example, and preferably GCS-100.

[0216] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an Nrf-2 inhibitor, for example, and preferably bardoxolone.

[0217] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a BMP-7 agonist, for example, and preferably THR-184.

[0218] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a NOX1 / 4 inhibitor, for example, and preferably GKT-137831.

[0219] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a pharmaceutical agent that affects vitamin D metabolism, for example, and preferably, calcitriol, alfacalcidol, dexercalciferol, maxacalcitol, paricalcitol, cholecalciferol, or paracalcitol.

[0220] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with a cell proliferation inhibitor, for example, and preferably, cyclophosphamide.

[0221] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an immunosuppressant, for example, and preferably, cyclosporine.

[0222] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a phosphate adsorbent, for example, preferably cholestylane, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[0223] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a renal proximal tubular sodium phosphate cotransporter, for example, and preferably, niacin or nicotinamide.

[0224] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a calcium receptor agonist for the treatment of hyperparathyroidism.

[0225] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an agent for the treatment of iron deficiency, for example, and preferably, an iron product.

[0226] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a drug for the treatment of hyperuricemia, for example, and preferably allopurinol or rasburicase.

[0227] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with glycoprotein hormones for the treatment of anemia, such as and preferably erythropoietin, daprodustat, moridustat, roxadustat, vadadustat, and desidustat.

[0228] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a biological agent for immunotherapy, for example, and preferably, abatacept, rituximab, eculizumab, or belimumab.

[0229] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with vasopressin antagonists (vaptans) for the treatment of heart failure, for example, and preferably, tolvaptan, conivaptan, lixivaptan, mozavaptan, satavaptan, pecapaptan, or relcovaptan.

[0230] In preferred embodiments of the present invention, the compounds of the present invention are administered in combination with a Jak inhibitor, for example, and preferably, ruxolitinib, tofatitinib, baricitinib, CYT387, GSK2586184, restaurtinib, pacritinib (SB1518), or TG101348.

[0231] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a prostacyclin analog for the therapy of microthrombi.

[0232] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an alkaline therapy, for example, and preferably, sodium bicarbonate.

[0233] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an mTOR inhibitor, for example, and preferably everolimus or rapamycin.

[0234] In preferred embodiments of the present invention, the compound of the present invention is administered in combination with an NHE3 inhibitor, for example, and preferably AZD1722 or tenapanor.

[0235] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an eNOS modulator, for example, and preferably, sapropterin.

[0236] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a CTGF inhibitor, for example, and preferably FG-3019.

[0237] The present invention further provides a pharmaceutical product comprising, typically, one or more inert, non-toxic, and pharmaceutically suitable adjuvants, and its use for the aforementioned purposes.

[0238] The compounds according to the present invention may act systemically and / or locally. In this regard, they may be administered by suitable methods, for example, orally, parenterally, through the lungs, nose, sublingually, tongue, oral cavity, rectum, skin, percutaneously, conjunctiva, ear route, or as implants or stents.

[0239] The compounds according to the present invention can be administered in a dosage form suitable for these administration routes.

[0240] Suitable dosage forms for oral administration include those that function in accordance with the prior art, rapidly and / or in a controlled manner to release the compound according to the present invention, and containing the compound according to the present invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, e.g., having gastric acid-resistant, delayed-dissolving, or insoluble coatings that control the release of the compound according to the present invention), tablets or films / wafers, films / lyophilized products, or capsules (e.g., hard or soft gelatin capsules) that disintegrate rapidly in the oral cavity, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols, or liquids.

[0241] Parenteral administration may involve avoiding the absorption step (e.g., intravenous, arterial, intracardiac, intravertebral, or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, transdermal, or intraperitoneal). Suitable dosage forms for parenteral administration include injectable and infusion formulations in the form of liquids, suspensions, emulsions, lyophilized products, or sterile powders.

[0242] Other suitable routes of administration include inhalable pharmaceutical forms (such as powder inhalers and nebulizers), nasal drops, liquids or sprays, tablets, films / wafers or capsules for tongue, sublingual or oral administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, transdermal systems (e.g., patches), emulsions, pastes, foams, powders for application, implants, or stents.

[0243] Oral or parenteral administration is preferred, with oral and intravenous administration being particularly preferred.

[0244] The compounds according to the present invention can be converted into the dosage forms mentioned. This can be done by mixing them with inert, non-toxic, and pharmaceutically suitable excipients in a manner known to the present. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), dyes (e.g., inorganic pigments, e.g., iron oxide), and flavoring agents and / or odor correctors.

[0245] In general, for parenteral administration, it has been found that administering a dose of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg, is advantageous for obtaining effective results. For oral administration, the dose is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg, and most preferably 0.1 to 10 mg / kg.

[0246] Nevertheless, where appropriate, it may be necessary to deviate from the stated dose, specifically as a function of body weight, route of administration, individual response to the active compound, nature of the formulation, and the time or interval at which administration is performed. For example, in some cases, less than the aforementioned minimum dose may be sufficient, and in other cases, the aforementioned upper limit must be exceeded. In the case of relatively large doses, it may be desirable to divide them into several individual doses per day.

[0247] The total amount of active ingredient administered is typically in the range of about 0.001 mg / kg to about 200 mg / kg / day, preferably about 0.01 mg / kg to about 50 mg / kg / day, and more preferably about 0.01 mg / kg to about 20 mg / kg / day. Clinically useful administration schedules range from three times a day to once every four weeks. Furthermore, "drug-free days" during which the patient does not receive the drug for a certain period may be beneficial for the overall balance between pharmacological effect and tolerability. The unit dose can contain about 0.5 mg to about 1500 mg of the active ingredient and can be administered once or less than once a day. The average daily dose for administration by injection, e.g., intravenous, intramuscular, subcutaneous, and parenteral injection, and administration using infusion techniques is preferably 0.01 to 200 mg / kg of total body weight. The average daily rectal administration schedule is preferably 0.01 to 200 mg / kg of total body weight. The average daily vaginal administration regimen is preferably 0.01 to 200 mg / kg of total body weight. The average daily topical administration regimen is preferably 0.1 to 200 mg, administered 1 to 4 times a day. The transdermal concentration is preferably what is necessary to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation administration regimen is preferably 0.01 to 100 mg / kg of total body weight.

[0248] Naturally, the specific initial and ongoing administration plan for each patient will vary depending on the nature and severity of the condition as determined by the diagnosing physician, the activity of the specific compound used, the patient's age and overall condition, the time of administration, the route of administration, the rate of drug excretion, and concomitant medications. The desired therapeutic form and dosage of the compound of the present invention or its pharmaceutically acceptable salt or ester or composition can be confirmed by those skilled in the art using conventional therapeutic studies.

[0249] Nevertheless, it may be necessary to deviate from the specified dose, depending on body weight, route of administration, the individual's response to the active substance, the type of formulation, and the time point or time interval at which administration is performed. Therefore, in some cases, it may be sufficient to use a dose less than the minimum dose mentioned above, while in other cases, the specified upper limit must be exceeded. When administering relatively large doses, it may be desirable to divide them into several individual doses throughout the day.

[0250] In further embodiments, the compound of formula (I) according to the present invention is administered orally once, twice, or three times daily. In further embodiments, the compound of formula (I) according to the present invention is administered orally once or twice daily. In further embodiments, the compound of formula (I) according to the present invention is administered orally once daily. For oral administration, a rapid-release formulation or a controlled-release formulation may be used.

[0251] Unless otherwise specified, percentages in the following tests and examples are weight percentages, and parts are parts by weight. Solvent ratios, dilution ratios, and concentration data for liquids / liquid solutions are volume-based in each case. "w / v" means "weight / volume". For example, "10% w / v" means that 100 mL of solution or suspension contains 10 g of the substance.

[0252] Experiment Section Experiment Section - General Part NMR peak shapes are described as they appear in the spectrum, and possible higher-order effects are not considered.

[0253] Chemical names were assigned using ACD / Labs naming software. In some cases, the commonly accepted names of commercially available reagents were used instead of the names assigned by ACD / Labs.

[0254] Table 1 below lists the abbreviations used in this paragraph and the section on embodiments, unless otherwise explained in the text. Other abbreviations have their own customary meanings to those skilled in the art.

[0255] Table 1: Abbreviations The table below lists the abbreviations used in this specification. [Table 1] TIFF0007915213000039.tif208144TIFF0007915213000040.tif28144

[0256] Various aspects of the present invention described in this application will be explained by the following examples, but these examples do not limit the present invention in any way.

[0257] The experiments testing the examples described herein are for illustrative purposes only, and the invention is not limited to the examples provided.

