Substituted pyrazolopyridine carboxylic acids

Abstract

This invention relates to substituted pyrazolopiperidine carboxylic acids, their salts and methods of preparation thereof, and also to their use in the preparation of medicaments for the treatment and / or prevention of diseases, particularly cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and 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), and wound healing disorders such as diabetic foot ulcers (DFU).

Description

[0001] This invention relates to substituted pyrazolopiperidine carboxylic acids, their salts, and methods for their preparation, as well as their use in the preparation of medicaments for the treatment and / or prevention of diseases, particularly cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH) and other diseases, preferably neurodegenerative diseases and various forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), and wound healing disorders such as diabetic foot ulcers (DFU).

[0002] Furthermore, the same pathophysiological mechanisms described above are also effective when transfusing blood to patients with indications for transfusion (e.g., by increasing the concentration of free hemoglobin through storage, for example).

[0003] Furthermore, in the future, the combination of sGC activators with synthetic hemoglobin oxygen carriers may alleviate the side effects caused by reduced NO availability that have been found to date [Weiskopf, Anaesthesia & Analgesia, 110:3;659-661, 2010], thus allowing for clinical application.

[0004] Cyclic guanosine monophosphate (cGMP) is one of the most important cell signaling systems in mammalian cells. It forms the NO / cGMP system together with nitric oxide (NO), which transmits hormones and mechanotransmitters released by endothelial cells. Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). Currently, representatives of this family can be divided into two categories based on structural characteristics and ligand type: granular guanylate cyclases stimulated by natriuretic peptide and soluble guanylate cyclases stimulated by NO. Soluble guanylate cyclases consist of two subunits, and each heterodimer likely contains a heme, which is part of the regulatory site. The latter is crucial for the activation mechanism. NO can bind to the iron atom of heme, thereby significantly increasing enzyme activity. In contrast, formulations without heme cannot be stimulated by NO. Carbon monoxide (CO) can also attach to the central iron atom of heme, but the stimulatory effect of CO is significantly less than that of NO.

[0005] By producing cGMP and regulating the phosphodiesterases, ion channels, and protein kinases generated therefrom, guanylate cyclases play a crucial role in various physiological processes, particularly in smooth muscle cell relaxation and proliferation, platelet aggregation and adhesion, neuronal signaling, and the pathogenesis of diseases resulting from impaired processes. Under pathophysiological conditions, the NO / cGMP system may be inhibited, which may lead to, for example, hypertension, platelet activation, increased cell proliferation and fibrosis, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke, and myocardial infarction.

[0006] A NO-independent approach to treating such diseases and designed to affect cGMP signaling pathways in organisms is promising because it is efficient and has few expected side effects.

[0007] Compounds such as organic nitrates, which act based on NO, have so far been specifically used for the therapeutic stimulation of soluble guanylate cyclase. NO is produced by biotransformation and activates soluble guanylate cyclase by attaching to the central iron atom of heme. In addition to side effects, the development of tolerance is one of the major drawbacks of this treatment [OV Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

[0008] In recent years, substances that can directly stimulate soluble guanylate cyclase (sGC) without pre-releasing NO have been discovered. The indazole derivative YC-1 is the first NO-independent but heme-dependent sGC stimulator [Evgenov et al., ibid.]. Based on YC-1, other substances with stronger potency than YC-1 and no associated inhibitory activity on phosphodiesterase (PDE) have been discovered. This led to the discovery of pyrazolopyridine derivatives BAY 41-2272, BAY 41-8543, BAY 63-2521, and BAY 102-1189. These compounds, along with the recently published structurally different substances CMF-1571 and A-350619, form a new class of sGC stimulators [Evgenov et al., ibid.]. A common characteristic of this class of substances is their NO-independent and selective activation of heme-containing sGCs. Furthermore, based on the stabilizing effect of the nitroso-heme complex, the sGC stimulators have a synergistic effect with NO binding on sGC activation. The exact binding site of sGC stimulants on sGC remains controversial. If the heme group is removed from soluble guanylate cyclase, the enzyme still retains detectable basal catalytic activity, i.e., it continues to form cGMP. None of the aforementioned stimulants can stimulate the remaining basal catalytic activity of heme-free enzymes [Evgenov et al., ibid.].

[0009] Furthermore, NO- and heme-independent sGC activators were discovered, with BAY 58-2667 being the prototype of such activators. These substances share the characteristic that, when bound to NO, they have only an additive effect on enzyme activation, and the activation of oxidized or heme-free enzymes is significantly higher than that of heme-containing enzymes [Evgenov et al., ibid.; JP Stasch et al., Br. J. Pharmacol. 136 (2002), 773; JP Stasch etal., J. Clin. Invest. 116 (2006), 2552]. Spectroscopic studies indicate that BAY 58-2667 replaces the oxidized heme groups that were only weakly attached to sGCs due to the weakening of the iron-histidine bond. The study also showed that the characteristic sGC heme-binding motif Tyr-x-Ser-x-Arg is essential for the interaction of the negatively charged propionic acid group of the heme group and the function of BAY58-2667. In this context, it is assumed that the binding site of BAY 58-2667 on sGC is the same as the binding site of heme [JP Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0010] The sGC activator Runcaciguat (Hahn et al., Drugs Future 43 (2018), 738, WO2012 / 139888) is currently undergoing clinical development by BAYER (https: / / www.clinicaltrials.gov / NCT04507061). Our understanding of the redox balance of sGC in health and disease is limited. Therefore, the therapeutic potential of sGC activators is not fully understood. However, since oxidative stress can provide sGC activators for heme-free sGC enzymes, sGC activators may have broader therapeutic potential, but this potential remains to be further identified and confirmed in the future.

[0011] The compounds described in this invention can now also activate heme-free soluble guanylate cyclases. This is also supported by the fact that, firstly, these novel activators do not synergize with NO on heme-containing enzymes, and secondly, their effects cannot be blocked by the heme-dependent inhibitor of soluble guanylate cyclase, 1H-1,2,4-oxadiazolo[4,3-a]quinoxaloline-1-one (ODQ), but can even be enhanced by this inhibitor [see OV Evgenov et al., NatureRev. Drug Disc. 5 (2006), 755; JP Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0012] In WO 2012 / 058132, substituted pyrazolopyridine carboxylic acids are disclosed as sGC activators. These compounds do indeed possess a heteroaromatic pyridine moiety linking the pyrazolopyridine carboxylic acid to the remainder of the molecule, compared to the compounds of the present invention. Furthermore, the pyridine nitrogen has a different position than the piperidine nitrogen in the compounds of the present invention. However, in preclinical pharmacokinetic models, these compounds exhibit only general pharmacokinetic characteristics, such as moderate clearance (CL) and moderate half-life and mean residence time (MRT), after intravenous (iv) administration.

[0013] Therefore, one 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 and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and various forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), and wound healing disorders such as diabetic foot ulcers (DFU). These compounds exhibit favorable pharmacokinetic behavior, possess good pharmacological activity characteristics, and beneficial physicochemical properties (e.g., solubility).

[0014] Surprisingly, certain substituted pyrazolopiperidine carboxylic acids and their corresponding salts have been found to be highly efficient sGC activators, exhibiting favorable pharmacokinetic behavior, good pharmacological activity characteristics, and beneficial physicochemical properties (e.g., solubility).

[0015] This invention provides compounds of formula (I), their salts, their solvates, and solvates of their salts.

[0016] (I),

[0017] in

[0018] R 1 Represents hydrogen or halogen,

[0019] R 2 Represents hydrogen or halogen,

[0020] R 3 Represents chloro or trifluoromethyl.

[0021] R 4 Represents hydrogen or C1-C4-alkyl

[0022] R 5 Represents C1-C6-alkyl

[0023] X1 represents nitrogen or carbon.

[0024] X2 represents nitrogen or carbon.

[0025] The term "substitution" means that one or more hydrogen atoms on a specified atom or group are replaced by a group selected from the specified group, provided that the replacement does not exceed the normal valence state of the specified atom under normal conditions. Combinations of substituents and / or variables are allowed.

[0026] As used herein, the term "one or more," for example in the definition of substituents in compounds of general formula (I) of the present invention, means "1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more specifically 1, 2 or 3, or even more specifically 1 or 2."

[0027] In the context of this invention, unless otherwise stated, substituents are defined as follows:

[0028] The term “halogen” or “halogenated” as in combination, such as in a haloalkyl group, refers to a fluorine, chlorine, bromine or iodine atom, especially a fluorine, chlorine or bromine atom, or even more specifically, a fluorine or chlorine atom.

[0029] The terms "C1-C4 alkyl", "C1-C5 alkyl", and "C1-C6 alkyl" refer to straight-chain or branched saturated monovalent hydrocarbon groups containing 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, etc. 1-Ethylpropyl, 1,2-dimethylpropyl, neopentyl, 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, or isomers thereof. Specifically, the group has 1, 2, 3, or 4 carbon atoms (“C1-C4 alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, has 1, 2, or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl, or isopropyl.

[0030] The terms “C1-C6-haloalkyl,” “C2-C6-haloalkyl,” “C1-C4-haloalkyl,” “C2-C4-haloalkyl,” “C1-C3-haloalkyl,” and “C1-C2-haloalkyl” represent straight-chain or branched saturated monovalent hydrocarbon groups, wherein “alkyl” is defined as above, and one or more hydrogen atoms are replaced by halogen atoms in the same or different ways. Specifically, the halogen atom is a fluorine atom. The C1-C6 haloalkyl groups are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl-1-yl, 1,1,1-trifluoropropyl-2-yl, 1,3-difluoropropyl-2-yl, 3-fluoropropyl-1-yl, 1,1,1-trifluorobutyl-2-yl, and 3,3,3-trifluoro-1-methyl-propyl-1-yl.

[0031] The terms "C1-C4-haloalkoxy" and "C1-C3-haloalkoxy" refer to straight-chain or branched saturated monovalent C1-C4-alkoxy or C1-C3-alkoxy (wherein the alkoxy group represents a straight-chain or branched saturated monovalent alkoxy group having 1 to 4 or 1 to 3 carbon atoms, such as and preferably methoxy, ethoxy, n-propoxy, isopropoxy), wherein one or more hydrogen atoms are replaced by halogen atoms in the same or different ways. In particular, the halogen atom is a fluorine atom. For example, the C1-C3 haloalkoxy group is fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or pentafluoroethoxy.

[0032] The term "C3-C6 cycloalkyl" refers to a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms. For example, the C3-C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0033] The compounds described in this invention are compounds of formula (I) and their salts, their solvates and their solvates, provided that the compounds covered by formula (I) and described in detail below are not salts, solvates and solvates of salts.

[0034] Depending on their structures, the compounds of the present invention can exist in different stereoisomeric forms, i.e., as configurational isomers, or, where appropriate, as conformational isomers (enantiomers and / or diastereomers, including rotational and rotation-resistant isomers). Therefore, the present invention comprises enantiomers and diastereomers, and mixtures thereof. Stereoisomerically homogeneous components can be separated from mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, chromatography, particularly HPLC on achiral or chiral phases, is preferred.

[0035] This invention includes all possible tautomers of the compounds of this invention, as a single tautomer, or as any mixture of said tautomers in any proportion.

[0036] In this invention, the term "enantiomerically pure" should be understood as the presence of an enantiomer excess of greater than 95%, preferably greater than 97%, in terms of the absolute configuration of the chiral center. In this case, the enantiomer excess value (ee value) is calculated by evaluating the corresponding HPLC chromatogram on the chiral phase using the following formula:

[0037] ee = [E A (Area%) -E B (Area%) x 100% / [E A (Area%) + E B (area%)]

[0038] (E A : More enantiomers, E B (fewer enantiomers)

[0039] This invention also covers all suitable isotopic variants of the compounds of this invention. Isotopic variants of the compounds of this invention are understood herein as compounds in which at least one atom is replaced by another atom of the same atomic number but with a different atomic mass than that commonly or predominantly found in nature. Examples of isotopes included in the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as... 2 H (deuterium) 3 H (tritium), 13 C 14 C 15 N、 17 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 variants of the compounds of the present invention, particularly variants containing one or more radioactive isotopes, can be beneficial for studies such as the mechanism of action or the distribution of active ingredients in vivo; they are also relatively easy to prepare and detect, especially using... 3 H or 14 Compounds labeled with the C isotope are suitable for this purpose. Furthermore, the incorporation of an isotope (e.g., deuterium) can lead to specific therapeutic effects due to enhanced metabolic stability of the compound, such as prolonged in vivo half-life or reduced required active dose. Therefore, in certain circumstances, such modification of the compounds of the present invention can also constitute a preferred embodiment of the invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by means of appropriate isotopic modification of the corresponding reagents and / or starting compounds, as described in the methods further described below and the steps described in the examples.

[0040] The preferred salts in this invention are physiologically acceptable salts of the compounds of this invention. However, this invention also includes salts that are not inherently suitable for pharmaceutical applications but can be used for purposes such as isolating or purifying the compounds of this invention.

[0041] Physiologically acceptable salts of the compounds of this invention include acid addition salts of inorganic acids, carboxylic acids, and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

[0042] Physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, such as and 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, such as and preferably ethylamine, diethylamine, triethylamine, ethyl diisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, and choline.

[0043] This invention includes all possible salts of the compounds of this invention, as a single salt or any mixture of said salts in any proportion.

[0044] The solvates described in this invention refer to those compounds of the invention that form complexes in a solid or liquid state through coordination with solvent molecules. The compounds of the invention may contain a polar solvent, particularly, for example, water, methanol, or ethanol, as structural units of the compound's crystal lattice. Hydrates are a specific form of solvates coordinated with the aqueous phase. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates such as hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates are all possible. The invention includes all such hydrates or solvates.

[0045] Furthermore, the compounds described in this invention can exist as N-oxides, defined as compounds in which at least one nitrogen atom is oxidized in a known manner. This invention includes all such possible N-oxides.

[0046] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" includes compounds that may be biologically active or non-biologically active themselves, but which are converted into the compounds of the present invention during their residence time in the body (e.g., through metabolism or hydrolysis).

[0047] The preferred formula (I) includes compounds and their salts, solvates, and solvates of their salts, wherein...

[0048] R 1 Represents hydrogen and fluorine

[0049] R 2 Represents hydrogen and fluorine

[0050] R 3 Represents chlorine or trifluoromethyl

[0051] R 4 Represents hydrogen or methyl

[0052] R 5 Indicates C1-C5-alkyl

[0053] X1 represents nitrogen or carbon.

[0054] X2 represents nitrogen or carbon.

[0055] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0056] R 1 Represents hydrogen and fluorine

[0057] R 2 Represents hydrogen and fluorine

[0058] R 3 Represents chlorine or trifluoromethyl

[0059] R 4 Represents hydrogen or methyl

[0060] R 5 This indicates methyl, ethyl, n-propyl, isopropyl, 2,2'-dimethylpropyl, and isobutyl.

[0061] X1 represents nitrogen or carbon.

[0062] X2 represents nitrogen or carbon.

[0063] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0064] R 1 Represents hydrogen

[0065] R 2 Represents hydrogen

[0066] R 3 Represents chlorine or trifluoromethyl

[0067] R 4 Represents hydrogen or methyl

[0068] R 5 This indicates methyl, ethyl, n-propyl, isopropyl, 2,2'-dimethylpropyl, and isobutyl.

[0069] X1 represents carbon or CF.

[0070] X2 represents carbon.

[0071] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0072] R 1 Represents hydrogen

[0073] R 2 Represents hydrogen

[0074] R 3Represents chlorine or trifluoromethyl

[0075] R 4 Represents hydrogen

[0076] R 5 This indicates methyl, ethyl, n-propyl, isopropyl, 2,2'-dimethylpropyl, and isobutyl.

[0077] X1 represents carbon.

[0078] X2 represents carbon.

[0079] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0080] R 1 Represents hydrogen

[0081] R 2 Represents hydrogen

[0082] R 3 Represents chlorine

[0083] R 4 Represents hydrogen

[0084] R 5 Indicates isobutyl

[0085] X1 represents carbon.

[0086] X2 represents carbon.

[0087] Furthermore, compounds of the following formula and their salts, solvates thereof, or solvates of their salts are preferred.

[0088] .

[0089] Compounds of the following formula are particularly preferred

[0090] .

[0091] The present invention also provides a method for preparing a compound of formula (I) or a salt thereof, a solvate thereof or a solvate of a salt thereof, wherein

[0092] In step [B], in the presence of a reducing agent, a suitable solvent, and a base, the compound of formula (IV) is reacted with the compound of formula (III) to produce the compound of formula (II).

[0093] (IV),

[0094] Where R 1 R 2 R 3 R 4 And X1 and X2 are as defined above,

[0095] R 5a -CHO (III),

[0096] Where R 5a Represents C1-C3-alkyl, preferably isopropyl.

[0097] (II)

[0098] Where R 1 R 2 R 3 R 4 R 5 As defined above, X1 and X2,

[0099] and

[0100] In step [A],

[0101] The compound of formula (II) is reacted with a base to produce the compound of formula (I).

[0102] (I)

[0103] Where R 1 R 2 R 3 R 4 R 5 As defined above, X1 and X2,

[0104] Optionally, in the presence of a suitable acid and a suitable solvent, the compound of formula (I) is subjected to [A] in step three. * The salt is converted into the corresponding salt of formula (Ia).

[0105] (Ia)

[0106] Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are as defined above.

[0107] Reaction [A]* (salt formation)

[0108] The reaction [A]* is usually carried out in an inert solvent in the presence of an acid, preferably at atmospheric pressure in a temperature range of 0°C to 60°C.

[0109] Suitable acids for salt formation are typically 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, optionally added to water. Hydrogen chloride, hydrogen bromide, toluenesulfonic acid, methanesulfonic acid, or sulfuric acid are preferred.

[0110] Suitable inert solvents for salt formation include ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene 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'-dimethylacrylamide (DMPU), or N-methylpyrrolidone (NMP). Mixtures of the above solvents may also be used. Diethyl ether, dioxane, tetrahydrofuran, or mixtures of these solvents are preferred.

[0111] Reaction [A] (Ester hydrolysis)

[0112] The hydrolysis of the ester group in the compounds of Formula II is carried out by conventional methods, by treating the ester with an acid or a base in an inert solvent, wherein in the latter case, the initially formed salt is converted into a free carboxylic acid by acid treatment. In the case of tert-butyl esters, ester hydrolysis is preferably carried out with an acid.

[0113] Suitable inert solvents for these reactions are water or organic solvents commonly used for ester cracking. 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. In the case of basic ester hydrolysis, a mixture of water with dioxane, tetrahydrofuran, methanol, ethanol, and / or dimethylformamide, or a mixture of tetrahydrofuran with methanol or ethanol, is preferred. In the case of reaction with trifluoroacetic acid, dichloromethane is preferred; in the case of reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water is preferred.

[0114] Suitable bases are conventional inorganic bases. These particularly 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.

[0115] Acids suitable for ester hydrolysis are typically 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, optionally with the addition of water. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0116] Ester hydrolysis is usually carried out at temperatures ranging from -20°C to +120°C, preferably from 0°C to +80°C.

[0117] The compound of formula (II) is novel.

[0118] (II)

[0119] Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are as defined above.

[0120] In the presence of a reducing agent, a suitable base, and a suitable solvent, compounds of formula (II) can be synthesized from the starting compounds of the corresponding formula (IV) by reacting the compounds of formula (IV) with the compounds of formula (III) via [B] to produce compounds of formula (II).

[0121] (IV),

[0122] Where R 1 R 2 R 3 R 4 And X1 and X2 are as defined above,

[0123] R 5a -CHO(III),

[0124] Where R 5a Represents C1-C3-alkyl, preferably isopropyl.

[0125] (II)

[0126] Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are as defined above.

[0127] Reaction [B] (reductive amination)

[0128] The reaction in step [B] is usually carried out in an inert solvent in the presence of a reducing agent, or, if appropriate, in the presence of a base and / or a dehydrating agent, preferably at atmospheric pressure in a temperature range of 0°C to 60°C.

[0129] The reducing agents suitable for reductive amination are alkali metal borohydrides commonly used for this purpose, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; sodium triacetoxyborohydride is preferred.

[0130] Adding acids, especially acetic acid, and / or dehydrating agents, such as molecular sieves, trimethyl orthoformate, or triethyl orthoformate, to these reactions may be advantageous.

[0131] The base can be an organic base, such as a trialkylamine like triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, or diisopropylethylamine or pyridine. Bases, especially N,N-diisopropylethylamine and triethylamine, may be advantageous in these reactions.

[0132] Solvents suitable 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) or mixtures of these solvents; tetrahydrofuran is preferred.

[0133] The reaction is generally carried out at a temperature between 0°C and +60°C.

[0134] The aldehyde in formula (III) is commercially available, known, or can be synthesized from known raw materials by known methods.

[0135] The compounds of formula (IV) are novel.

[0136] (IV),

[0137] Where R 1 R 2 R 3 R 4 X1 and X2 are as defined above.

[0138] Compounds of formula (IV) can be synthesized by reacting the corresponding compound of formula (V) with [C] in the presence of a suitable acid and a suitable solvent:

[0139] (V),

[0140] Where R 1 R 2 R 3 R 4 And X1 and X2 are as defined above.

[0141] Reaction [C] (deprotection)

[0142] The reaction [C] is generally carried out in an inert solvent in the presence of a suitable acid, preferably at atmospheric pressure and at a temperature of 0°C to 60°C.

[0143] The acid is, for example, 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, optionally added to water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0144] Solvents suitable 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) or mixtures of such solvents; tetrahydrofuran is preferred.

[0145] The reaction is usually carried out at temperatures ranging from 0°C to +60°C.

[0146] Compound (V) is novel.

[0147] (V),

[0148] Where R 1 R 2 R 3 R 4 X1 and X2 are as defined above.

[0149] In the presence of a suitable palladium catalyst, a base, and a suitable solvent, compounds of formula (V) can be synthesized from the corresponding compounds of formula (VIII) by reacting the compounds of formula (VIII) with the compounds of formula (VI) via [D]:

[0150] (VIII),

[0151] Where R 1 R 2 and R 3 As defined above.

[0152] (VI).

[0153] Reaction [D](Suzuki coupling)

[0154] The reaction [D] is typically carried out in an inert solvent in the presence of a suitable palladium catalyst and a suitable base, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0155] The inert solvent used in reaction step [D] is, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; a hydrocarbon such as benzene, mixed xylenes, toluene, hexane, cyclohexane, or petroleum; or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile, or water. Mixtures of the above solvents may also be used. A mixture of dimethylformamide / water and toluene / ethanol is preferred.

[0156] Suitable bases for the reaction step are conventional inorganic bases. These particularly include alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide; alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate; or alkali metal or alkaline earth metal carbonates, such as carbonates of lithium, sodium, potassium, calcium, or cesium; or alkali metal hydrogen phosphates, such as disodium hydrogen phosphate or dipotassium hydrogen phosphate. Sodium carbonate or potassium carbonate are preferred bases.

[0157] Examples of suitable palladium catalysts for the reaction step [“Suzuki coupling”] are, for example, palladium on carbon, palladium(II) acetate, tetra-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II) chloride, bis-(acetonitrile)-palladium(II) chloride, and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II)-dichloromethane complex [see Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].

[0158] This reaction step is typically carried out in a temperature range of +20°C to +150°C, preferably +50°C to +100°C.

[0159] The compounds of formula (VI) are novel, commercially available, or obtainable by known methods.

[0160] The compounds of formula (VIII) are novel.

[0161] (VIII),

[0162] Where R 1 R 2 and R 3 As defined above.

[0163] The compound of formula (VIII) can be prepared by reacting the compound of formula (IX) with trifluoromethanesulfonic anhydride in the presence of a base and an inert solvent via [E].

[0164] (IX),

[0165] Where R 1 R 2 and R 3 As defined above.

[0166] Reaction [E] (triflatization)

[0167] The reaction [E] is generally carried out in an inert solvent, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0168] The base is, for example, an organic base such as a basic amine or pyridine, 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-dimethylpyridine, or a basic amine such as triethylamine or N,N-diisopropylethylamine; preferably triethylamine.

[0169] Inert solvents include, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents; preferably dichloromethane.

[0170] The compounds of formula (IX) are novel.

[0171] (IX),

[0172] Where R 1 R 2 and R 3 As defined above.

[0173] Compounds of formula (IX) can be prepared by reacting compounds of formula (X) with an acid, optionally in an inert solvent, using [F].

[0174] (X)

[0175] Where R 1 R 2 and R 3 As defined above.

[0176] Reaction [F] (acidic deprotection)

[0177] The reaction [F] is usually carried out in an inert solvent or in the absence of a solvent, preferably at atmospheric pressure in the range of 0°C to solvent reflux.

[0178] Inert solvents include, for example, 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 such as dimethylformamide, dimethoxyethane, N-methylpyrrolidone, dimethylacetamide, acetonitrile, acetone or pyridine, or mixtures of solvents; preferably dichloromethane or dioxane.

[0179] Suitable acids for acidic deprotection are typically 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, optionally with water added. Hydrogen chloride or trifluoroacetic acid is preferred.

[0180] The compound of formula (X) is novel.

[0181] (X),

[0182] Where R 1 R 2 and R 3 As defined above.

[0183] Compounds of formula (X) can be prepared by reacting compounds of formula (XII) with compounds of formula (XI) in the presence of a palladium source, a suitable ligand, and a base via [G].

[0184] (XII),

[0185] Where R 1 and R 2 As defined above,

[0186] (XI),

[0187] in

[0188] R 3 As defined above.

[0189] Reaction [G] (Buchwald Hartwig coupling)

[0190] The reaction [G] is typically carried out in an inert solvent in the presence of a palladium source, a suitable ligand and a base, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0191] Palladium sources and suitable ligands are, for example, palladium on carbon, palladium(II) acetate, tris(dibenzylacetone)palladium(O), tetra-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II) chloride, bis-(acetonitrile)-palladium(II) chloride, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complexes, optionally with other phosphine ligands such as 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (XPhos-Pd-G3, CAS-No: 1445085-55-1), (2-biphenyl) di-tert-butylphosphine, dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos, CAS-No: CAS-No: 564483-18-7), bis(2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos: CAS-No: 161265-03-8) [see, for example, Hassan J. et al., Chem. Rev. 2002,102, 1359-1469], 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos, CAS-No: 1070663-78-3), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, CAS-No: 657408-07-6), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, CAS-No: 787618-22-8), 2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-ButylXPhos) are used in combination. Alternatively, a suitable precatalyst such as chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)-phenyl]palladium(II) (BrettPhos precatalyst) [see, for example, SL Buchwaldet al., Chem. Sci. 2013, 4, 916] may be used, optionally in combination with other phosphine ligands such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos).