[0258] All reagents whose synthesis is not described in the experimental section can be obtained from commercially available sources, known compounds, or by methods known to those skilled in the art.

[0259] Compounds and intermediates produced by the method of the present invention may require purification. Purification of organic compounds is known to those skilled in the art, and there are several possible methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by stirring using a suitable solvent. In some cases, the compound can be purified by chromatography, particularly by flash column chromatography using a pre-packed silica gel cartridge, such as a Biotage SNAP cartridge KP-Sil® or KP-NH®, in combination with an eluent such as a hexane / ethyl acetate or DCM / methanol gradient. In some cases, the compound can be purified by preparative HPLC using a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, in combination with a suitable pre-packed reversed-phase column and an eluent such as water and acetonitrile gradient (which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia).

[0260] Depending on the circumstances, the purification method described above may provide the compounds of the present invention having a sufficiently basic or acidic functional group in the form of a salt. For example, in the case of a sufficiently basic compound of the present invention, this may be a trifluoroacetate or formate salt, or, for example, in the case of a sufficiently acidic compound of the present invention, this may be an ammonium salt. These types of salts can be converted to the free basic form or the free acid form, respectively, or used as salts in subsequent biological assays by various methods known to those skilled in the art. It should be understood that a particular form of the compounds of the present invention isolated and described herein (e.g., a salt, a free base, etc.) is not necessarily the only form in which the compound can be used in a biological assay for the purpose of quantifying a specific physiological activity.

[0261] In the case of the synthetic intermediates and working examples of the present invention described below, any compound specified in the form of a corresponding base or acid salt is generally an undefined salt with unknown exact stoichiometric composition obtained by the respective preparation and / or purification process. Therefore, unless otherwise specified in more detail, "hydrochloride", "trifluoroacetate", "sodium salt" or "xHCl", "xCF3COOH", "xNa + " and other additions to names and structural formulas should not be understood stoichiometrically in the case of such salts, and merely have descriptive properties with respect to the salt-forming component present therein.

[0262] This also applies mutatis mutandis to cases where a synthetic intermediate or working example or a salt thereof is obtained by the described preparation and / or purification process in the form of a solvate, for example a hydrate, of unknown stoichiometric composition, when they are of a defined type.

[0263] NMR peak shapes are described as they are observed in the spectrum, and possible higher-order effects are not taken into consideration.

[0264] For selected compounds 1 1H-NMR data are 1 listed in the form of a 1H-NMR peak list. For each signal peak, the δ value in ppm is given, followed by the signal intensity reported in parentheses. The δ value / signal intensity pairs from different peaks are separated from each other by commas. Accordingly, the peak list has the following general form: δ1(intensity1), δ2(intensity2), ..., δ i (intensity i ), ..., δ n (intensity n ).

[0265] The intensity of sharp signals correlates with the signal height (in cm) in the printed NMR spectrum. This data can be correlated to the true signal intensity ratio when comparing it to other signals. For broad signals, the relative intensities of multiple peaks, or the signal center compared to the strongest signal shown in the spectrum, are indicated. 1 The H-NMR peak list is a conventional 1 Since it is similar to 1H-NMR printing, it usually includes all the peaks that would be listed in conventional NMR interpretation. Furthermore, conventional 1 Similar to 1H-NMR printing, the peak list can show solvent signals, signals originating from stereoisomers of the target compound (which are also the subject of this invention), and / or impurity peaks. Stereoisomer peaks and / or impurity peaks are typically shown at lower intensities compared to the target compound peak (e.g., purity >90%). Since such stereoisomers and / or impurities may be representative of a particular manufacturing method, their peaks can be useful in verifying the reproducibility of the inventors' manufacturing method based on a "by-product fingerprint." If necessary, experts who calculate the target compound peak by known methods (MestreC, ACD simulation, or using empirically evaluated predicted values) can isolate the target compound peak using additional intensity filters as appropriate. Such operations are conventional. 1This is considered to be similar to the corresponding peak selection in 1H-NMR interpretation. A detailed explanation of reporting NMR data in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (Research Disclosure Database Number 605005, 2014, August 1, 2014, or see http: / / www.researchdisclosure.com / searching-disclosures). In the peak selection routine, the parameter "MinimumHeight" can be adjusted from 1% to 4%, as described in Research Disclosure Database Number 605005. Depending on the chemical structure and / or the concentration of the compound being measured, it may be appropriate to set the parameter "MinimumHeight" to <1%.

[0266] In the NMR spectrum of a mixture of stereoisomers, the numbers preceded by " / " indicate that the stereoisomers show separate signals for each hydrogen atom. For example, "... / ...(2s,1H)" means that one hydrogen atom is represented by two singlets, each singlet representing one or more different stereoisomers.

[0267] The IUPAC names of the intermediates and example compounds listed below were created using a naming tool run with ACD / Name software (batch version 14.00; Advanced Chemistry Development, Inc.) or BIOVIA Draw software (version 4.2 SP1; Dassault Systemes SE).

[0268] HPLC and LC-MS methods Method 1 (LC-MS) MS instrument type: SHIMADZU LCMS-2020, Column: Kinetex EVO C18 30×2.1mm, 5μm, Mobile phase A: 0.0375% TFA / water (volume ratio), B: 0.01875% TFA / acetonitrile (volume ratio), Gradient: 0.0 min 0%B → 0.8 min 95%B → 1.2 min 95%B → 1.21 min 5%B → 1.55 min 5%B, Flow rate: 1.5 mL / min, Oven temperature: 50℃; UV detection: 220nm & 254nm.

[0269] Method 2 (LC-MS) HPLC instrument model: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 50×4.6mm, 5μm; Mobile phase A: 0.0375% TFA / water (volume ratio), B: 0.01875% TFA / acetonitrile (volume ratio); Gradient: 0.0 min 10% B → 2.4 min 80% B → 3.7 min 80% B → 3.71 min 10% B → 4.0 min 10% B; Flow rate: 1.5 mL / min; Oven temperature: 50℃; UV detection: 220nm, 215nm, and 254nm.

[0270] Method 3 (LC-MS) Equipment: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50×1mm; Eluent A: 1 liter water + 0.25 mL formic acid, Eluent B: 1 liter acetonitrile + 0.25 mL formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50℃; Flow rate: 0.40 mL / min; UV detection: 210 nm.

[0271] Method 4 (LC-MS) Instrument MS: Thermo Scientific FT-MS; UHPLC+ instrument: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 × 75 mm, C18 1.8 μm; Eluent A: 1 liter water + 0.01% formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven: 50℃; Flow rate: 0.90 mL / min; UV detection: 210 nm / Optimal integration path 210-300 nm.

[0272] Method 5 (LC-MS) Equipment: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50×1mm; Eluent A: 1 liter water + 0.25 mL formic acid, Eluent B: 1 liter acetonitrile + 0.25 mL formic acid; Gradient: 0.0 min 95% A → 6.0 min 5% A → 7.5 min 5% A; Oven: 50℃; Flow rate: 0.35 mL / min; UV detection: 210 nm.

[0273] Method 6 (LC-MS) Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8μm 50×2.1mm; Eluent A: 1 liter water + 0.25 mL formic acid, Eluent B: 1 liter acetonitrile + 0.25 mL formic acid; Gradient: 0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0 min 5% A; Oven: 50℃; Flow rate: 1.20 mL / min; UV detection: 205-305 nm.

[0274] Method 7 (LC-MS) System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8μm 50×1mm; Eluent A: 1 liter water + 0.100 mL 99% formic acid; Eluent B: 1 liter acetonitrile + 0.100 mL 99% formic acid; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Oven: 50℃; Flow rate: 0.40 mL / min; UV detection: 210 nm.

[0275] Method 8 (LC-MS): System MS: Waters TOF instrument; System ULC: Waters Acquity I-CLASS; Column: Waters HSST3, 2.1 × 50 mm, C18 1.8 μm; Eluent A: 1 liter water + 0.01% formic acid; Eluent B: 1 liter acetonitrile + 0.01% formic acid; Gradient: 0.0 min 2% B → 0.5 min 2% B → 7.5 min 95% B → 10.0 min 95% B; Oven: 50℃; Flow rate: 1.00 mL / min; UV detection: 210 nm.