[0192] Preferably, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), tris(dibenzylideneacetone)palladium (0), or in combination with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthocyanidin (Xantphos) or dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos) is used.

[0193] The base is, for example, a suitable inorganic or organic base, such as alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonates, or sodium bicarbonate or potassium bicarbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, barium hydroxide or potassium hydroxide; alkali metal or alkaline earth metal phosphates such as potassium phosphate; alkali metal alkoxides such as sodium tert-butyrate or potassium tert-butyrate and sodium methoxide, alkali metal phenolates such as sodium phenoxide, potassium acetate, amides such as 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), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Cesium carbonate, sodium carbonate, potassium carbonate or sodium bicarbonate are preferred.

[0194] The inert solvent is, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, di-n-butyl ether, cyclopentylmethyl ether, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as tert-butanol or pentanol, or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene or acetonitrile or a mixture of said solvents; preferably tert-butanol, 1,4-dioxane and toluene.

[0195] The compounds of formula (XI) are known, or can be synthesized by known methods from the corresponding commercially available starting compounds.

[0196] The compound of formula (XII) is novel.

[0197] (XII),

[0198] Where R 1 and R 2 As defined above.

[0199] Compounds of formula (XII) can be prepared by reacting compounds of formula (XIII) with an acid in an inert solvent using [H].

[0200] (XIII),

[0201] Where R 1 and R 2 As defined above.

[0202] The reaction [H] (debocylation)

[0203] The reaction [H] is usually 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.

[0204] The acid is, for example, 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, optionally added to water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0205] Inert 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, dichloromethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of such solvents; 1,4-dioxane is preferred.

[0206] The compound of formula (XIII) is novel.

[0207] (XIII),

[0208] in

[0209] R 1 and R 2 As defined above.

[0210] The compound of formula (XIII) can be prepared by reacting the compound of formula (XV) with the compound of formula (XIV) in a solvent via [I].

[0211] (XV),

[0212] in

[0213] R 1 and R 2 As defined above,

[0214] (XIV).

[0215] Reaction [I] (Pyrazole formation)

[0216] Reaction [I] is usually carried out in a solvent at room temperature to reflux temperature.

[0217] 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, dichloromethane; polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of these solvents; ethanol is preferred.

[0218] The compounds of formula (XIV) are known, commercially available, or can be synthesized from the corresponding starting compounds by known methods.

[0219] The compound of formula (XV) is novel.

[0220] (XV),

[0221] Where R 1 and R 2 As defined above.

[0222] Compounds of formula (XV) can be prepared by reacting compounds of formula (XVI) with hydrogen in a suitable solvent in the presence of palladium on carbon [J].

[0223] (XVI),

[0224] Where R 1 and R 2 As defined above.

[0225] Reaction [J](Z deprotection)

[0226] The reaction [J] is usually carried out in a suitable solvent in the presence of palladium on carbon at room temperature to reflux temperature, preferably at 1 bar.

[0227] 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, dichloromethane; and polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), NMP, acetic acid, or water, or mixtures of such solvents; preferably ethanol / acetic acid.

[0228] Compounds of formula (XVI) are novel.

[0229] (XVI),

[0230] Where R 1 and R 2 As defined above.

[0231] Compounds of formula (XVI) can be prepared by reacting compounds of formula (XVII) with compounds of formula (XVIII) in the presence of a reducing agent and a suitable solvent via [K].

[0232] (XVII),

[0233] in

[0234] R 1 and R 2 As defined above,

[0235] (XVIII).

[0236] Reaction [K] (reductive hydrazination)

[0237] The reaction [K] is usually carried out at atmospheric pressure in the presence of a reducing agent and a suitable solvent, at room temperature to the temperature range of solvent reflux.

[0238] 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 these solvents; tetrahydrofuran / methanol is preferred.

[0239] Suitable reducing agents are alkali metal borohydrides, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; sodium borohydride is preferred.

[0240] The compounds of formula (XVIII) are known and commercially available or can be synthesized from the corresponding starting compounds by known methods.

[0241] The compounds of formula (XVII) are known and commercially available or can be synthesized from the corresponding starting compounds by known methods.

[0242] The preparation of the starting compound and the compound of formula (I) can be described by the following synthetic schemes 1 to 3.

[0243] Option 1

[0244]

[0245] Option 2

[0246]

[0247] Option 3

[0248]

[0249] The compounds of this invention have important pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0250] The compounds of this invention are potent activators of soluble guanylate cyclase. These compounds induce vasodilation, inhibit platelet aggregation, lower blood pressure, and increase coronary and renal blood flow. These effects are mediated by direct, heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP.

[0251] Furthermore, the compounds of the present invention have favorable pharmacokinetic properties, specifically in terms of their bioavailability and / or duration of action after intravenous or oral administration.

[0252] Compared to compounds disclosed in the prior art (WO 2012 / 058132), the compounds of the present invention exhibit superior pharmacokinetic (PK) properties (see Experimental Section, Tables 3 to 6). For example, Example 2 of the present invention showed a lower plasma clearance (CL) in both rats and dogs compared to the prior art compound disclosed as Example 174 in WO 2012 / 058132. 血浆 (Up to 10 times) and the resulting significantly higher exposure. Example 2 also showed a long half-life and mean residence time (MRT) after oral (po) administration of all test species. Because all test species showed significantly lower plasma clearance and the resulting extremely high exposure (AUC) after oral administration... 标准 With good bioavailability, we see a significant advantage in pharmacokinetic (PK) characteristics compared to Example 174 disclosed in WO 2012 / 058132, based on the exposure (area under normalized curve) and pharmacokinetic (PK) properties.

[0253] The compounds of this invention possess an unpredictable and useful pharmacological activity spectrum and favorable pharmacokinetic behavior, particularly with adequate blood exposure above the minimum effective concentration within a given dosing interval after oral administration. This characteristic results in an increased peak-to-trough ratio (the quotient of the maximum and minimum concentrations) within a given dosing interval, which has the advantage of allowing the compound to be administered at less frequency and significantly lower doses to achieve its effect. They are compounds that activate soluble guanylate cyclase.

[0254] In the context of this invention, the term "treatment" or "treating" includes the suppression, delay, hindering, alleviating, reducing, limiting, weakening, preventing, resisting, or curing of a disease, symptom, obstacle, injury, or health problem, or the development, course, or progression of these states and / or symptoms of these states. The term "therapy" is to be understood herein as synonymous with the term "treatment."

[0255] In the context of this invention, "prevention," "prophylaxis," and "preclusion" are used synonymously and refer to avoiding or reducing the risk of the development or progression of infection, illness, ailment, disorder, injury, or health problem, or the symptoms of these conditions.

[0256] Treatment or prevention of a disease, symptom, disorder, injury, or health problem may be partial or complete.

[0257] Furthermore, the compounds described in this invention possess more superior properties, particularly in terms of their lung-selective effect (compared to systemic effects), lung retention time, and / or duration of action after intrapulmonary administration.

[0258] The compounds described in this invention are particularly suitable for the treatment and / or prevention of cardiovascular and heart diseases, cardiorenal and kidney diseases, cardiopulmonary and lung diseases, neurodegenerative diseases, thromboembolic diseases, fibrotic diseases, and wound healing disorders.

[0259] The compounds of 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), cardiorenal diseases and kidney diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiopulmonary diseases and lung 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), and wound healing disorders such as diabetic foot ulcers (DFU).

[0260] Therefore, the compounds described in this invention can be used in medicaments for the treatment and / or prevention of the following diseases: cardiovascular, cardiopulmonary, and cardiorenal diseases, such as hypertension (hypertension), heart failure, coronary artery disease, stable and unstable angina, pulmonary arterial hypertension (PAH) and secondary pulmonary arterial hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal hypertension, renovascular hypertension and refractory hypertension, peripheral and cardiovascular diseases, arrhythmias, atrial and ventricular arrhythmias and conduction disorders, such as grade I-III atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular premature contractions, atrioventricular junctional premature contractions, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, and acute coronary syndrome (ACS). The following medications are permitted for use in treating and / or preventing: autoimmune heart disease (pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy), boxer cardiomyopathy, aneurysm, shock such as cardiogenic shock, septic shock, and anaphylactic shock; thromboembolic diseases and local ischemia such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular disease, coronary and peripheral artery spasm, edema such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, impaired peripheral perfusion, reperfusion injury, arterial and venous thrombosis, microalbuminuria, heart failure, endothelial dysfunction, microvascular and large vessel injury (vasculitis); and medications for preventing restenosis such as thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), and restenosis after heart transplantation and bypass surgery.

[0261] In this invention, the term "pulmonary hypertension" includes two subtypes: primary and secondary, as defined below according to their respective etiologies in the Dana Point classification [see D. Montana and G. Simonneau, in the following articles: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206; MM Hoeper et al., J. Am. Coll. Cardiol. 2009, 54 (1), S85-S96]. Specifically, this includes Group 1 pulmonary hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively). In addition, pulmonary hypertension also includes persistent pulmonary hypertension in newborns and associated pulmonary hypertension (APAH) associated with the following conditions: collagenous disorders, congenital systemic pulmonary shunts, portal hypertension, HIV infection, intake of certain medications and agents (e.g., appetite suppressants), diseases with a significant venous / capillary component such as pulmonary venous occlusion and pulmonary capillary hemangioma, or other conditions such as thyroid disease, glycogen storage disease, Gaucher disease, hereditary teleangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. Group 2 of the Dana Point classification includes patients with pulmonary hypertension due to left ventricular disease (e.g., ventricular, atrial, or valvular disease). Group 3 includes forms of pulmonary hypertension associated with lung diseases (e.g., 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 sickness, hereditary malformations). Group 4 includes patients with pulmonary hypertension who have chronic thrombotic and / or embolic diseases, such as proximal and distal pulmonary thromboembolic occlusion (CTEPH) or non-thrombotic embolism (e.g., due to tumors, parasites, foreign bodies, etc.). Group 5 summarizes less common forms of pulmonary hypertension, such as those present in patients with sarcoidosis, histiocytosis X, or lymphangioma.

[0262] In this invention, the term "heart failure" includes acute heart failure and chronic heart failure, as well as more specific or related types of diseases such as acute decompensated heart failure, right heart failure, left heart failure, biventricular heart failure, diastolic heart failure and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with moderate ejection fraction (HFmEF), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease and cardiomyopathy, valvular heart defects, heart failure associated with valvular heart defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, mixed valvular heart defects, myocarditis (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, and cardiac storage diseases.

[0263] In addition, the compounds described in this invention can also be used to treat and / or prevent arteriosclerosis, lipid metabolism disorders, hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, mixed hyperlipidemia, hypercholesterolemia, abeta-lipoproteinemia, sitosterolemia, xanthomas, Tangier disease, obesity, and metabolic syndrome.

[0264] Furthermore, the compounds described in this invention can be used to treat and / or prevent primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, hearing impairment, tinnitus, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcers, gangrene, CREST syndrome, lupus erythematosus, onychomycosis, and rheumatism.

[0265] Furthermore, the compounds described in this invention can be used to treat sickle cell disease (SCD), sickle cell anemia, and other symptoms of diseases associated with sickle cell disease (e.g., end-organ damage affecting the lungs, brain, kidneys, or heart). They can also be used to treat vascular occlusive events or pain crises, achalasia, hemolytic angiopathy for the treatment of malaria, thalassemia, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemia, or rhabdomyopathies. Moreover, since similar pathophysiological mechanisms are effective in transfusing blood to patients with indications for transfusion (e.g., by increasing free hemoglobin concentration through storage), these compounds can be used in patients receiving transfusions. Finally, in the future, the combination of sGC activators with synthetic hemoglobin-like oxygen carriers may alleviate the side effects caused by reduced NO availability that have been identified to date [Weiskopf, Anesthesia & Analgesia, 110:3; 659-661, 2010], thereby allowing for further clinical applications.

[0266] The compounds described in this invention can also be used to prevent ischemic injury and / or reperfusion-related injury to organs or tissues, and can also be used as additives to perfusion and preservation solutions of organs, organ parts, tissues or tissue parts derived from humans or animals, particularly in the fields of surgical intervention or transplant medicine.

[0267] Furthermore, the compounds described in this invention are suitable for the treatment and / or prevention of kidney diseases, particularly renal insufficiency and renal failure. In this invention, renal insufficiency and renal failure include acute and chronic symptoms (chronic kidney disease; CKD), as well as underlying or related kidney diseases such as renal hypoperfusion, dialysis-related hypotension, obstructive urinary tract disease, glomerulonephropathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, kidney diseases such as primary and congenital kidney diseases, nephritis, immune-mediated kidney diseases such as kidney transplant rejection and immune complex-induced kidney diseases, toxic substance-induced kidney diseases, contrast agent-induced kidney diseases, and diabetes. This invention relates to diabetic and non-diabetic nephropathy, diabetic nephropathy (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, characterized by features such as abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme (e.g., gamma-glutamyl synthase) activity, altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar damage, renal tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The invention also covers the use of the compounds of this invention in the treatment and / or prevention of the sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hypercalcemia, hyponatremia), and bone and carbohydrate metabolism disorders.

[0268] Furthermore, the compounds described in this invention are suitable for the treatment and / or prevention of urinary system diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), urinary incontinence such as mixed, urge, stress, or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC), as well as erectile dysfunction and female sexual dysfunction.

[0269] The compounds described in this invention are also suitable for the treatment and / or prevention of asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), α-1 antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (e.g., emphysema caused by cigarette smoke) and cystic fibrosis (CF).