[0276] Method 9 (preparative HPLC) Instrument: Waters Prep LC / MS system, Column: Phenomenex Kinetex C18 5μm 100×30mm, UV detection 200-400nm, Room temperature, At-column injection (complete injection), Eluent A: Water, Eluent B: Acetonitrile, Eluent C: 2% Formic Acid / Water, Eluent D: Acetonitrile / Water (80 vol% / 20 vol%); Flow rate: 80 mL / min, Gradient profile: 0 to 2 min: Eluent A 55 mL / min, Eluent B 15 mL / min; 2 to 10 min: Eluent A 55 mL / min to 31 mL / min, Eluent B 15 mL / min to 39 mL / min; 10 to 12 min: Eluent A 0 mL / min and Eluent B 70 mL / min; Eluent C and Eluent D each maintain a constant flow rate of 5 mL / min throughout the entire operating time.

[0277] Method 10 (preparative HPLC) Instrument: Waters Prep LC / MS system, Column: XBridge C18 5μm 100×30mm, UV detection 200-400nm, Room temperature, At-column injection (complete injection), Eluent A: Water, Eluent B: Acetonitrile, Eluent C: 2% ammonia water, Eluent D: Acetonitrile / water (80 vol% / 20 vol%); Flow rate: 80 mL / min, Gradient profile: 0 to 2 min: Eluent A 55 mL / min, Eluent B 15 mL / min; 2 to 10 min: Eluent A 55 mL / min to 31 mL / min, Eluent B 15 mL / min to 39 mL / min; 10 to 12 min: Eluent A 0 mL / min and Eluent B 70 mL / min; Eluent C and Eluent D each maintain a constant flow rate of 5 mL / min throughout the entire operating time.

[0278] Method 11 (preparative HPLC) Instrument: Waters Prep LC / MS system, Column: Phenomenex Kinetex C18 5μm 100×30mm, UV detection 200-400nm, Room temperature, At-column injection (complete injection), Eluent A: Water, Eluent B: Acetonitrile, Eluent C: 2% Formic Acid / Water, Eluent D: Acetonitrile / Water (80 vol% / 20 vol%); Flow rate: 80 mL / min, Gradient profile: 0 to 2 min: Eluent A 47 mL / min, Eluent B 23 mL / min; 2 to 10 min: Eluent A 47 mL / min to 23 mL / min, Eluent B 23 mL / min to 47 mL / min; 10 to 12 min: Eluent A 0 mL / min and Eluent B 70 mL / min; Eluent C and Eluent D each maintain a constant flow rate of 5 mL / min throughout the entire operating time.

[0279] Method 12 (preparative HPLC) Instrument: Waters Prep LC / MS system, Column: Phenomenex Kinetex C18 5μm 100×30mm, UV detection 200-400nm, Room temperature, At-column injection (complete injection), Eluent A: Water, Eluent B: Acetonitrile, Eluent C: 2% Formic Acid / Water, Eluent D: Acetonitrile / Water (80 vol% / 20 vol%); Flow rate: 80 mL / min, Gradient profile: 0 to 2 min: Eluent A 23 mL / min, Eluent B 47 mL / min; 2 to 10 min: Eluent A 23 mL / min to 0 mL / min, Eluent B 47 mL / min to 70 mL / min; 10 to 12 min: Eluent A 0 mL / min and Eluent B 70 mL / min; Eluent C and Eluent D each maintain a constant flow rate of 5 mL / min throughout the entire operating time.

[0280] Method 13 (preparative HPLC) Instrument: Waters Prep LC / MS system, Column: Phenomenex Kinetex C18 5μm 100×30mm, UV detection 200-400nm, Room temperature, At-column injection (complete injection), Eluent A: Water, Eluent B: Acetonitrile, Eluent C: 2% Formic Acid / Water, Eluent D: Acetonitrile / Water (80 vol% / 20 vol%), Flow rate: 80 mL / min, Gradient profile: Eluent A 0 to 2 min 70 mL / min, Eluent B 0 to 2 min 0 mL / min, Eluent A 2 to 10 min 70 mL / min to 0 mL / min and Eluent B 0 mL / min to 70 mL / min, 10 to 12 min 0 mL / min Eluent A and 70 mL / min Eluent B; Eluent C and Eluent D maintain a constant flow rate of 5 mL / min throughout the entire operating time.

[0281] Microwaves: The microwave irradiation reactor used was an Initator equipped with a robot sixty from Biotage®. + It was a microwave system.

[0282] When a compound according to the present invention is purified by preparative HPLC using the above method, in which the eluent contains an additive, such as trifluoroacetic acid, formic acid, or ammonia, if the compound according to the present invention contains sufficiently basic or acidic functionalities, the compound according to the present invention can be obtained in the form of a salt, such as a trifluoroacetic acid salt, formate salt, or ammonium salt. Such salts can be converted to the corresponding free base or free acid by various methods known to those skilled in the art.

[0283] In the case of the synthetic intermediates and working examples of the present invention described below, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition obtained by the respective manufacturing and / or purification steps. Thus, unless otherwise specified in more detail, "hydrochloride salt," "trifluoroacetate salt," "sodium salt," or "xHCl," "xCF3COOH," "xNa" + The addition of names and structural formulas such as "[...]" should not be understood stoichiometrically in the case of such salts, but merely serves as an explanatory property regarding the salt-forming components present. This also applies if the synthetic intermediate or working example or its salt is obtained by the described manufacturing and / or purification steps in the form of a solvate, for example, a hydrate, of an unknown stoichiometric composition (if they are of a defined type).

[0284] Enantiomer 1 This is the enantiomer that first eluted from the column when preparative separation was performed under separation conditions (see, for example, Example 4A). Enantiomer 2 This is the second enantiomer to elute from the column. An exception is Example 4A, in which enantiomer 1 eluted second from the column and enantiomer 2 eluted first.

[0285] Diastereomer mixture 1 This refers to a compound in which the starting material is defined as enantiomer 1, reacts with a component containing at least one chiral center, and whose stereochemistry is undefined. Diastereomer mixture 2This defines a compound in which the starting material is defined as enantiomer 2, reacts with a component containing at least one chiral center, and the stereochemistry is undefined. Diastereomer 1 and Diastereomer 2 This defines the two compounds resulting from the chiral separation of the above diastereomer mixture 1. Diastereomer 3 and Diastereomer 4 This defines the two compounds resulting from the chiral separation of the diastereomer mixture 2 described above. stereoisomer 1 This defines a compound in which the starting material is defined as enantiomer 1, and its stereochemistry is defined by reacting it with a component containing at least one chiral center. stereoisomer 2 This defines a compound in which the starting material is defined as enantiomer 2, and its stereochemistry is defined by reacting it with a component containing at least one chiral center.

[0286] Experimental Section - Starting Compounds and Intermediates Example 1A tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (racemic mixture) [ka] A solution of tert-butyl 3-oxopiperidine-1-carboxylate [CAS No. 989-36-7] (300 g, 1.51 mol) in THF (1.50 L) and methanol (300 mL) was treated with benzylhydrazine carboxylate [CAS No. 5331-43-1] (250 g, 1.51 mol) and stirred at 25°C for 1 hour. Then, sodium borohydride (114 g, 3.01 mol) was added to the reaction mixture in small amounts, and the resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was cooled to 10°C, and the pH was adjusted to approximately 6 by adding a saturated solution of ammonium chloride dropwise. The aqueous phase was extracted with ethyl acetate (twice with 300 mL), and the combined organic layer was removed by solvent evaporation. The residue was dissolved in MTBE (300 mL), and petroleum ether (300 mL) was added to the solution. The resulting suspension was filtered, and the precipitate was washed with petroleum ether (100 mL) to obtain 400 g of the title compound (yield 76.0%) as a white solid. LC-MS: (Method 1)R t =0.832 min, MS(M-100+1=250.4).

[0287] Example 2A tert-butyl 3-hydrazinopiperidine-1-carboxylate acetate (racemic mixture) [ka] To a solution of tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (prepared in the same manner as in Example 1A, 1.20 kg, 3.43 mol) in ethanol (11.0 liters) and acetic acid (415 g, 6.91 mol, 395 mL), Pd / C (120 g, 20% purity) was added. The resulting suspension was stirred at 25°C for 12 hours under a hydrogen atmosphere (approximately 103 kPa (15 psi)). The mixture was filtered, and the precipitate was washed with ethanol (11.0 liters) to obtain a solution of the title compound in ethanol (945 g) as a black liquid, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.52 (s, 5H), 3.59 (d, J = 6.0 Hz, 12H), 3.30 - 3.24 (m, 2H), 2.75 - 2.71 (m, 2H), 1.38 - 1.34 (m, 1H), 1.20 - 1.18 (m, 1H), 1.10 (s, 9H) LC-MS: (Method 1)R t =0.263 min, MS(M-56+1=160.2).