[0270] The compounds described in this invention are also active compounds for controlling central nervous system diseases characterized by NO / cGMP system disorders. They are particularly suitable for improving perception, attention, learning, or memory following cognitive impairment, such as those associated with: mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia, post-traumatic brain injury, general attention deficit, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontal lobe degenerative dementia including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, corticobasal degenerative dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating diseases, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia, or Korsakoff psychosis. They are also applicable to the treatment and / or prevention of central nervous system disorders, such as anxiety, tension and depression, central nervous system-related dysfunction and sleep disorders, as well as pathological disorders for controlling the intake of food, stimulants and addictive substances.

[0271] Furthermore, the compounds described in this invention are also suitable for regulating cerebral blood flow, and are therefore effective agents for controlling migraines. They are also suitable for preventing and controlling sequelae of stroke, such as cerebral infarction, ischemic stroke, and traumatic brain injury. The compounds of this invention can also be used to control pain states.

[0272] Furthermore, the compounds described in this invention have anti-inflammatory effects and can therefore be used as anti-inflammatory drugs for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases, and inflammatory eye diseases.

[0273] Furthermore, the compounds of this invention are also applicable to the treatment and / or prevention of fibrotic conditions of internal organs such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatological fibrosis and ocular fibrosis. In this invention, the term "fibrotic condition" specifically includes diseases such as liver fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, endocardial myocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, systemic sclerosis, morphine, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue diseases (e.g., sarcoidosis). The compounds of this invention can also be used to promote wound healing, including the healing of finger ulcers and diabetic foot ulcers, to control postoperative scarring, such as scars caused by glaucoma surgery, and for cosmetic purposes on aging and keratinized skin.

[0274] Based on their active properties, the compounds of the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiac diseases and cardiopulmonary diseases, such as primary and secondary pulmonary hypertension, heart failure, angina pectoris and hypertension, and also for the treatment and / or prevention of thromboembolic diseases, local ischemia, vascular diseases, impaired microcirculation, renal insufficiency, fibrotic diseases and arteriosclerosis.

[0275] The present invention also provides the use of the compounds described herein for the treatment and / or prevention of diseases, particularly the aforementioned diseases.

[0276] The present invention also provides the use of the compounds described herein in the preparation of medicaments for treating and / or preventing diseases, particularly the aforementioned diseases.

[0277] The present invention also provides a medicament comprising at least one compound of the present invention for treating and / or preventing diseases, particularly the aforementioned diseases.

[0278] The present invention also provides the use of the compounds of the present invention in methods for treating and / or preventing diseases, particularly the aforementioned diseases.

[0279] The present invention also provides a method for treating and / or preventing diseases, particularly the aforementioned diseases, using an effective amount of at least one compound of the present invention.

[0280] Therefore, they are suitable for use as medicines for the treatment and / or prevention of diseases in humans and animals.

[0281] The present invention further provides the use of the compounds of the present invention for the treatment and / or prevention of the following diseases, particularly cardiovascular diseases, preferably thrombotic diseases or thromboembolic diseases and / or thrombotic complications or thromboembolic complications, such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral artery occlusive disease, and / or diabetes and / or genitourinary diseases, especially those associated diseases.

[0282] For the purposes of this invention, "thrombotic disease or thromboembolic disease" includes diseases preferably occurring within arterial vessels and treatable with the compounds described herein, particularly diseases causing peripheral arterial occlusive disease and diseases occurring within the coronary arteries of the heart, such as acute coronary syndrome (ACS), ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis following coronary interventions (such as angioplasty, stenting, or aortic coronary artery bypass grafting), and thrombotic or thromboembolic diseases in cerebral arteries, such as transient ischemic attack (TIA), ischemic stroke including cardiogenic stroke such as stroke caused by atrial fibrillation, non-cardiogenic stroke such as lacunar stroke, stroke caused by disease of large or small arteries, or stroke due to uncertain factors, cryptogenic stroke, embolic stroke, embolic stroke of unknown origin, or thrombotic and / or thromboembolic origin events leading to stroke or TIA.

[0283] Furthermore, the compounds described in this invention are particularly suitable for treating and / or preventing diseases in which pro-inflammatory components play an important role, including vasculitis such as Kawasaki disease, aortitis, and thromboangiitis obliterans (Bergler's disease), as well as inflammatory diseases such as myocarditis.

[0284] Furthermore, the compounds described in this invention are suitable for the treatment and / or prevention of urogenital diseases such as overactive bladder, interstitial cystitis, and bladder pain syndrome.

[0285] Furthermore, the compounds described in this invention are suitable for the treatment and / or prevention of diabetes, including its end-organ manifestations such as diabetic retinopathy and diabetic nephropathy.

[0286] Furthermore, the compounds described in this invention are particularly suitable for the treatment and / or prevention of neurological diseases such as neuropathic pain, neurodegenerative diseases, and dementias such as vascular dementia or Alzheimer's disease and Parkinson's disease.

[0287] Furthermore, the compounds described in this invention are particularly suitable for treating and / or preventing lung diseases such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD).

[0288] The present invention further provides the use of the compounds of the present invention for treating and / or preventing diseases, especially the aforementioned diseases.

[0289] The present invention further provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing diseases, especially the aforementioned diseases.

[0290] The present invention further provides a method for treating and / or preventing diseases, particularly the aforementioned diseases, using a therapeutically effective amount of the compound of the present invention.

[0291] The present invention further provides the compound of the present invention in a method for treating and / or preventing diseases, especially the aforementioned diseases, wherein the method uses a therapeutically effective amount of the compound of the present invention.

[0292] The present invention specifically provides compounds of the invention for use in methods of treating and / or preventing thrombotic or thromboembolic, particularly atherosclerotic, thrombotic conditions, wherein the method uses a therapeutically effective amount of the compounds of the invention.

[0293] The present invention also provides a medicament comprising the compound described herein and one or more other active compounds.

[0294] Furthermore, the compounds described in this invention can also be used to prevent in vitro clotting, for example, to protect organs to be transplanted from organ damage caused by blood clot formation and to protect organ recipients from thromboembolism from transplanted organs, to preserve blood and plasma products, to clean / pretreat catheters and other medical assistive devices and instruments, to coat synthetic surfaces of medical assistive devices and instruments used in vivo or in vitro, or to biological samples that may contain factor XIa or plasma kallikrein.

[0295] The present invention also provides a method for preventing blood clotting in vitro, particularly in bank blood or biological samples that may contain factor XIa or plasma kallikrein or both of these enzymes, characterized by the addition of an effective amount of the compound of the present invention for anticoagulation.

[0296] The compounds of the present invention can act systemically and / or locally. Therefore, they can be administered in suitable ways, such as via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival, or ear canal routes, or as implants or stents.

[0297] For these routes of administration, the compounds of the present invention can be administered in a suitable form.

[0298] For oral administration, the compounds of the present invention can be formulated into dosage forms known in the art that can deliver the compounds of the present invention rapidly and / or in an improved manner, such as tablets (uncoated or coated tablets, e.g., enteric or controlled-release coatings with delayed dissolution or insolubility), orally disintegrating tablets, films / capsules, films / lyophilized forms, capsules (such as hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. The compounds according to the present invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved forms.

[0299] Parenteral administration can be performed without absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or including absorption steps (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable forms of administration for parenteral administration are especially preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized forms, or sterile powders.

[0300] Suitable for extraocular (topical) administration are administration forms operated according to existing technology that release the active compound rapidly and / or in an improved or controlled manner, and contain the active compound in crystalline and / or amorphous and / or dissolved forms, such as eye drops, sprays, and lotions (e.g., solutions, suspensions, vesicle / colloid systems, emulsions, aerosols), powders for eye drops, sprays, and lotions (e.g., ground active compounds, mixtures, lyophilized substances, precipitated active compounds), semi-solid ocular preparations (e.g., hydrogels, in situ hydrogels, creams, and ointments), and ocular inserts (solid and semi-solid preparations, such as bioadhesives, films / capsules, tablets, and contact lenses).

[0301] Intraocular drug delivery includes intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar, and subconjunctival administration. Suitable forms of administration for intraocular drug delivery are those that operate according to existing technology, enabling rapid and / or modified or controlled release of the active compound, and containing the active compound in crystalline and / or amorphous and / or dissolved forms, such as injectable formulations and concentrates for injectable formulations (e.g., solutions, suspensions, vesicle / colloid systems, emulsions), powders for injectable formulations (e.g., ground active compounds, mixtures, lyophilized substances, precipitated active compounds), gels (semi-solid formulations, such as hydrogels, in-situ hydrogels) for injectable formulations, and implants (solid formulations, such as biodegradable and non-biodegradable implants, implantation pumps).

[0302] Oral administration is preferred.

[0303] Examples of other routes of administration include inhaled drug forms [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / capsules / sacs for administration via the tongue, sublingual or oral cavity; suppositories; eye drops, eye ointments, eye washes, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear plugs; vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapy systems (e.g., patches), lotions, pastes, foams, powders, implants or stents.

[0304] The compounds of the present invention can be incorporated into the described dosage form. This can be achieved by mixing with pharmaceutically suitable excipients in a manner known per se. Pharmaceutically suitable excipients particularly include

[0305] Fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., Avicel)) ® ), lactose, mannitol, starch, calcium phosphate (e.g., Di-Cafos), ® )),

[0306] Ointment bases (e.g., petroleum glue, paraffin wax, triglycerides, waxes, lanolin, lanolin alcohol, hydrophilic ointments, polyethylene glycol),

[0307] Suppository base (e.g., polyethylene glycol, cocoa butter, stearin),

[0308] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0309] Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl 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) ® ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamer (e.g., Pluronic ® ),

[0310] Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, glycerol, triethanolamine),

[0311] Isotonic agents (e.g., glucose, sodium chloride),

[0312] Adsorbents (e.g., highly dispersed silica),

[0313] Tackifiers, gelling agents, thickeners and / or adhesives (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g., Carbopol)) ® (alginate, gelatin)

[0314] Disintegrants (e.g., modified starch, sodium carboxymethyl cellulose, sodium glycolate starch (e.g., Explotab)) ® ), croscarmellose, croscarmellose sodium carboxymethyl cellulose (e.g., AcDiSol) ® )),

[0315] Flow conditioners, lubricants, flow aids, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g., Aerosil)). ® )),

[0316] Coating materials (e.g., sugar, shellac) and film-forming agents for rapidly dissolving or in a modified manner dissolving films or diffusion films (e.g., polyvinylpyrrolidone, such as Kollidon). ® Polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate, such as Eudragit ® )),

[0317] Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[0318] Synthetic polymers (e.g., polylactic acid, polyglycolic acid, polyacrylate, polymethacrylate (e.g., Eudragit)) ® ), polyvinylpyrrolidone (e.g., Kollidon) ® Polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers),

[0319] Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerin, triacetyl triacetate, triacetyl citrate, dibutyl phthalate),

[0320] Penetration enhancer

[0321] Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbate palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[0322] Preservatives (such as parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0323] Colorants (e.g., inorganic pigments, such as iron oxide and titanium dioxide),

[0324] Flavoring agents, sweeteners, flavor and / or odor masking agents.

[0325] The present invention also relates to pharmaceutical compositions comprising at least one compound of the present invention, typically together with one or more pharmaceutically suitable excipients, and to their use according to the present invention.

[0326] One embodiment of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) as described in the present invention, preferably together with at least one inert, non-toxic, pharmaceutically suitable excipient, and use of such pharmaceutical composition for the above-mentioned purpose.

[0327] According to another aspect, the present invention covers pharmaceutical compositions, particularly medicines, which comprise at least one compound of the general formula (I) of the present invention and at least one or more other active ingredients, particularly for the treatment and / or prevention of cardiovascular diseases, preferably thrombotic or thromboembolic diseases and diabetes, as well as genitourinary and ophthalmic diseases.

[0328] The term "combination" in this invention is used as is known to those skilled in the art, and the combination can be a fixed combination, a non-fixed combination, or kit-of-parts.

[0329] In this invention, a “fixed combination” is used as is known to those skilled in the art and is defined as a combination in which, for example, a first active ingredient such as one or more compounds of general formula (I) as described in this invention, and other active ingredients are present together in a unit dose or a single entity. An example of a “fixed combination” is a pharmaceutical composition in which the first active ingredient and other active ingredients are present in a mixture, such as a formulation, for simultaneous administration. Another example of a “fixed combination” is a pharmaceutical combination in which the first active ingredient and other active ingredients are present in a single unit rather than in a mixture.

[0330] The non-fixed combination or "kit component" of the present invention is used as is known to those skilled in the art and is defined as a combination in which a first active ingredient and other active ingredients are present in more than one unit. An example of a non-fixed combination or kit component is a combination in which the first active ingredient and other active ingredients are present separately. The components of a non-fixed combination or kit component may be administered individually, sequentially, simultaneously, synchronously, or in a time-sequential manner.

[0331] The compounds of the present invention can be used alone or, if desired, in combination with other active ingredients. The present invention further provides medicaments comprising at least one compound of the present invention and one or more other active ingredients, particularly medicaments for treating and / or preventing the aforementioned diseases. Preferred examples of suitable combinations of active ingredients include:

[0332] Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0333] Compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP), such as phosphodiesterase (PDE) 1, 2, 5 and / or 9 inhibitors, especially PDE5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, mironafil, lodenafil or PF-00489791;

[0334] Compounds that inhibit the breakdown of cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 3 and 4 inhibitors, especially cilostazol, milrinone, roflumilast, apremilast, or crisaborole.