[0288] Example 3A tert-butyl 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-carboxylate (racemic mixture) [ka] Tert-butyl 3-hydrazinopiperidine-1-carboxylate acetate (Example 2A, 945 g, 3.43 mol) in ethanol (20 liters) was treated with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (907 g, 3.78 mol). The resulting mixture was stirred at 25°C for 16 hours, diluted with saturated sodium bicarbonate solution (2.0 liters), and concentrated to approximately 5.0 liters. The resulting mixture was diluted with water (5.0 liters) and extracted with ethyl acetate (5.0 liters). The organic phase was washed with saturated sodium chloride solution (5.0 liters), and the solvent was removed by distillation. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate, 10:1) to obtain 548 g of the title compound (yield 41%). 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.90 (s, 1H), 4.33 - 3.09 (m, 5H), 3.26 - 3.12 (m, 1H), 2.89 - 2.61 (m, 1H), 2.35 - 2.05 (m, 2H), 1.98 - 1.78 (m, 1H), 1.71 - 1.51 (m, 1H), 1.50 - 1.37 (m, 9H), 1.32 (m, 3H)

[0289] Example 4A Ethyl 1-(piperidine-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (racemic mixture) [ka] tert-butyl 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-carboxylate (Example 3A, 548 g, 1.40 mol) was treated with a solution of hydrogen chloride in dioxane (4 M, 2.38 L), stirred at 25°C for 2 hours, and the solvent was removed by distillation. The residue was taken again in 1.0 L of water and extracted with MTBE (once with 500 mL). The aqueous phase was separated and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (twice with 1.0 L), and the combined organic layers were washed with saturated sodium chloride solution (1 L), dehydrated with sodium sulfate, and the solvent was removed by distillation to obtain 325 g of the title compound (80% yield). LC-MS: (Method 1)R t =0.955 min, MS(M+1)=299.2. The two enantiomers were separated by SFC [325g, column: Phenomenex-cellulose-2 (250mm × 50mm, 10μm); eluent: CO2 / (methanol + 0.1% aqueous ammonia); 75:25, 4.5 min; 1400 min] to obtain 103.0g of enantiomer 1 (Example 5A) and 110.1g of enantiomer 2 (Example 6A).

[0290] Example 5A Ethyl 1-(piperidine-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 1) [ka] For separation conditions, refer to Example 4A. Analysis SFC:R t =1.345 min, ee=99% [Column: Cellulose 2-3: 50 × 4.6 mm; Eluent: CO2 / [Methanol + 0.5% Diethylamine]: 95:5 to 60:40; Flow rate: 3.0 mL / min; Temperature: 35°C; UV detection: 220 nm, back pressure 100 bar]. LCMS (Method 2), R t =0.906 min, MS(M+1)=292.1. 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.89 (s, 1H), 4.50 - 4.47 (m, 1H), 4.31 - 4.25 (m, 2H), 3.24 - 3.05 (m, 4H), 2.70 - 2.67 (m, 1H), 2.10 - 2.02 (m, 2H), 1.92 - 1.79 (m, 1H), 1.74 - 1.56 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).

[0291] Example 6A Ethyl 1-(piperidine-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 2) [ka] For separation conditions, refer to Example 4A. Analysis SFC:R t =1.071 min, ee=99% [Column: Cellulose 2-3: 50 × 4.6 mm; Eluent: CO2 / [Methanol + 0.5% Diethylamine]: 95:5 to 60:40; Flow rate: 3.0 mL / min; Temperature: 35°C; UV detection: 220 nm, back pressure 100 bar]. LCMS (Method 2), R t=0.906 min, MS(M+1)=292.1. 1H-NMR (400 MHz, CDCl3) δ [ppm]: 7.91 (s, 1H), 4.58 - 4.41 (m, 1H), 4.35 - 4.23 (m, 2H), 3.70 - 3.56 (m, 1H), 3.31 - 3.12 (m, 2H), 3.11 - 3.02 (m, 1H), 2.75 - 2.62 (m, 1H), 2.15 - 2.02 (m, 2H), 1.92 - 1.79 (m, 1H), 1.74 - 1.56 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H).

[0292] Example 7A 2-Bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene [ka] A solution of 2-bromo-4-chlorophenol [CAS No. 695-96-5] (10.0 g, 48.2 mmol) in acetone (75 mL) was treated with potassium carbonate (13.3 g, 96.4 mmol), potassium iodide (12.0 g, 72.3 mmol), and 1-(chloromethyl)-4-methoxybenzene (7.55 g, 48.2 mmol). The resulting mixture was stirred at 70°C for approximately 19 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was dehydrated with sodium sulfate and the solvent was removed by distillation. The residue was purified by flash chromatography (silica gel, cyclohexane / ethyl acetate gradient) to obtain 13.8 g of the title compound (yield 86%). LC-MS (Method 4):R t =2.48min;MS(ESIneg):m / z=324[MH] - . 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 3.349 (10.98), 5.124 (16.00), 6.949 (0.87), 6.954 (8.36), 6.957 (2.68), 6.965 (2.83), 6.968 (8.92), 6.973 (1.00), 7.218 (5.23), 7.233 (6.21), 7.380 (0.90), 7.384 (7.80), 7.399 (7.44), 7.402 (4.47), 7.406 (3.89), 7.417 (3.04), 7.421 (3.07), 7.697 (6.51), 7.702 (6.34).

[0293] Example 8A Ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 1) [ka] Under argon light, solutions of ethyl 1-[piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared in the same manner as in Example 5A, enantiomer 1, 75.0 g, 257 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared in the same manner as in Example 7A, 84.4 g, 257 mmol) in 1,4-dioxane (1.1 liter) were treated with Pd2dba3 (23.6 g, 25.7 mmol), rac-BINAP (32.1 g, 51.5 mmol), and cesium carbonate (252 g, 772 mmol). The resulting mixture was stirred at 100°C for 3 days and cooled to room temperature. The reaction mixture was diluted with aqueous sodium chloride solution (10%) and ethyl acetate, filtered through Celite, and washed with ethyl acetate. The aqueous phase of the filtrate was separated and extracted with ethyl acetate. The combined organic layers were washed with a 10% aqueous sodium chloride solution, dehydrated with sodium sulfate, and the solvent was removed by distillation. The residue was purified by flash chromatography (silica gel, dichloromethane / petroleum ether gradient) to obtain 119 g of the title compound (yield 71%). LC-MS (Method 4):R t =2.81 min;MS(ESIpos):m / z=538[M+H] + .

[0294] Example 9A Ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 1) [ka] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 8A, enantiomer 1, 119 g, 221 mmol) in dichloromethane (1.8 liters) was treated with trifluoroacetic acid (170 mL, 2.2 mol), and the resulting mixture was stirred at room temperature for 3 days. The reaction was carefully stopped with aqueous sodium bicarbonate (10%) until the pH became 8. The phases were separated. The organic layer was removed by solvent evaporation, and the residue was purified by flash chromatography (silica gel, dichloromethane / petroleum ether gradient) to obtain 85 g of the title compound (purity 90%, yield 92%). LC-MS (Method 4):R t =2.47min;MS(ESIpos):m / z=418[M+H] + .

[0295] Example 10A Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 1) [ka] Under argon, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 9A, enantiomer 1, 85.0 g, purity 90%, 184 mmol) in dichloromethane (520 mL) was cooled to -50°C and treated with triethylamine (77 mL, 550 mmol). Anhydrous trifluoromethanesulfonic acid (43 mL, 260 mmol) was added dropwise to the reaction mixture, and the resulting solution was stirred at -50°C for 1 hour. The reaction mixture was diluted with dichloromethane (520 mL) and ice-cold water (590 mL). The aqueous layer was extracted with dichloromethane (520 mL). The combined organic layers were washed once with ice-cold water (590 mL), dehydrated with sodium sulfate, and the solvent was removed by distillation. The residue was purified by flash chromatography (silica gel, dichloromethane / petroleum ether gradient) to obtain 94 g of the title compound (yield 93%). LC-MS (Method 4):R t =2.79min;MS(ESIpos):m / z=550[M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.259 (7.63), 1.271 (16.00), 1.282 (7.94), 1.771 (0.45), 1.779 (0.80), 1.786 (0.61), 1.793 (0.61), 1.800 (0.94), 1.807 (0.61), 1.821 (0.45), 1.932 (1.22), 1.955 (0.96), 2.099 (0.77), 2.106 (0.73), 2.120 (1.04), 2.126 (1.33), 2.138 (1.91), 2.820 (0.73), 2.825 (0.87), 2.841 (1.56), 2.845 (1.61), 2.861 (0.93), 2.865 (0.82), 3.140 (1.18), 3.159 (1.09), 3.186 (1.39), 3.204 (2.87), 3.222 (1.78), 3.318 (1.51), 3.324 (1.60), 3.336 (1.08), 3.342 (1.04), 4.247 (2.31), 4.259 (7.26), 4.270 (7.27), 4.282 (2.41), 4.669 (0.70), 4.679 (0.84), 4.686 (1.34), 4.694 (0.96), 4.704 (0.72), 4.711 (0.42), 7.286 (2.29), 7.290 (2.44), 7.300 (2.89), 7.304 (3.11), 7.415 (5.01), 7.430 (4.13), 7.457 (5.11), 7.461 (5.05), 8.123 (6.61).