[0335] The active ingredients for lowering blood pressure include, and preferably, calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, angiopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, and diuretics.

[0336] Antiarrhythmic drugs, such as and preferably sodium channel blockers, beta-blockers, potassium channel blockers, calcium channel antagonists, If-channel blockers, digitalis, parasympathomimetic drugs, sympathomimetic drugs and other antiarrhythmic drugs such as adenosine, adenosine receptor agonists and vinakalan.

[0337] Positive cardiotonic agents, such as cardiac glycosides (Dogoxin), β-adrenergic and dopaminergic agonists, such as isoproterenol, epinephrine, noradrenaline, dopamine or dobutamine;

[0338] Vasopressin receptor antagonists, such as and preferably conivatan, tolvaptan, lisiputan, mozavaputan, satavaptan, pecavaptan, SR-121463, RWJ 676070 or BAY 86-8050, and compounds described in WO2010 / 105770, WO2011 / 104322 and WO 2016 / 071212;

[0339] Active ingredients that alter lipid metabolism, such as, and preferably, thyroid receptor agonists, cholesterol synthesis inhibitors, such as, and preferably, 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, polymerized bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein(a) antagonists.

[0340] Bronchodilators, such as and preferably β-adrenergic receptor agonists, such as and preferably salbutamol, isoproterenol, orosinol, terbutaline, formoterol or salmeterol, or anticholinergic drugs, such as and preferably ipratropium bromide;

[0341] Anti-inflammatory agents, such as and preferably glucocorticoids, such as and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolone, budesonide or fluticasone, and nonsteroidal anti-inflammatory drugs (NSAIDs), such as and preferably acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminosalicylic acid derivatives, leukotriene antagonists, TNF-α inhibitors and chemokine receptor antagonists, such as CCR1, 2 and / or 5 inhibitors;

[0342] Drugs that regulate the immune system, such as immunoglobulins;

[0343] Drugs that inhibit signal transduction cascades, such as, and preferably, kinase inhibitors, such as, and preferably, tyrosine kinase and / or serine / threonine kinase inhibitors;

[0344] Drugs that inhibit the degradation and modification of the extracellular matrix, such as and preferably matrix metalloproteinase (MMP) inhibitors, such as and preferably inhibitors of chymotrypsin, matrix lysin, collagenase, gelatinase and agglutinase (preferably 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), such as cevelexat or DX-890;

[0345] Drugs that block the binding of serotonin to its receptors, such as, and preferably, 5-HT2b receptor antagonists;

[0346] Organic nitrates and NO donors, such as and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0347] NO-independent but heme-dependent stimulants for soluble guanylate cyclase, such as and preferably the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO2012 / 028647 and WO 2012 / 059549.

[0348] NO-independent but heme-dependent activators of soluble guanylate cyclase, such as and preferably the compounds described in WO01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;

[0349] Drugs that stimulate the synthesis of cyclic guanosine monophosphate, such as soluble guanylate cyclase modulators, such as and preferably riociguat, cinasquat, vericiguat, or runcaciguat;

[0350] Prostacyclin analogues, such as, and preferably, iloprost, belaprost, treprost, or eprostol;

[0351] Drugs that inhibit soluble epoxide hydrolase (sEH), such as and preferably N,N'-dicyclohexylurea, 12-(3-adamantane-1-ylureido)-dodecanoic acid or 1-adamantane-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea;

[0352] Drugs that interact with glucose metabolism, such as and preferably insulin, biguanide, thiazolidinedione, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-2 inhibitors, such as empagliflozin, dapagliflozin, canagliflozin, soragliflozin;

[0353] Natriuretic peptides, such as and preferably atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, Nesiritid), natriuretic peptide type C (CNP), or urodilatin.

[0354] Activators of cardiac myosin, such as and preferably omecamtiv mecarbil (CK-1827452);

[0355] Calcium sensitizers, such as, and preferably, levosimendan;

[0356] Drugs that affect cardiac energy metabolism, such as and preferably etomoxi, dichloroacetate, ranolazine or trimetazine, complete or partial adenosine A1 receptor agonists, such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate.

[0357] Drugs that affect heart rate, such as, and preferably, ivabradine;

[0358] Cyclooxygenase inhibitors, such as bromfenac and napafenamide;

[0359] Inhibitors of the kallikrein-kinin system, such as saliband and icolantide;

[0360] Inhibitors of the sphingosine 1-phosphate signaling pathway, such as sonepcizumab;

[0361] Complement C5a receptor inhibitors, such as eculizumab;

[0362] Plasminogen activators (thrombolytics / fibrinolytics) 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, such as Actilyse®), streptokinase, reteplase and urokinase or plasminogen regulators that lead to increased plasmin formation;

[0363] Anticoagulants, such as heparin (UFH), low molecular weight heparin (LMW), such as tinzaparin, sertoparin, parheparin, nadroparin, adeparin, enoxaparin, low molecular weight heparin, dalteparin, danateparin, smoparin (AVE5026), adorimiparin (M118) and EP-42675 / ORG42675;

[0364] Direct thrombin inhibitors (DTIs), such as Pradaxa (dabigatran), ategatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanoside (BIBT-986 and prodrug BIBT-1011), and hirudin;

[0365] Direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban (DU-176b), betraxaban (PRT-54021), R-1663, daressaban (YM-150), oxexaban (FXV-673 / RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanoxacrine (BIBT-986, prodrug: BIBT-1011), epoxetine, and fondaparinux sodium;

[0366] Inhibitors of coagulation factors XI and XIa, such as FXI ASO-LICA, fesomersen, BAY121-3790, MAA868, BMS986177, EP-7041, and AB-022;

[0367] Substances that inhibit platelet aggregation (platelet aggregation inhibitors, serum cell aggregation inhibitors), such as acetylsalicylic acid (e.g., aspirin), P2Y12 antagonists, such as ticlopidine (ticlad), clopidogrel (pulidone), prasugrel, ticagrelor, canagrelor and enoxaparin, and PAR-1 antagonists, such as vorapazol and PAR-4 antagonists;

[0368] Platelet adhesion inhibitors, such as GPVI and / or GPIb antagonists, such as Revacept or caplacizumab;

[0369] Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists), such as abciximab, epitubatide, tirofiban, lamifiban, legafiban, and frafafiban;

[0370] Recombinant human activated protein C, such as thrombectomycin (Xigris) or recombinant thrombomodulin (trombomodulin).

[0371] Antithrombotic agents are preferably understood as compounds derived from platelet aggregation inhibitors, anticoagulants, or fibrinolytic substances.

[0372] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a platelet aggregation inhibitor, such as and preferably aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or dipyridamole.

[0373] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thrombin inhibitor, such as and preferably tamegatran, dabigatran, melagatan, bivalirudin, or ketamine.

[0374] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a GPIIb / IIIa antagonist, such as, and preferably, tirofiban or abciximab.

[0375] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a factor Xa inhibitor, such as and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, betrixaban, omexaban, fildexaban, razaxan, letaxaban, eribaxaban, fondaparinux sodium, epoxetine, PMD-3112, darixaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

[0376] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an inhibitor of factor XI or factor XIa, for example and preferably FXI ASO-LICA, fexomethenol, BAY 121-3790, MAA868, BMS986177, EP-7041 or AB-022.

[0377] In a preferred embodiment of the invention, the compound of the invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0378] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vitamin K antagonist, such as, and preferably, coumarin.

[0379] Antihypertensive agents are preferably understood to be compounds selected from calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, and diuretics.

[0380] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil, or diltiazem.

[0381] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an α-1-receptor blocker, such as, and preferably, prazosin.

[0382] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a β-receptor blocker, such as and preferably propranolol, atenolol, timolol, indolol, alpraolol, propranolol, pentbuprofen, chlorotoluene, metenolol, naldolol, metinolol, carazalol, sotalol, metoprolol, betalolol, celylolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adalolol, landilolol, nebivolol, epamnoxol, or bucilolol.

[0383] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an angiotensin II antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embusartan, or with a dual angiotensin II antagonist / neprilysin inhibitor, such as and preferably LCZ696 (valsartan / sacubitril).

[0384] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril, or trandopril.

[0385] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an endothelin antagonist, such as and preferably bosentan, darusentan, ambesentan or sitasentan.

[0386] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a renin inhibitor, such as and preferably aliskiren, SPP-600 or SPP-800.

[0387] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a mineralocorticoid receptor antagonist, such as and preferably spironolactone, AZD9977, fenelitonee or eplerenone.

[0388] In a preferred embodiment of the invention, the compound of the invention is administered in combination with the following substances: loop diuretics, such as furosemide, torasemide, bumetanide, and pyrrolizidine; potassium-sparing diuretics, such as amiloride and triamterene; aldosterone antagonists, such as spironolactone, canilenate potassium, and eplerenone; and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, sipamide, and indapamide.

[0389] Lipid metabolism regulators are preferably understood to be derived from the following compounds: 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.

[0390] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CETP inhibitor, such as and preferably dacetrapip, acetrapip, tochepus (CP-529 414), JJT-705 or the CETP vaccine (Avant).

[0391] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thyroid receptor agonist, such as and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or acitirox (CGS26214).

[0392] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a statin HMG-CoA reductase inhibitor, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0393] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

[0394] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACAT inhibitor, such as and preferably avamidib, methyllinoleamide, partemidib, irubib, or SMP-797.

[0395] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an MTP inhibitor, such as and preferably impetatae, BMS-201038, R-103757 or JTT-130.

[0396] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-γ agonist, such as, and preferably, pioglitazone or rosiglitazone.

[0397] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-δ agonist, such as and preferably GW 501516 or BAY 68-5042.

[0398] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tequila, or pambalidine.

[0399] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a lipase inhibitor, a preferred example being orlistat.

[0400] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a polymeric bile acid adsorbent, such as and preferably cholestyramine, colestipol, colesolvam, colestigule, or colestilan.

[0401] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a bile acid reabsorption inhibitor, such as and preferably an ASBT (= IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0402] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipoprotein (a) antagonist, such as and preferably gemcarbene calcium (CI-1027) or niacin.

[0403] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipoprotein (a) antagonist, such as and preferably gemcarbene calcium (CI-1027) or niacin.

[0404] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an sGC modulator, such as and preferably riociguat, cinaciguat, or veliciguat.

[0405] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an agent that affects glucose metabolism, such as and preferably insulin, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors empagliflozin, dapagliflozin, kanagliflozin, and soragliflozin.

[0406] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a TGFβ antagonist, such as, and preferably, pirfenidone or fresolimumab.

[0407] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CCR2 antagonist, such as and preferably CCX-140.

[0408] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a TNFα antagonist, such as, and preferably, adalimumab.

[0409] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a galactolectin-3 inhibitor, such as and preferably GCS-100.

[0410] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an Nrf-2 inhibitor, such as, and preferably, bardoxazoline.

[0411] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a BMP-7 agonist, such as and preferably THR-184.

[0412] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a NOX1 / 4 inhibitor, such as and preferably GKT-137831.

[0413] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug that affects vitamin D metabolism, such as and preferably calcitriol, alfacalcidol, doxorubicin, mascaracalcidol, paricalcitol, cholecalciferol, or paracalcitol.

[0414] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a cell growth inhibitor, such as, and preferably, cyclophosphamide.

[0415] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an immunosuppressant, such as, and preferably, cyclosporine.

[0416] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a phosphate binder, such as and preferably colestilan, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[0417] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a sodium phosphate cotransporter in the proximal renal tubules, such as, and preferably, nicotinic acid or nicotinamide.

[0418] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcimimetic agent for the treatment of hyperparathyroidism.

[0419] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug for treating iron deficiency, such as, and preferably, an iron product.

[0420] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug for treating hyperuricemia, such as, and preferably, allopurinol or raburicase.

[0421] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a glycoprotein hormone for treating anemia, such as and preferably erythropoietin, dapoxetine, molistat, roxadustat, vadadustat, or dedustat.

[0422] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a biological agent for immunotherapy, such as and preferably abatacept, rituximab, eculizumab or belimumab.

[0423] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vasopressin antagonist (vaptanes) for the treatment of heart failure, such as and preferably tolvaptan, conivatan, lishiptan, mozavaptan, shadavaptan, pecavaptan, or relcovaptan.

[0424] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a Jak inhibitor, such as and preferably ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, retasinib, paricitinib (SB1518) or TG101348.

[0425] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a prostacyclin analogue for treating microthrombosis.

[0426] In a preferred embodiment of the invention, the compound of the invention is administered in combination with alkali therapy, such as, and preferably, sodium bicarbonate.

[0427] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an mTOR inhibitor, such as and preferably everolimus or rapamycin.

[0428] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an NHE3 inhibitor, such as and preferably AZD1722 or ternapanol.

[0429] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an eNOS modulator, such as, and preferably, sapropterin.

[0430] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CTGF inhibitor, such as and preferably FG-3019.

[0431] The present invention also provides a medicament comprising at least one compound of the present invention, typically with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and provides use of the medicament for the purposes described above.

[0432] The compounds of the present invention can act systemically and / or locally. Therefore, they can be administered in suitable ways, such as via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival, or ear routes, or as implants or scaffolds.

[0433] The compounds described in this invention can be administered in a manner suitable for these routes of administration.

[0434] Suitable oral administration forms are those that function according to the prior art, rapidly and / or in a modified manner release the compounds of the invention, and contain the compounds of the invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, for example having an anti-gastric juice or slow-dissolving or insoluble coating that controls the release of the compounds of the invention), tablets or films / capsules that rapidly disintegrate in the oral cavity, films / lyophilized forms or capsules (e.g., hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions.

[0435] Parenteral administration can bypass absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or include absorption steps (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable forms of administration for parenteral administration include injectable and infusion formulations in the form of solutions, suspensions, emulsions, lyophilized forms, or sterile powders.

[0436] For other routes of administration, suitable examples are inhalable drug forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films / capsules 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 therapy systems (e.g., patches), lotions, creams, foams, powders, implants or stents.

[0437] Oral or parenteral administration is preferred, especially oral and intravenous administration.

[0438] The compounds of the present invention can be converted into the described dosage form. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. 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, polysorbate oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxide), and flavoring and / or taste-enhancing agents.

[0439] Generally, it has been found that, in the case of parenteral administration, a dosage of about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight, is advantageous for obtaining effective results. In the case of oral administration, the dosage is about 0.01-100 mg / kg body weight, preferably about 0.01-20 mg / kg body weight, and most preferably 0.1-10 mg / kg body weight.

[0440] However, deviations from the prescribed dosage may be necessary in appropriate circumstances, particularly based on body weight, route of administration, individual response to the active compound, the nature of the formulation, and the time or interval of administration. For example, in some cases, less than the minimum dosage mentioned above may be sufficient, while in others, the mentioned upper limit must be exceeded. In cases involving large doses, it is recommended to divide these medications into several individual doses throughout the day.

[0441] The total amount of active ingredient to be administered typically ranges from about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 50 mg / kg body weight per day, and more preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules range from once to three times daily to once every four weeks. Furthermore, "drug holidays," i.e., periods during which patients do not take the medication, may be beneficial for the overall balance between pharmacological effects and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more or less daily. For injectable administration, including intravenous, intramuscular, subcutaneous, and parenteral injections, and using infusion techniques, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. For rectal administration, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. For vaginal administration, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. For topical administration, the average daily dose is preferably from 0.1 to 200 mg, administered 1 to 4 times daily. The preferred transdermal concentration is the concentration required to maintain a daily dose of 0.01 to 200 mg / kg. The preferred average daily inhalation dosing regimen is 0.01 to 100 mg / kg of total body weight.

[0442] Of course, the specific initial and continuous dosing regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending physician, the activity of the specific compound used, the patient's age and general condition, the timing of administration, the route of administration, the drug excretion rate, and the combination of drugs. The desired treatment modality and dosage of the compounds described in this invention, or their pharmaceutically acceptable salts or esters, or combinations thereof, can be determined by those skilled in the art through routine treatment trials.

[0443] However, it may be necessary to deviate from the prescribed amount, depending on body weight, route of administration, individual response to the active substance, type of formulation, and the time or interval of administration. Therefore, in some cases, using less than the minimum amount mentioned above may be sufficient, while in others, the prescribed upper limit must be exceeded. When administering larger doses, it is recommended to divide these medications into several separate doses throughout the day.

[0444] According to another embodiment, the compound of formula (I) of the present invention is administered orally once, twice, or three times daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once or twice daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once daily. For oral administration, rapid-release or modified-release formulations can be used.

[0445] Unless otherwise stated, all percentages in the following tests and examples are weight percentages; parts are parts by weight. Solvent ratios, dilution ratios, and concentration data for liquid / liquid solutions are based on volume 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 substance.

[0446] Experimental Section

[0447] Experimental Section – General Principles

[0448] The NMR peaks are presented in the manner in which they appear in the spectrum, without taking into account possible higher-order effects.

[0449] Chemical names are generated using ACD / Labs' ACD / Name software. In some cases, the names of commonly accepted commercially available reagents are used instead of the names generated by ACD / Name.

[0450] Table 1 below lists the abbreviations used in this paragraph and the examples section, unless they are explained in the text. Other abbreviations have their usual meaning to those skilled in the art.

[0451] Table 1: Abbreviations

[0452] The following table lists the abbreviations used in this article.

[0453]

[0454] The various aspects of the invention described in this application are illustrated by the following embodiments, which are not intended to limit the invention in any way.

[0455] The embodiments and test experiments described herein are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0456] All reagents not described in the experimental section are commercially available or known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0457] The compounds and intermediates generated according to the methods described in this invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several methods may be available for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, the compound may be purified by chromatography, particularly rapid column chromatography, for example using a pre-packed silica column, such as a Biotage SNAP cartidges KP-Sil® or KP-NH®, combined with a Biotage automated purification system (SP4® or Isolera Four®) and eluent (such as a gradient solution of hexane / ethyl acetate or dichloromethane / methanol). In some cases, the compound may be purified by preparative HPLC, for example using a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, combined with a suitable pre-packed reversed-phase column and eluent, such as a gradient solution of water and acetonitrile containing additives such as trifluoroacetic acid, formic acid, or ammonia.

[0458] In some cases, the purification methods described above can provide the compounds of the invention in the form of salts, which possess sufficient basic or acidic functionality, such as trifluoroacetate or formate salts for sufficiently basic compounds of the invention, or ammonium salts for sufficiently acidic compounds of the invention. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that the specific form (e.g., salt, free base, etc.) of the compounds of the invention isolated as described herein is not necessarily the only form in which the compounds can be used in bioassays to quantify specific biological activities.

[0459] In the synthetic intermediates and working examples of the invention described below, any compound described as a salt of a corresponding base or acid is generally a salt with an unknown exact stoichiometric composition, obtained by its respective preparation and / or purification methods. Therefore, unless otherwise specified, additional terms such as "hydrochloride," "trifluoroacetate," "sodium salt," or "x HCl," "x CF3COOH," "x Na" are used in names and structural formulas. + In the case of such salts, the term should not be understood in a stoichiometric sense, but rather should be interpreted only in a descriptive sense regarding the salt-forming components present.

[0460] This applies if the synthetic intermediate or working example or its salt is obtained by the preparation and / or purification methods described herein in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0461] NMR peak shapes are described according to their appearance in the spectrum, without taking into account possible higher-order effects.

[0462] The selected compound 1 H-NMR data with 1 The peaks are listed in the form of an H-NMR table. For each signal peak, the δ value is given in ppm, followed by the signal intensity in parentheses. δ value-signal intensity pairs for different peaks are separated by commas. Therefore, a list of peaks is described in a general form: δ1 (intensity 1), δ2 (intensity 2), ..., δ i (strength i ), ..., δ n (strength n ).

[0463] In a printed NMR spectrum, the intensity of a sharp signal is related to the signal height (in cm). This data can be correlated with the actual ratio of signal intensity when compared to other signals. In the case of a wide signal, more than one peak or signal center and its relative intensity are shown compared to the strongest signal displayed in the spectrum. 1 The H-NMR peaks are similar to those of the classic NMR spectrum. 1 H-NMR readings, therefore, typically contain all the peaks listed in the classical NMR interpretation. Furthermore, similar to classical... 1 The 1H-NMR spectrum, with its peak table, can display solvent signals, signals from stereoisomers of the target compound (also the subject of this invention), and / or impurity peaks. The peaks of stereoisomers and / or impurities typically show lower intensities compared to the peaks of the target compound (e.g., with a purity > 90%). These stereoisomers and / or impurities may be typical of a particular manufacturing process, and therefore their peaks may help identify reproducibility of our manufacturing process based on a “byproduct fingerprint.” Experts who calculate the target compound peaks using known methods (MestReC, ACD simulation, or expected values ​​evaluated empirically) can separate the target compound peaks as needed, optionally using additional intensity filters. Such operation is similar to classical... 1Peak-picking in H-NMR interpretation. A detailed description of reporting NMR data in peak list form can be found in the publication Citation of NMR Peaklist Data within Patent Applications (see ResearchDisclosure Database Number 605005, 2014, 01 Aug 2014 or http: / / www.researchdisclosure.com / searching-disclosures). During peak-picking, as described in Research Disclosure Database Number 605005, the parameter “minimum height” can be adjusted between 1% and 4%. Depending on the chemical structure and / or the concentration of the compound being measured, setting the parameter “minimum height” <1% may be reasonable.

[0464] In the NMR spectrum of a mixture of stereoisomers, the numbers marked with " / " indicate that the stereoisomers show a separate signal for each hydrogen atom. That is, ".... / ..... (2s, 1H)" means that one hydrogen atom is represented by two singlets, each singlet coming from one or more different stereoisomers.

[0465] The IUPAC names of the intermediates and example compounds below were generated using the naming tools provided in ACD / Name software (volume version 14.00; Advanced Chemistry Development, Inc.) or in BIOVIA Draw software (version 4.2 SP1; Dassault Systèmes SE).

[0466] HPLC and LC-MS methods:

[0467] Method 1 (LC-MS)

[0468] MS instrument type: SHIMADZU LCMS-2020; column: Kinetex EVO C18 30*2.1mm, 5um; mobile phase A: 0.0375% TFA aqueous solution (v / v), B: 0.01875% TFA acetonitrile solution (v / v); 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: 220 nm and 254 nm.

[0469] Method 2 (LC-MS)

[0470] HPLC instrument model: SHIMADZU LCMS-2020; column: Kinetex EVO C18 50*4.6mm, 5um; mobile phase A: 0.0375% TFA aqueous solution (v / v), B: 0.01875% TFA acetonitrile solution (v / v); 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: 220 nm & 215 nm & 254 nm.

[0471] Method 3 (LC-MS)

[0472] Instruments: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 1 mm; Eluent A: 1 L water + 0.25 mL formic acid, Eluent B: 1 L 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.

[0473] Method 4 (LC-MS)

[0474] Instrument MS: Thermo Scientific FT-MS; Instrument type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 µm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven temperature: 50℃; Flow rate: 0.90 ml / min; UV detection: 210 nm / optimal integration path 210 -300 nm.

[0475] Method 5 (LC-MS)

[0476] Instruments: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T31.8 µm 50 x 1 mm; Eluent A: 1 L water + 0.25 mL formic acid, Eluent B: 1 L 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.

[0477] Method 6 (LC-MS)

[0478] Instruments: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters AcquityUPLC HSS T3 1.8 µm 50 x 2.1 mm; Eluent A: 1 L water + 0.25 mL formic acid, Eluent B: 1 L 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.

[0479] Method 7 (LC-MS)

[0480] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: WatersAcquity UPLC HSS T3 1.8 µm 50 x 1 mm; Eluent A: 1 L water + 0.100 ml 99% ig e formic acid; Eluent B: 1 L acetonitrile + 0.100 ml 99% ig e 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.

[0481] Method 8 (LC-MS)

[0482] MS system: Waters TOF instrument; UPLC system: Waters Acquity I-CLASS; Column: Waters HSST3, 2.1 x 50 mm, C18 1.8 µm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L 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

[0483] Method 9 (Preparative HPLC)

[0484] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5 µm 100 x 30 mm; UV detection 200-400 nm; room temperature; at-column injection (complete injection); eluent A: water; eluent B: acetonitrile; eluent C: 2% formic acid aqueous solution; eluent D: acetonitrile / water (80 v / 20 v%); flow rate: 80 ml / min; gradient curve: 0 to 2 minutes: eluent A 55 ml / min, eluent B 15 ml / min; 2 to 10 minutes: eluent A from 55 ml / min to 31 ml / min, eluent B from 15 ml / min to 39 ml / min; 10 to 12 minutes: eluent A 0 ml / min and eluent B 70 ml / min; eluent C and eluent D each at a constant flow rate of 5 ml / min throughout the run.

[0485] Method 10 (Preparative HPLC)

[0486] Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5µm 100 x 30 mm; UV detection 200-400 nm; Room temperature; Column head injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% ammonia solution; Eluent D: Acetonitrile / water (80 vol% / 20 vol%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 55 ml / min, Eluent B 15 ml / min; 2 to 10 minutes: Eluent A from 55 ml / min to 31 ml / min, Eluent B from 15 ml / min to 39 ml / min; 10 to 12 minutes: Eluent A 0 ml / min and Eluent B 70 ml / min; Eluent C and Eluent D were each at a constant flow rate of 5 ml / min throughout the run.

[0487] Method 11 (Preparative HPLC)

[0488] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5µm 100x30mm; UV detection 200-400 nm; Room temperature; Column head injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80 vol% / 20 vol%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 47 ml / min, Eluent B 23 ml / min; 2 to 10 minutes: Eluent A from 47 ml / min to 23 ml / min, Eluent B from 23 ml / min to 47 ml / min; 10 to 12 minutes: Eluent A 0 ml / min and Eluent B 70 ml / min; Eluent C and Eluent D were each at a constant flow rate of 5 ml / min throughout the run.

[0489] Method 12 (Preparative HPLC)

[0490] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5µm 100x30mm; UV detection 200-400 nm; Room temperature; Column head injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80% v / v / 20%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 23 ml / min, Eluent B 47 ml / min; 2 to 10 minutes: Eluent A from 23 ml / min to 0 ml / min, Eluent B from 47 ml / min to 70 ml / min; 10 to 12 minutes: Eluent A 0 ml / min and Eluent B 70 ml / min; Eluent C and Eluent D were each at a constant flow rate of 5 ml / min throughout the run.

[0491] Method 13 (Preparative HPLC)

[0492] Instrument: Waters Prep LC / MS system, Size: Phenomenex Kinetex C18 5µm 100x30mm, UV detection 200-400 nm, room temperature, column head injection (complete injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid aqueous solution, eluent D: acetonitrile / water (80 vol% / 20 vol%), flow rate: 80 ml / min, gradient curve: eluent A 0 to 2 min 70 ml / min, eluent B 0 to 2 min 0 ml / min, eluent A 2 to 10 min, from 70 ml / min to 0 ml / min, and eluent B from 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 were constant flow rates of 5 ml / min throughout the run.