[0296] Example 11A tert-butyl4-(4′-chloro-2′-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazole-1-yl]piperidine-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (enantiomer 1) [ka] Under argon, solutions of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 10A, enantiomer 1, 92.1 g, 167 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (78.0 g, 201 mmol) in toluene (840 mL) and ethanol (840 mL) were treated with aqueous sodium carbonate solution (250 mL, 2.0 M, 500 mmol) and Pd(PPh3)4 (9.68 g, 8.37 mmol). The resulting mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and the solvent was removed by distillation. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate gradient) to obtain 94 g of the title compound (yield 85%). LC-MS (Method 4):R t =3.19min;MS(ESIpos):m / z=662[M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (0.66), 0.008 (0.84), 1.038 (0.55), 1.088 (0.76), 1.232 (1.60), 1.250 (3.49), 1.268 (1.69), 1.419 (0.77), 1.431 (16.00), 1.989 (0.77), 2.957 (0.43), 3.127 (0.91), 3.140 (1.32), 3.152 (1.09), 3.457 (0.99), 3.470 (1.25), 3.481 (0.88), 4.211 (0.45), 4.228 (1.43), 4.246 (1.38), 4.264 (0.43), 6.985 (1.10), 7.007 (1.20), 7.068 (0.79), 7.073 (1.06), 7.089 (0.49), 7.109 (0.80), 7.114 (0.69), 7.146 (1.34), 7.166 (0.65), 7.433 (1.33), 7.455 (1.19), 8.062 (1.56).

[0297] Example 12A Ethyl 1-{1-[4-chloro-4′-(piperazine-1-yl)[1,1′-biphenyl]-2-yl]piperidine-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (enantiomer 1) [ka] tert-butyl 4-(4′-chloro-2′-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1′-biphenyl]-4-yl)piperazine-1-carboxylate (Example 11A, enantiomer 1, 93.0 g, 140 mmol) in dichloromethane (290 mL) was treated with a solution of hydrogen chloride in dioxane (350 mL, 4.0 M, 1.4 mol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to remove the solvent, and the residue was co-evaporated with MTBE to obtain 95 g (quantitative yield) of the title compound, which was used in the next step without further purification. LC-MS (Method 4): R t = 1.97 min; MS (ESIpos): m / z = 562 [M+H] + .

[0298] Example 13A Ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (enantiomer 1)

Chemical Formula

[0299] Experimental Section - Example Compounds Example 1 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazine-1-yl][1,1′-biphenyl]-2-yl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (enantiomer 1) [ka] An aqueous solution of lithium hydroxide (1.2 L, 1.0 M, 1.2 mol) was added to a solution of ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 13A, enantiomer 1, 77.0 g, 125 mmol) in a THF / methanol mixture (9:1) (1.5 L). The resulting mixture was stirred overnight at room temperature and acidified to approximately pH 2 with aqueous hydrogen chloride solution (2N). The reaction mixture was diluted with dichloromethane. The organic layer was washed with water, and the solvent was removed to obtain 74 g (quantitative) of the title compound, which was used in the next step without further purification. LC-MS (Method 4):R t =1.74 min;MS(ESIpos):m / z=590[M+H] + . 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.830 (0.48), 0.841 (0.49), 1.009 (16.00), 1.020 (16.00), 1.045 (0.89), 1.094 (1.29), 1.187 (0.45), 1.363 (0.58), 1.528 (0.64), 1.549 (0.68), 1.750 (2.54), 1.755 (2.82), 1.760 (5.81), 1.766 (2.92), 1.771 (2.27), 1.919 (0.75), 1.926 (0.61), 1.940 (0.72), 1.946 (0.67), 2.003 (0.92), 2.019 (0.59), 2.105 (0.70), 2.117 (0.84), 2.128 (0.67), 2.579 (0.64), 2.863 (1.29), 2.981 (1.01), 2.998 (1.83), 3.016 (1.09), 3.051 (1.01), 3.069 (0.93), 3.216 (1.08), 3.238 (1.70), 3.256 (1.35), 3.573 (0.51), 3.594 (2.25), 3.604 (4.74), 3.615 (1.96), 4.383 (0.57), 4.394 (0.64), 4.400 (0.96), 4.407 (0.64), 4.418 (0.51), 7.033 (4.04), 7.048 (4.15), 7.082 (3.12), 7.085 (3.80), 7.099 (1.74), 7.102 (1.19), 7.113 (2.42), 7.116 (2.08), 7.155 (4.12), 7.168 (2.53), 7.473 (4.69), 7.488 (4.22), 8.020 (5.33).

[0300] Example 2 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazine-1-yl][1,1′-biphenyl]-2-yl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (enantiomer 1) [ka] Method A A solution of 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazine-1-yl][1,1′-biphenyl]-2-yl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 1, enantiomer 1, 78.0 g, 132 mmol) in diethyl ether (1.5 L) was treated with a solution of hydrogen chloride in diethyl ether (150 mL, 150 mmol). The resulting mixture was stirred overnight at room temperature, and the solvent was removed by distillation to obtain 82 g (quantitatively) of the title compound. LC-MS (Method 4):R t =1.77 min;MS(ESIpos):m / z=590[M-HCl+H] + . 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.839 (0.40), 1.013 (0.67), 1.029 (15.68), 1.039 (16.00), 1.057 (0.67), 1.081 (1.77), 1.092 (3.56), 1.104 (1.68), 1.360 (0.54), 1.520 (0.54), 1.540 (0.60), 1.741 (0.73), 1.750 (0.52), 1.761 (0.83), 1.921 (0.56), 1.927 (0.52), 1.941 (0.61), 1.947 (0.58), 2.004 (0.77), 2.020 (0.52), 2.147 (0.46), 2.158 (0.88), 2.169 (1.10), 2.180 (0.89), 2.192 (0.47), 2.578 (0.57), 2.984 (0.91), 2.995 (1.90), 3.004 (3.37), 3.016 (1.95), 3.044 (0.88), 3.062 (0.77), 3.119 (0.77), 3.125 (0.78), 3.135 (1.02), 3.145 (0.85), 3.151 (0.86), 3.244 (0.80), 3.258 (0.71), 3.361 (1.04), 3.368 (0.87), 3.380 (3.28), 3.391 (1.89), 3.403 (1.41), 3.570 (1.41), 3.589 (1.33), 3.603 (0.52), 3.785 (0.79), 3.814 (0.99), 3.838 (0.75), 4.383 (0.46), 4.394 (0.53), 4.400 (0.79), 4.407 (0.55), 4.418 (0.46), 7.055 (3.42), 7.070 (3.66), 7.085 (2.44), 7.089 (3.02), 7.105 (1.54), 7.108 (1.13), 7.118 (2.11), 7.121 (1.92), 7.157 (3.63), 7.171 (2.19), 7.485 (3.98), 7.500 (3.68), 8.023 (4.23), 10.650 (0.49).

[0301] Method B Ethyl 1-[1-{4-chloro-4′-[4-(2-methylpropyl)piperazin-1-yl][1,1′-biphenyl]-2-yl}piperidine-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared in the same manner as in Example 13A, enantiomer 1, 149 mg, 241 μmol) was dissolved in THF / ethanol (6.3 / 0.63 mL). 1 M aqueous lithium hydroxide solution (2.4 mL, 2.4 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was removed from the mixture, then it was acidified and purified using preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). The product fractions were combined and the solvent was removed. The residue was then dissolved in acetonitrile, mixed with 0.1 M hydrochloric acid / dioxane, and carefully removed the solvent at 30°C (3 times), followed by lyophilization. 130 mg of the target compound (85% of the theoretical value) was obtained. LC-MS (Method 4):R t =1.81 min;MS(ESIpos):m / z=590[M-HCl+H] + . 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.014 (15.69), 1.025 (16.00), 1.522 (0.64), 1.543 (0.70), 1.747 (0.89), 1.769 (0.75), 1.916 (0.67), 1.935 (0.74), 2.003 (0.95), 2.020 (0.62), 2.133 (0.48), 2.144 (0.96), 2.155 (1.17), 2.166 (0.94), 2.177 (0.49), 2.588 (0.65), 2.605 (1.20), 2.624 (0.66), 2.968 (0.93), 2.986 (1.83), 3.006 (2.63), 3.017 (3.24), 3.027 (1.95), 3.052 (1.01), 3.070 (0.94), 3.115 (0.97), 3.133 (1.36), 3.148 (1.12), 3.230 (1.08), 3.251 (1.98), 3.273 (2.05), 3.292 (1.01), 3.578 (1.97), 3.597 (1.82), 3.800 (1.79), 3.823 (2.21), 3.841 (2.82), 4.367 (0.59), 4.385 (1.02), 4.403 (0.56), 7.051 (3.88), 7.065 (4.03), 7.092 (3.43), 7.110 (1.41), 7.123 (2.32), 7.155 (3.64), 7.169 (1.99), 7.486 (4.35), 7.501 (3.97), 8.028 (4.91), 10.135 (0.55). [α] D 20 = -68.23°, c = 0.49 g / 100 cm 3 Trichloromethane.

[0302] Comparative Example 174 (WO2012 / 058132) 1-{1-[4-chloro-4′-(4-cyclopropylmethylpiperazine-1-yl)[biphenyl]-2-yl]pyridine-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] The compound was synthesized according to the procedure disclosed in WO2012 / 058132 (Experimental section, pp. 58-84).

[0303] B. Evaluation of pharmacological efficacy and pharmacokinetic profiles The following abbreviations will be used. ATP: Adenosine triphosphate Brij35: Polyoxyethylene (23) Lauryl Ether BSA: Bovine serum albumin DTT: Dithiothreitol TEA: Triethanolamine

[0304] physiological research The examples and experimental procedures described herein are for illustrative purposes only, and the present invention is not limited to the given examples.

[0305] The following assays can be used to illustrate the commercial utility of the compounds according to the present invention. The examples were tested one or more times with the selected biological assay. If multiple tests were performed, the data were reported as either the mean or the median, in which case, The mean, also called the arithmetic mean, represents the sum of the obtained values ​​divided by the number of tests, and The median is the middle value when a set of values ​​is sorted in ascending or descending order. If the number of values ​​in a dataset is odd, the median is the middle value. If the number of values ​​in a dataset is even, the median is the arithmetic mean of the two middle values.

[0306] The examples were synthesized one or more times. When multiple syntheses were performed, the data from the physiological assay represent the average value calculated using the dataset obtained from one or more synthesis batches.

[0307] The in vitro activity of the compounds of the present invention can be demonstrated by the following assay.

[0308] The pharmacological effects of the compounds of the present invention can be demonstrated by the following assay.

[0309] B-1. Effects on recombinant guanylate cyclase reporter cell lines The cellular activity of the compounds according to the present invention was measured using a recombinant guanylate cyclase reporter cell system according to the method described in F. Wunder et al, Anal. Biochem. 339, 104-112 (2005).

[0310] Typical MEC value (MEC = minimum effective concentration) and EC of the compound of the present invention 50 The values ​​(semi-maximal effective concentration) are shown in the table below (in some cases, as the average value from individual measurements).

[0311] Table 2: [Table 2]

[0312] B-2. In vitro vasodilatory effect Rabbits were euthanized under deep anesthesia and bled. The aorta was removed, the attached tissue was removed, and it was divided into 1.5 mm wide rings. These rings were individually placed under prestress in a 5 mL organ bath containing a Krebs-Henselite solution sprayed with carbogen at 37°C, with the following composition (each mM): sodium chloride: 119, potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2; sodium bicarbonate: 25; glucose: 10. Phenylephrine was added to the bath cumulatively while increasing the concentration to induce contraction. After several control cycles, the amount of the study substance was further increased with each subsequent addition, and the magnitude of the contraction was compared to the magnitude of the contraction obtained immediately before. Using this, the concentration (IC) required to reduce the magnitude of the control value by 50% was determined. 50 The value was calculated. The standard administration volume is 5 μL, and the DMSO content in the bath solution corresponds to 0.1%.

[0313] B-3. Blood pressure measurement in anesthetized rats Male Wistar rats weighing 300-350g were anesthetized with thiopental (100mg / kg ip). After tracheostomy, a catheter was inserted into the femoral artery to measure blood pressure. The test substance was administered orally by forced ingestion or intravenously via the femoral vein as a liquid (Stasch et al., Br. J. Pharmacol. 2002;135:344-355).

[0314] B-4. Wireless telemetry of blood pressure in unanesthetized spontaneously hypertensive rats For blood pressure measurements in unanesthetized rats, as described below, a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI (Data Sciences International) in the United States was used. The system consists of three main components. Embedded transmitter (Physiotel® telemetry transmitter) A receiver (Physiotel® receiver) linked to the data acquisition computer via a multiplexer (DSI Data Exchange Matrix 2.0). This telemetry system makes it possible to continuously record the blood pressure, heart rate, and body movement of non-anesthetic animals in their normal habitat.

[0315] animal materials The study was conducted in adult female spontaneously hypertensive rats (SHR Okamoto) weighing >200g. SHR / NCrl, from the Okamoto Kyoto School of Medicine, 1963, were crosses of male Wistar Kyoto rats with significantly elevated blood pressure and female rats with slightly elevated blood pressure, and were transferred to the National Institutes of Health (NIH) in the F13 generation.

[0316] After the transmitter was implanted, the experimental animals were housed individually in Type 3 macrolon cages. The experimental animals had free access to standard feed and water. The day-night rhythm in the laboratory was altered by changing the room's lighting at 6 AM and 7 PM.

[0317] Embedding of the transmitter The HD S 10 telemetry transmitters used were surgically implanted in experimental animals under sterile conditions at least 14 days prior to the first experimental use. Animals implanted in this manner can be used repeatedly after the wound has healed and the implant has taken hold. For transplantation, fasted animals were anesthetized with isoflurane (Rimadyl analgesia), and a large area of ​​the abdomen was shaved and disinfected. After opening the abdominal cavity along the linea alba, the liquid-filled measurement catheter of this system was inserted into the descending aorta cranially from the bifurcation and fixed with tissue adhesive (VetBonD™, 3M). The transmitter housing was fixed to the abdominal wall muscle inside the abdominal cavity, and the wound was closed layer by layer. To prevent infection, antibiotics (ursocyclin 10% pro inj., Serumwerk, sc) were administered postoperatively.

[0318] Substances and solutions Unless otherwise stated, the test substance was administered orally to one group of animals (n=6) in each case. The test substance was dissolved in a suitable solvent mixture or suspended in 0.5% tyloses according to the administration volume of 2 mL / kg. A group of animals treated with solvents was used as a control.

[0319] Experimental Procedure The current telemetry measurement system is configured for 24 animals. Each experiment was recorded under the experiment number (Year / Month / Day). Each rat fitted with the device living in the system was assigned a separate receiving antenna (RPC-1 receiver, DSI). The embedded transmitter can be activated externally via a built-in magnetic switch. It was switched to transmit mode in preparation for the experiment. The transmitted signal can be detected online and processed accordingly by the data acquisition system (Physio Tel HD, DSI). The data was stored in a file created specifically for this purpose and numbered with an experiment number for each case.

[0320] Following standard procedures, the following were measured for 10 seconds in each case: Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Mean arterial pressure (MAP) Heart rate (HR) Activity (TEMP).

[0321] Measurements were acquired under computer control at 5-minute intervals. The raw data, obtained as absolute values, was corrected graphically using the atmospheric pressure (Ambient Pressure Reference Monitor; APR-1) measured at that time, and saved as individual data. Further technical details were found in the detailed documentation from the manufacturer (DSI).

[0322] Unless otherwise specified, the test substance was administered at 9:00 AM on the day of the test. The parameters listed above were measured over a 24-hour period after administration.

[0323] evaluation After the trial, the collected individual data were classified using analysis software (Ponemah V 6.x). The data from two hours prior to administration was used as a blank value, and the selected data set covered the period from 7:00 AM on the trial day to 9:00 AM the following day.

[0324] The data was smoothed over a predetermined period by determining the mean (30-minute average) and transferred to a storage medium as an Excel file. The pre-classified and compressed measurements were then transferred to an Excel template and presented as a table. The obtained data was saved in a dedicated file with an experiment number assigned to each test day. The results and test protocols were saved in paper form in files, classified by number.