[0493] Microwave: The microwave reactor used is an initiator with a robot 60 from Biotage. + Microwave system.

[0494] When the compounds of the present invention are purified by preparative HPLC using the above-described method where the eluent contains an additive (such as trifluoroacetic acid, formic acid, or ammonia), if the compounds of the present invention contain sufficient basic or acidic functionality, the compounds of the present invention can be obtained in the form of salts, such as trifluoroacetate salts, formate salts, or ammonium salts. Such salts can be converted into the corresponding free bases or acids by those skilled in the art using various known methods.

[0495] In the synthetic intermediates and working examples of the invention described below, any compound described as a salt of a corresponding base or acid is generally a salt of unknown exact stoichiometry obtained by its respective preparation and / or purification methods. Therefore, unless otherwise specified, additional terms such as “hydrochloride,” “trifluoroacetate,” “sodium salt,” or “x HCl,” “x CF3COOH,” “x Na…” are used in names and structural formulas. + In the case of this type of salt, it should not be understood in a stoichiometric sense, but rather in a descriptive sense regarding the salt-forming components present.

[0496] This applies if the synthetic intermediate or working example or its salt is obtained by the preparation and / or purification methods described herein in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0497] Enantiomer 1 The enantiomers that are first eluted from the chromatographic column when the preparative separation is completed under the separation conditions (see Example 4A).

[0498] Enantiomer 2 is The second enantiomer eluted from the column.

[0499] An exception is Example 4A, in which enantiomer 1 is the second eluted from the column, while enantiomer 2 is the first eluted from the column.

[0500] diastereomer mixture 1 A compound is defined as the starting material, which is defined as enantiomer 1, reacts with a structural unit containing at least one chiral center, and whose configuration is not limited.

[0501] diastereomer mixture 2 A compound is defined as the starting material, which is defined as enantiomer 2, and reacts with a structural unit containing at least one chiral center, and whose configuration is not limited.

[0502] diastereomer 1 and diastereomer 2 Two compounds generated by the chiral separation of the above diastereomer mixture 1 are defined.

[0503] diastereomer 3 and diastereomer 4 Two compounds generated by the chiral separation of the above diastereomer mixture 2 are defined.

[0504] Stereoisomer 1 A compound is defined as the starting material, which is defined as enantiomer 1, reacts with a structural unit containing at least one chiral center, and its configuration is defined.

[0505] Stereoisomer 2A compound is defined as the starting material, which is defined as enantiomer 2, reacts with a structural unit containing at least one chiral center, and its configuration is defined.

[0506] Experimental Section – Starting Materials and Intermediates

[0507] Example 1A

[0508] 3-{2-[(benzyloxy)carbonyl]hydrazinoyl}piperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[0509]

[0510] A solution of tert-butyl 3-oxopiperidinium-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. Sodium borohydride (114 g, 3.01 mol) was then added to the reaction mixture in portions, and the resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was cooled to 10 °C and adjusted to pH approximately 6 by dropwise addition of a saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (300 mL x 2), and the combined organic layers were evaporated. The residue was dissolved in MTBE (300 mL), and petroleum ether (300 mL) was added to the solution. The resulting suspension was filtered off and the precipitate was washed with petroleum ether (100 mL) to give 400 g (76.0% yield) of the title compound as a white solid.

[0511] LC-MS: (Method 1) Rt = 0.832 min, MS (M-100+1 = 250.4).

[0512] Example 2A

[0513] 3-Hydroxypiperidine-1-carboxylic acid tert-butyl acetic acid (racemic mixture)

[0514]

[0515] Pd / C (120 g, 20% purity) was added to a solution of tert-butyl piperidine-1-carboxylate (similar to the preparation in Example 1A, 1.20 kg, 3.43 mol) in ethanol (11.0 L) and acetic acid (415 g, 6.91 mol, 395 mL). The resulting suspension was stirred at 25 °C for 12 hours under a hydrogen atmosphere (15 Psi). The mixture was filtered and the precipitate was washed with ethanol (11.0 L) to give a black liquid solution of the title compound in ethanol (945 g), which was used in the next step without further purification.

[0516] 1 H-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).

[0517] LC-MS: (Method 1) Rt = 0.263 min, MS (M-56+1 = 160.2).

[0518] Example 3A

[0519] 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (racemic compound)

[0520]

[0521] 3-Hydroxypiperidine-1-carboxylic acid tert-butyl acetic acid (Example 2A, 945 g, 3.43 mol) in ethanol (20 L) was treated with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (907 g, 3.78 mol). The resulting mixture was stirred at 25 °C for 16 h, diluted with saturated sodium bicarbonate solution (2.0 L), and concentrated to about 5.0 L. The resulting mixture was diluted with water (5.0 L) and extracted with ethyl acetate (5.0 L). The organic phase was washed with saturated sodium chloride solution (5.0 L) and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate, 10:1) to give 548 g (41% yield) of the title compound.

[0522] 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).

[0523] Example 4A

[0524] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (racemic mixture)

[0525]

[0526] 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 3A, 548 g, 1.40 mol) was treated with a solution of dioxane (4 M, 2.38 L) containing hydrogen chloride, stirred at 25 °C for 2 h, and evaporated. The residue was redissolved in 1.0 L of water and extracted with MTBE (500 mL x 1). 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 (1.0 L x 2), and the combined organic layers were washed with saturated sodium chloride solution (1 L), dried over sodium sulfate, and evaporated to give 325 g (80% yield) of the title compound.

[0527] LC-MS: (Method 1) Rt = 0.955 min, MS (M +1) = 299.2.

[0528] The two enantiomers were subjected to SFC [325 g, column: Phenomenex-Cellulose-2 (250 mm * 50 mm, 10 µm); eluent: CO2 / (methanol + 0.1% ammonia); 75:25, 4.5 min; 1400 min] to obtain 103.0 g of enantiomer 1 (Example 5A) and 110.1 g of enantiomer 2 (Example 6A).

[0529] Example 5A

[0530] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0531]

[0532] For separation conditions, see Example 4A.

[0533] Analytical SFC: R t = 1.345 min, ee = 99% [Column Cellulose 2-3: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.5% diethylamine]: 95:5 to 60:40; flow rate: 3.0 ml / min; temperature: 35℃; UV detection: 220 nm, back pressure 100 bar].

[0534] LCMS (Method 2), R t = 0.906 min, MS (M +1) = 292.1.

[0535] 1 H-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).

[0536] Example 6A

[0537] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0538]

[0539] See Example 4A for separation conditions.

[0540] Analytical SFC: R t = 1.071 min, ee = 99% [Column Cellulose 2-3: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.5% diethylamine]: 95:5 to 60:40; flow rate: 3.0 ml / min; temperature: 35℃; UV detection: 220 nm, back pressure 100 bar].

[0541] LCMS (Method 2), R t = 0.906 min, MS (M +1) = 292.1.

[0542] 1 H-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).

[0543] Example 7A

[0544] 2-Bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene

[0545]

[0546] 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 19 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 13.8 g (86% yield) of the title compound.

[0547] LC-MS (Method 4): R t = 2.48 min; MS (ESIneg): m / z = 324 [MH] -

[0548] 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).

[0549] Example 8A

[0550] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0551]

[0552] Under argon atmosphere, a solution of 1,4-dioxane (1.1 L) of ethyl 1-[piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 5A, enantiomer 1, 75.0 g, 257 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared similarly to Example 7A, 84.4 g, 257 mmol) was treated with Pd2dba3 (23.6 g, 25.7 mmol), racemic-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 an aqueous solution of sodium chloride (10%) and ethyl acetate, filtered through diatomaceous earth, 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 an aqueous sodium chloride solution (10%), dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 119 g (71% yield) of the title compound.

[0553] LC-MS (Method 4): R t = 2.81 min; MS (ESIpos): m / z = 538 [M+H] +

[0554] Example 9A

[0555] 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0556]

[0557] A solution (1.8 L) of 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 8A, enantiomer 1, 119 g, 221 mmol) in dichloromethane was treated with trifluoroacetic acid (170 ml, 2.2 mol), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was carefully quenched with an aqueous solution of sodium bicarbonate (10%) until pH = 8. The phases were separated. The organic layer was evaporated, and the residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 85 g (90% purity, 92% yield) of the title compound.

[0558] LC-MS (Method 4): R t = 2.47 min; MS (ESIpos): m / z = 418 [M+H] +

[0559] Example 10A

[0560] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0561]

[0562] Under argon atmosphere, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 9A, enantiomer 1, 85.0 g, 90% purity, 184 mmol) in dichloromethane (520 ml) was cooled to -50 °C and treated with triethylamine (77 ml, 550 mmol). Trifluoromethanesulfonic anhydride (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-cooled water (590 ml). The aqueous layer was extracted with dichloromethane (520 ml). The combined organic layers were washed once with ice-cooled water (590 ml), dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 94 g (93% yield) of the title compound.

[0563] LC-MS (Method 4): R t = 2.79 min; MS (ESIpos): m / z = 550 [M+H] +

[0564] 1 H-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).

[0565] Example 11A

[0566] 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (enantiomer 1)

[0567]

[0568] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 10A, enantiomer 1, 92.1 g, 167 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)phenyl]piperazine-1-carboxylate tert-butyl ester (78.0 g, 201 mmol) in toluene (840 ml) and ethanol (840 ml) was treated with an aqueous solution of sodium carbonate (250 ml, 2.0 M, 500 mmol) and Pd(PPh3)4 (9.68 g, 8.37 mmol), and the resulting mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate gradient) to give 94 g (85% yield) of the title compound.

[0569] LC-MS (Method 4): R t = 3.19 min; MS (ESIpos): m / z = 662 [M+H] +

[0570] 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).

[0571] Example 12A

[0572] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (enantiomer 1)

[0573]

[0574] A solution of 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (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 stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was co-evaporated with MTBE to give 95 g (quantitative) of the title compound, which was used in the next step without further purification.

[0575] LC-MS (Method 4): R t= 1.97 min; MS (ESIpos): m / z = 562 [M+H] +

[0576] Example 13A

[0577] 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0578]

[0579] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (Example 12A, enantiomer 1, 95.0 g, 150 mmol) in THF (1.8 L) was treated with N,N-diisopropylethylamine (100 ml, 600 mmol) and 2-methylpropionaldehyde [CAS No. 78-84-2] (53.9 g, 748 mmol) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (127 g, 598 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate (10%) and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate gradient) to give 78 g (84% yield) of the title compound.

[0580] LC-MS (Method 4): R t = 2.03 min; MS (ESIpos): m / z = 618 [M+H] +

[0581] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.827 (0.53), 0.839 (0.55), 0.867(0.66), 0.871 (0.81), 0.883 (15.73), 0.894 (16.00), 1.041 (0.92), 1.090(1.35), 1.241 (4.62), 1.252 (9.48), 1.264 (4.77), 1.554 (0.58), 1.575 (0.64), 1.753 (0.80), 1.775 (0.81), 1.786 (0.63), 1.798 (0.90), 1.809 (1.08), 1.820 (0.88), 1.831 (0.48), 1.889 (0.64), 1.895 (0.58), 1.909 (0.66), 1.916 (0.63), 1.988 (0.94), 1.998 (0.79), 2.015 (0.59), 2.085 (4.57), 2.097 (4.16), 2.467 (3.65), 2.476 (5.06), 2.483 (4.05), 2.595 (0.61), 2.612 (1.08), 2.615 (1.10), 2.631 (0.59), 2.937 (0.86), 2.955 (1.65), 2.972 (0.98), 3.073 (0.84), 3.093(0.80), 3.156 (3.65), 3.164 (4.72), 3.172 (3.66), 3.212 (0.97), 3.227 (0.83), 4.221 (1.39), 4.233 (4.19), 4.245 (4.15), 4.256 (1.41), 4.362 (0.49), 4.379(0.85), 4.397 (0.49), 6.949 (3.70), 6.963 (3.93), 7.060 (2.66), 7.063 (3.31), 7.082 (1.52), 7.085 (1.15), 7.095 (2.12), 7.099 (1.92), 7.141 (3.61), 7.154 (2.29), 7.411 (4.15), 7.426 (3.95), 8.049 (4.51).

[0582] Experimental Section – Compounds of Examples

[0583] Example 1

[0584] 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (enantiomer 1)

[0585]

[0586] An aqueous solution of lithium hydroxide (1.2 L, 1.0 M, 1.2 mol) was added to a solution of 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (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 a pH of approximately 2 with an aqueous solution of hydrogen chloride (2N). The reaction mixture was diluted with dichloromethane. The organic layer was washed with water and evaporated to give 74 g (quantitative) of the title compound, which was used in the next step without further purification.

[0587] LC-MS (Method 4): R t = 1.74 min; MS (ESIpos): m / z = 590 [M+H] +

[0588] 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).

[0589] Example 2

[0590] 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (enantiomer 1)

[0591]

[0592] Method A

[0593] A solution of 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-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 evaporated to give 82 g (quantitative) of the title compound.

[0594] LC-MS (Method 4): R t = 1.77 min; MS (ESIpos): m / z = 590 [M-HCl+H] +

[0595] 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)。

[0596] Method B

[0597] 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 (prepared similarly to Example 13A, enantiomer 1, 149 mg, 241 μmol) was dissolved in THF / ethanol (6.3 / 0.63 ml). A 1 M lithium hydroxide aqueous solution (2.4 ml, 2.4 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was evaporated, acidified, and purified using preparative HPLC (RP18 column, acetonitrile / water gradient, with 0.1% TFA added). The product fractions were combined and evaporated. The residue was then dissolved in acetonitrile, mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated (three times) at 30 °C, and then lyophilized. 130 mg of the target compound was obtained (85% of the theoretical value).