[0325] Literature: Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Mussig, Georg Ertl and Bjoern Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227- 270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4): 783-787, 1994.

[0326] B-5. Determination of pharmacokinetic parameters after intravenous and oral administration. The pharmacokinetic parameters of the compounds according to the present invention were measured in male Wistar rats and / or female beagle dogs and / or cynomolgus monkeys and / or male CD-1 mice. Intravenous administration in mice and rats was performed using species-specific plasma / DMSO formulations, and in dogs and monkeys using water / PEG400 / ethanol formulations. In all animal species, oral administration of the dissolved substance was performed by forced oral administration based on water / PEG400 / ethanol formulations.

[0327] An internal standard (which may be a chemically unrelated substance) was added to a sample of the compound of the present invention, a calibration sample, and qualifiers, and the protein was precipitated with excess acetonitrile. A buffer solution matched to the LC conditions was added, followed by vortex stirring and centrifugation at 1000 g. The supernatant was analyzed by LC-MS / MS using a C18 reversed-phase column and a variable mobile phase mixture. The substance was quantified by peak height or area from the extracted ion chromatogram of a specific selected ion monitoring experiment.

[0328] Using the measured plasma concentration / time plot, a validated pharmacokinetic calculation program calculates AUC, C max t 1 / 2 Pharmacokinetic parameters such as terminal phase half-life, bioavailability (F), mean residence time (MRT), and clearance (CL) were calculated.

[0329] Since the quantification of the substance was performed in plasma, it was necessary to determine the blood / plasma distribution of the substance in order to adjust the pharmacokinetic parameters accordingly. To this end, a predetermined amount of the substance was incubated in K3 EDTA whole blood of the target animal species for 20 minutes using a rocking roller mixer. After centrifugation at 1000g, the plasma concentration was measured (by LC-MS / MS; see above), and C blood / C plasma It was determined by calculating the ratio of the values.

[0330] Table 3 shows data from rats after intravenous administration of representative compounds of the present invention. Table 3: [Table 3]

[0331] Table 4 shows the data from rats after oral administration of representative compounds of the present invention. Table 4: [Table 4]

[0332] Table 5 shows data after intravenous administration of representative compounds of the present invention to dogs. Table 5: [Table 5]

[0333] Table 6 shows data from dogs after oral administration (PO) of representative compounds of the present invention. Table 6: [Table 6]

[0334] The compounds according to the present invention exhibit superior pharmacokinetic (PK) properties compared to compounds disclosed in the prior art (WO2012 / 058132) (see Experimental Section, Tables 3-6). For example, Example 2 of the present invention showed lower plasma clearance (CL) in rats and dogs compared to the prior art compound disclosed as Example 174 in WO2012 / 058132. plasma ) (up to 10 times), thus showing a much higher exposure. Example 2 also shows a long half-life and mean residence time (MRT) in all test animal species after po (oral) administration. The remarkably low plasma clearance of Example 2 and, as a result, very high exposure (AUC) with good bioavailability after po administration in all test animal species. norm (Due to exposure and area under curve normalization), a clear superiority in pharmacokinetic (PK) properties is observed compared to Example 174 disclosed in WO2012 / 058132.

[0335] B-6. Metabolic test To determine the metabolic profile of the compounds of the present invention, the compounds were generally incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes, or fresh primary cultured hepatocytes from various animal species (e.g., rats, dogs) and human-derived sources to obtain and compare information on substantially complete hepatic phase I and II metabolism, as well as the enzymes involved in the metabolism.

[0336] The compounds of the present invention were incubated at a concentration of approximately 0.1–10 μM. To achieve this objective, stock solutions of the compounds of the present invention at a concentration of 0.01–1 mM in acetonitrile were prepared and then added to the incubation mixture by pipette to a 1:100 dilution. 1 mM NADP + Liver microsomes and recombinant enzymes were incubated at 37°C in 50 mM potassium phosphate buffer pH 7.4, with or without an NADPH production system consisting of 10 mM glucose-6-phosphate and one unit glucose-6-phosphate dehydrogenase. Primary cultured hepatocytes were similarly incubated at 37°C in Williams E medium suspension. After 0–4 hours of incubation, the incubation mixture was stopped with acetonitrile (final concentration approximately 30%), and the proteins were centrifuged at approximately 15000 × g. The thus stopped samples were either analyzed directly or stored at -20°C until analysis.

[0337] The analysis was performed by high-performance liquid chromatography (HPLC-UV-MS / MS) using ultraviolet light and mass spectrometry detection. For this purpose, the supernatant of the incubation sample was chromatographically treated using a preferred C18 reversed-phase column and a variable mobile phase mixture of acetonitrile and either a 10 mM ammonium formate aqueous solution or 0.05% formic acid. The UV chromatogram, combined with the mass spectrometry data, proved useful for identifying metabolites, elucidating their structure, quantitative estimation, and quantitatively determining the metabolic reduction of the compound of the present invention in the incubation mixture.

[0338] B-7. Caco-2 permeability test The permeability of the test substance was determined with the help of the Caco-2 cell line, an established in vitro model for predicting permeability at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991). Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. 175 (3), 880-885). Caco-2 cells (ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were seeded in 24-well plates with inserts and cultured for 14-16 days. For permeability testing, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks buffer solution, containing Gibco / Invitrogen, 19.9 mM glucose and 9.8 mM HEPES). Tip-to-base permeability of the test substance (P app To determine the AB ratio, a solution containing the test substance was applied to the apical side of a Caco-2 cell monolayer, and the transport buffer was applied to the basal side. The basal-apical permeability (P) of the test substance was then determined. app To determine the BA (Permeability Index), a solution containing the test substance was applied to the basal side of a Caco-2 cell monolayer, and transport buffer was applied to the apical side. At the start of the experiment, samples were taken from each donor compartment to ensure a material balance. After incubation at 37°C for 2 hours, samples were taken from both compartments. The samples were analyzed by LC-MS / MS to determine the apparent permeability index (P). app The following calculations were performed. For each cell monolayer, the permeability of Lucifer Yellow was measured to ensure the integrity of the cell layer. In each test run, the permeability of atenolol (a marker of low permeability) and sulfasalazine (a marker of active excretion) was also measured as a quality control measure.

[0339] B-8. Measurement of solubility of a substance at buffer pH 6.5 2 to 4 mg of the test substance was dissolved in DMSO to a concentration of 50 g / L (solution A, 515 μg / L). To 10 μL of this solution, 960 μL of PBS buffer pH 6.5 was added, and the mixture was shaken in a 96-well plate at room temperature for 24 hours. Aliquoted samples were centrifuged at 42000 rpm for 30 minutes. The supernatant was diluted 1:10 and 1:1000 respectively with ACN / water (8:2). This diluted sample was analyzed by LC-MSMS.

[0340] Calibration: 10 μL of solution A was diluted with 823 μL of DMSO (final concentration: 600 μg / mL), which was further diluted 100-fold with ACN / water 8:2 (solution B). Starting from solution B, further dilution was performed with ACN / water 8:2 to target concentrations of 1.2, 12, 60 and 600 ng / mL, these four solutions were injected for MS measurement to obtain a calibration curve.

[0341] Optimization of MS method: Solution B was used for optimization of the MS method. PBS buffer (Puffer): 6.18 g of sodium chloride and 3.96 g of sodium dihydrogen phosphate were dissolved in 1 liter of distilled water, and the pH was adjusted to 6.5 with 1N sodium hydroxide.

[0342] LC-MSMS optimization: Optimization was performed using the following configuration. AB Sciex TRIPLE QUAD 4500, Agilent 1260 Infinity (G1312B), degasser (G4225A), column oven (G1316C or G1316A), CTC Analytics PAL injection system HTS-xt or HTC-xt.

[0343] Eluent A: 0.5 mL / L formic acid (50%) in water, Eluent B: 0.5 mL formic acid (50%) / L acetonitrile

Table 7

[0344] Water Quattro Micro MS, Agilent 1100 (G1312A), degassing agent (G1322A), column oven (G1316A), CTC Analytics PAL injection system HTS, eluent is the same as above. [Table 8] Autosampler: Automatic injection forward head setting available. Column: Stainless steel capillary Oven temperature: 22℃ Flow rate: Flow gradient Injection volume: 5μL MS method: Flow injection analysis (FIA) for optimization ("MS-OPTI"); Ionization modes: ABSciex-MS: ESI-pos / neg, Waters-MS: ESI-pos

[0345] HPLC method for MSMS quantification: Eluents A and B are the same as above.

[0346] ABSciex-MS [Table 9] Autosampler: No automatic injection forward head setting. Column: Waters OASIS HLB, 2.1 × 20 mm, 25 μm Column temperature: 30℃ Flow rate: 2.5mL Injection volume: 2μL Distributor (before MS) 1:20

[0347] Waters-MS [Table 10] Autosampler: Automatic injection forward head setting available. Column: Waters OASIS HLB, 2.1 × 20 mm, 25 μm Column temperature: 30℃ Flow rate: 2.5mL Injection volume: 5μL Distributor (before MS): 1:20 MS method: Multiple reaction monitoring (MRM)

[0348] B-9. Measurement of solubility from solids For each solvent, 0.5–1 mg (accurate weight) of the test substance, 2–3 glass pearls (3 mm in diameter), and 1.0 mL of each solvent were packed into an Eppendorf plastic vial. The vials were closed and shaken at room temperature for 24 hours (1400 rpm; Thermomixer, Eppendorf). Subsequently, 230 μL each of the solution / suspension was transferred to one or more centrifugation vials (Beckman Coulter) and centrifuged at 42000 rpm for 30 minutes (Beckman Coulter Optima L90). At least 100 μL of the supernatant was withdrawn and further diluted with DMSO at two dilution strengths: 1:5 and 1:50 (the latter obtained from the 1:5 dilution step by subsequent addition of DMSO). This liquid handling was performed manually or with the help of a pipetting robot (Lissy, Zinsser Analytic).

[0349] Calibration solutions of the test compound in DMSO were prepared for HPLC quantification. Starting with an initial concentration of 600 μg / mL, three calibration solutions were prepared: 100 μg / mL, 20 μg / mL, and 2.5 μg / mL (manually or by Lissy).

[0350] Both the calibration solution and the supernatant were analyzed by HPLC / UV detection at appropriate wavelengths. Solubility was determined using a linear calibration curve.

[0351] HPLC system: Hewlett Packard / Agilent HPLC systems, G1311A+G1316A+G1315B and G1312A+G1316A+G1315A Injector System: CTC-Analytik HTC PAL Alternatively, with the Agilent UPLC System (G7117C, G7116B, G7167B, and G7120) Oven temperature: 30°C, Detection: 210 and / or 254 nm, Injection volume: 20 μL Eluent A: 0.1% TFA / water, Eluent B: 0.1% TFA / acetonitrile Column: ZORBAX Extend-C18, 3.0 × 50 mm, 3.5 μm

[0352] gradient: [Table 11]

[0353] C. Examples of work with pharmaceutical compositions The compounds of the present invention can be converted into pharmaceutical formulations by the following method.

[0354] tablet : composition : 100 mg of the compound according to the present invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP25) (from BASF, Ludwigshafen, Germany), and 2 mg of magnesium stearate. Tablet weight: 212 mg. Diameter: 8 mm, radius of curvature: 12 mm.

[0355] manufacturing : A mixture of the compound of the present invention, lactose, and starch is granulated with a 5% PVP aqueous solution (w / w). The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is compressed into tablets using a conventional tablet press (see above for tablet dimensions). The guideline value for tableting is a compression force of 15 kN.

[0356] Oral administration suspension: composition : 1000 mg of the compound of the present invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA), and 99 g of water. 10 mL of oral suspension corresponds to a single dose of 100 mg of the compound of the present invention.

[0357] manufacturing : Rhodigel is suspended in ethanol, and the compound of the present invention is added to the suspension. Water is added while stirring. The mixture is stirred for about 6 hours until the swelling of the Rhodigel is complete.

[0358] Oral administration solution: composition : 500 mg of the compound of the present invention, 2.5 g of polysorbate, and 97 g of polyethylene glycol 400. 20 g of the oral solution corresponds to a single dose of 100 mg of the compound of the present invention.

[0359] manufacturing : The compound of the present invention is suspended in a mixture of polyethylene glycol and polysorbate while stirring. The stirring process is continued until the compound of the present invention is completely dissolved.

[0360] Intravenous solution : The compound according to the present invention is dissolved in a physiologically tolerable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG400 solution) at a concentration below its saturation solubility. The solution is sterilized by filtration and used to fill sterile, pyrogen-free syringes.

Claims

1. Formula (I) below: 【Chemistry 1】 [In the formula, R １ This represents hydrogen or halogen, R ２ This represents hydrogen or halogen, R ３ This represents chloro or trifluoromethyl, R ４ is hydrogen or C １ -C ４ - Represents alkyl, R ５ represents C １ -C ６ 1 -C6 alkyl, X １ This represents nitrogen or carbon, X ２ [This represents nitrogen or carbon.] Compounds thereof or salts thereof, solvates thereof, or solvates of salts thereof.

2. R １ However, these represent hydrogen and fluorine. R ２ However, these represent hydrogen and fluorine. R ３ However, it represents chloro or trifluoromethyl, R ４ However, it represents hydrogen or methyl, R ５ However, it represents isobutyl, X １ However, it represents nitrogen or carbon, X ２ However, representing nitrogen or carbon, The compound described in claim 1, or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

3. The following formula: 【Chemistry 2】 The compound according to claim 1 or 2, or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R ５ C 2-C ４ - A method for producing an alkyl compound or a salt thereof, a solvate thereof, or a solvate of a salt thereof, In the first stage [B], the compound of the following formula (IV): 【Transformation 3】 [In the formula, R １ , R ２ , R ３ , R ４ and X １ and X ２ [This has the same meaning as defined in claim 1.] In the presence of a reducing agent, a suitable solvent and a base, a compound of the following formula (III): 【Chemistry 4】 [In the formula, R ５ａ is C １ -C ３ - Represents alkyl. Reacts with ] to form the compound of formula (II) below: 【Transformation 5】 [In the formula, R １ , R ２ , R ３ , R 4 and X １ and X ２ [The term has the same meaning as defined in claim 1, and R5 is C2-C4-alkyl.] Having obtained, In the second stage [A], When the compound of formula (II) is reacted with a base, the compound of formula (I) below is obtained: 【Transformation 6】 [In the formula, R １ , R ２ , R ３ , R 4 and X １ and X ２ [The term has the same meaning as defined in claim 1, and R5 is C2-C4-alkyl.] To obtain Optionally, the compound of formula (I) is used in the third step [A]. ＊ Then, in a suitable solvent, in the presence of hydrochloric acid, the salt corresponding to the following formula (Ia): 【Transformation 7】 How to convert it.

5. Compound of formula (I-2): 【Transformation 8】 (I-2) or a method for producing the salt thereof, the solvate thereof, or the solvate of the salt thereof, In the first stage [B], the compound of the following formula (IV-2): 【Chemistry 9】 (IV-2) This is reacted with 2-methylpropanal in the presence of a reducing agent, a suitable solvent, and a base to obtain the compound of the following formula (II-2): 【Chemistry 10】 (II-2) Having obtained, In the second stage [A], When the compound of formula (II-2) is reacted with a base, the compound of formula (I-2) below is obtained: 【Chemistry 11】 (I-2) To obtain Optionally, in step 3 [A]*, a compound of formula (I-2) is subjected to the corresponding salt of formula (Ia-2) below in a suitable solvent in the presence of hydrochloric acid: 【Chemistry 12】 (Ia-2) How to convert it.

6. A compound according to any one of claims 1 to 3, for use in the treatment and / or prevention of disease.

7. A compound according to any one of claims 1 to 3, for use in the treatment and / or prevention of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcer (DFU).

8. Use of the compound according to any one of claims 1 to 3 for the manufacture of a pharmaceutical product for use in the treatment and / or prevention of disease.

9. Use of the compound according to any one of claims 1 to 3 for manufacturing a pharmaceutical product for use in the treatment and / or prevention of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcer (DFU).

10. A pharmaceutical product comprising the compound according to any one of claims 1 to 3, in combination with an inert and non-toxic pharmaceutically suitable excipient.

11. The pharmacopoeia according to claim 10 for use in the treatment and / or prevention of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcers (DFU).

12. A method for producing a pharmaceutical composition for use in the treatment and / or prevention of heart failure (HFrEF, HFmrEF and HFpEF), hypertension (HTN), chronic and diabetic kidney disease (CKD, DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), and diabetic foot ulcer (DFU) in humans and animals by administering at least one therapeutically effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutical according to claim 10 or 11, or a pharmaceutical obtained according to claim 8 or 9, characterized in that the pharmaceutical composition contains a compound according to any one of claims 1 to 3, or a pharmaceutical according to claim 10 or 11.

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