[0598] LC-MS (Method 4): R t = 1.81 min; MS (ESIpos): m / z = 590 [M-HCl+H] +

[0599] 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).

[0600] [α] D 20 = -68.23°, c = 0.49 g / 100 cm 3 , chloroform.

[0601] Comparative Example 174 (WO2012 / 058132)

[0602] 1-{1-[4-chloro-4'-(4-cyclopropylmethylpiperazin-1-yl)[biphenyl]-2-yl]pyridin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0603]

[0604] The compound was synthesized according to the method disclosed in WO 2012 / 058132 (Experimental Section, pages 58 to 84).

[0605] B. Evaluation of pharmacological efficacy and pharmacokinetic characteristics

[0606] Use the following abbreviations:

[0607]

[0608] Biological research

[0609] The test experiments described in this article are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0610] The following tests can be used to illustrate the commercial use of the compounds of this invention.

[0611] Examples of the experiments involve one or more tests in selected biological experiments. When the tests are performed more than once, the recorded data are the average or median, where...

[0612] The mean, also known as the arithmetic mean, is the sum of the values ​​obtained divided by the number of tests.

[0613] The median represents the middle value in a set of values ​​when sorted in ascending or descending order. If the number of values ​​in the dataset is odd, the median is the middle value. If the number of values ​​in the dataset is even, the median is the arithmetic mean of the two middle values.

[0614] Examples are synthesized once or multiple times. When synthesized more than once, the data from the biological experiment represent the average value calculated using datasets obtained from tests of one or more synthetic batches.

[0615] The in vitro activity of the compounds of this invention can be demonstrated in the following tests.

[0616] The pharmacological effects of the compounds of this invention can be demonstrated in the following experiments:

[0617] B-1. Effects on recombinant guanylate cyclase reporter cell lines

[0618] The cellular activity of the compounds of the present invention was determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunderet al., Anal. Biochem. 339, 104-112 (2005).

[0619] Representative MEC values ​​(MEC = minimum effective concentration) and EC values ​​of the compounds of this invention 50The half-maximum effective concentration (WMC) values ​​are shown in the table below (in some cases, they are the average of multiple individual measurements):

[0620] Table 2:

[0621]

[0622] B-2. In vitro vasodilatory effect

[0623] Rabbits were euthanized and bled under deep anesthesia. The aorta was separated from the adhering tissue and divided into multiple rings 1.5 mm wide. At 37°C, under prestress, each ring was placed in a 5 ml organ bath containing a Krebs-Henseleit solution with supplied carbokin gas. The solution contained the following components (each component in mM): sodium chloride: 11g; potassium chloride: 4.8g; calcium chloride dihydrate: 1g; magnesium sulfate heptahydrate: 1.4g; potassium dihydrogen phosphate: 1.2g; sodium bicarbonate: 25g; glucose: 10g. To induce contraction, phenylephrine was added to the organ bath in increasing concentrations. After several control cycles, the study substance was added in increasing doses in each subsequent cycle, and the contraction amplitude was compared with that obtained in the previous cycle. The concentration required to reduce the control amplitude by 50% (IC50) was calculated. 50 (Value). The standard dosage volume is 5 µl; the DMSO content in the bath solution is equivalent to 0.1%.

[0624] B-3. ​​Blood pressure measurement in anesthetized rats

[0625] Male Wistar rats weighing 300-350 g were anesthetized with thiopental sodium (100 mg / kg ip). After tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. The test substance was administered in solution form, orally via tube feeding or via femoral vein injection (Stasch et al. Br. J. Pharmacol. 2002; 135: 344-355).

[0626] B-4. Radio telemetry of blood pressure in awake, spontaneously hypertensive rats

[0627] The DATA SCIENCES INTERNATIONAL DSI, USA commercially available telemetry system is used to measure the blood pressure of awake rats as described below.

[0628] The system consists of three main components:

[0629] - Implantable transmitter (Physiotel) ® Telemetry transmitter)

[0630] - Receiver (Physiotel) ® The receiver is connected to the data acquisition computer via a multiplexer (DSI Data Exchange Matrix2.0).

[0631] The telemetry system can continuously record the blood pressure, heart rate, and body movements of conscious animals in their usual habitat.

[0632] Animal materials

[0633] These studies were conducted on adult female spontaneously hypertensive rats (SHR Okamoto) weighing >200 g. The SHR / NCrl, originating from the Okamoto Kyoto Medical School in 1963, is a hybrid of a male Wistar Kyoto rat with significantly elevated blood pressure and a female rat with slightly elevated blood pressure, and was transferred to the National Institutes of Health in the US at F13.

[0634] After the transmitter was implanted, the experimental animals were housed individually in Type 3 Makrolon cages. They had free access to standard feed and water.

[0635] The laboratory's day / night rhythm was altered by the room lighting at 6:00 AM and 7:00 PM.

[0636] Transmitter Implantation

[0637] The HD S 10 telemetry transmitter used was surgically implanted into experimental animals under sterile conditions at least 14 days prior to its first experimental use. Animals with the device implanted in this manner can be reused after wound healing and implant stabilization.

[0638] For implantation, the fasted animal was anesthetized with isoflurane (Rimadyl analgesic), and its abdomen was extensively shaved and disinfected. After opening the abdominal cavity along the linea alba, the system's fluid measurement catheter was inserted into the descending aorta along the skull above the bifurcation and fixed with tissue glue (VetBonD™, 3M). The transmitter shell was then fixed to the abdominal wall muscles through the abdominal cavity, and the wound was closed layer by layer.

[0639] Postoperative antibiotics (Ursocyclin 10% pro inj., Serumwerk, sc) were administered to prevent infection.

[0640] Substances and solutions

[0641] Unless otherwise specified, the test substance was administered orally to one group of animals (n = 6) via tube feeding. The test substance was dissolved in a suitable solvent mixture or suspended in 0.5% methylcellulose at a dosage volume of 2 ml / kg body weight.

[0642] The group of animals treated with solvent served as a control.

[0643] Experimental methods

[0644] The telemetry measurement unit was deployed in 24 animals. Each experiment was recorded under an experiment number (V year month day).

[0645] Each rat in the system was equipped with an individual receiving antenna (RPC-1 Receiver, DSI).

[0646] The implanted transmitters can be activated externally via a built-in magnetic switch. Before testing begins, they are switched to transmission mode. The emitted signals can be detected and processed online by a data acquisition system (Physio Tel HD, DSI). In each case, the data is stored in a file created specifically for that experiment and numbered accordingly.

[0647] In the standard method, the following parameters are measured for 10 seconds in all cases:

[0648] Systolic blood pressure (SBP)

[0649] Diastolic blood pressure (DBP)

[0650] Mean arterial pressure (MAP)

[0651] Heart rate (HR)

[0652] Activity (TEMP).

[0653] Measurements are collected every 5 minutes under computer control. The source data, obtained as absolute values, are corrected in the charts using the currently measured air pressure (Ambient Pressure Reference Monitor; APR-1) and stored separately. More technical details are available in extensive documentation from the manufacturer, DSI.

[0654] Unless otherwise specified, the test substance was administered at 9:00 AM on the day of the experiment. The above parameters were measured over 24 hours after administration.

[0655] Evaluate

[0656] After the experiment, the acquired individual data were processed using analysis software (Ponemah V 6.x). This paper assumes that the blank period is 2 hours before drug administration; therefore, the selected dataset includes the time period from 7:00 AM on the day of the experiment to 9:00 AM the following day.

[0657] Data was smoothed by measuring averages (30-minute averages) over a predetermined time period and transferred to a storage medium as an Excel file. The pre-classified and compressed measurements were then transferred to an Excel template and tabulated. Data obtained each day of the experiment was stored in a dedicated file with an experiment number. Results and test protocols were stored in paper form, categorized by number.

[0658] literature:

[0659] Int RevExp Pathol 7: 227- 270, 1969; Maarten van den Buuse: Circadian Rhythms ofBlood Pressure, Heart Rate, and Locomotor Activity in SpontaneouslyHypertensive Rats as Measured With Radio-Telemetry. Physiology & Behavior 55(4): 783-787, 1994.

[0660] B-5. Determination of pharmacokinetic parameters after intravenous and oral administration

[0661] The pharmacokinetic parameters of the compounds of this invention were determined in male Wistar rats and / or female beagle dogs and / or cynomolgus monkeys and / or male CD-1 mice. Mice and rats were administered intravenously via species-specific plasma / DMSO formulations, while dogs and monkeys were administered intravenously via water / PEG400 / ethanol formulations. In all species, oral administration of the dissolved substances was performed via tube feeding based on the water / PEG400 / ethanol formulation.

[0662] An internal standard (which may also be a chemically unrelated substance) is added to the sample, calibration sample, and qualifier of the compound of this invention, and then the protein is precipitated with excess acetonitrile. A buffer solution matched to the LC conditions is added, followed by vortexing and centrifugation at 1000 g. The supernatant is analyzed by LC-MS / MS using a C18 reversed-phase column and a variable mobile phase mixture. Substances are quantified by peak height or peak area in the ion chromatograms extracted using a specific selected ion monitoring experiment.

[0663] Using a validated pharmacokinetic calculation program, the measured plasma concentration / time plot was used to calculate pharmacokinetic parameters such as AUC, Cmax, and t. 1 / 2 (Terminal half-life), F (bioavailability), MRT (mean residence time), and CL (clearance).

[0664] Since the substance is quantified in plasma, it is necessary to determine the blood / plasma distribution of the substance in order to adjust the pharmacokinetic parameters accordingly. For this purpose, a defined amount of the substance was incubated in K3 EDTA whole blood of the species in a rocking roller mixer for 20 minutes. After centrifugation at 1000 g, the plasma concentration was measured (by LC-MS / MS; see above) and Cp was calculated. 血液 / C 血浆 The ratio is used to determine this.

[0665] Table 3 shows data on the intravenous administration of representative compounds of the present invention to rats:

[0666] Table 3:

[0667]

[0668] Table 4 shows the data of oral administration of representative compounds of the present invention to rats:

[0669] Table 4:

[0670]

[0671] Table 5 shows data on the intravenous administration of representative compounds of the present invention in dogs:

[0672] Table 5:

[0673]

[0674] Table 6 shows data on the oral administration (po) of representative compounds of the present invention in dogs:

[0675] Table 6:

[0676]

[0677] Compared to compounds disclosed in the prior art (WO 2012 / 058132), the compounds of the present invention exhibit superior pharmacokinetic (PK) properties (see Experimental Section, Tables 3 to 6). For example, Example 2 of the present invention showed a lower plasma clearance (CL) in both rats and dogs compared to the prior art compound disclosed as Example 174 in WO 2012 / 058132. 血浆 (Up to 10 times) and the resulting high exposure. Example 2 also shows a longer half-life and mean residence time (MRT) after oral administration (po) for all test species. Because all test species were administered orally, Example 2 showed significantly lower plasma clearance and the resulting extremely high exposure (AUC). 标准 With good bioavailability, we see that the pharmacokinetic (PK) characteristics are significantly superior to those of Example 174 disclosed in WO 2012 / 058132.

[0678] B-6. Metabolic Research

[0679] To determine the metabolic characteristics of the compounds of the present invention, they were incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes, or primary fresh hepatocytes from various animal species (e.g., rats, dogs) and human sources to obtain and compare information on substantially intact phase I and II liver metabolism and the enzymes involved in said metabolism.

[0680] The compounds of the present invention were incubated at a concentration of about 0.1-10 μM. For this purpose, an acetonitrile stock solution of the compound of the present invention at a concentration of 0.01-1 mM was prepared and then pipetteted into the incubation mixture at a dilution of 1:100. Liver microsomes and recombinant enzymes were incubated at 37°C in 50 mM potassium phosphate buffer (pH 7.4), the buffer containing and not containing 1 mM NADP. + A NADPH-generating system consisting of 10 mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase was used. Primary hepatocytes were suspended and incubated in Williams E medium at 37°C. After 0–4 hours of incubation, the incubation mixture was terminated with acetonitrile (final concentration approximately 30%), and proteins were separated by centrifugation at approximately 15,000 xg. Samples terminated in this manner were used directly for analysis or stored at -20°C until analysis.

[0681] Analysis was performed using high-performance liquid chromatography-ultraviolet-mass spectrometry (HPLC-UV-MS / MS). For this purpose, the supernatant of the incubated sample was analyzed using a suitable C18 reversed-phase column and a variable mobile phase mixture of acetonitrile and 10 mM ammonium formate aqueous solution or 0.05% formic acid. The UV spectra combined with mass spectrometry data can be used for the identification, structural resolution, and quantitative estimation of metabolites, and can also be used to calculate the quantitative metabolic reduction of the compounds of this invention in the incubation mixture.

[0682] B-7. Caco-2 Permeability Test

[0683] The permeability of the tested substance was determined using the Caco-2 cell line, an established in vitro model for predicting gastrointestinal barrier permeability (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 to 16 days. For permeability studies, the tested substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks buffered saline, Gibco / Invitrogen, containing 19.9 mM glucose and 9.8 mM HEPES). To determine the permeability (P) of the tested material from the tip to the outer side of the substrate. app AB), a solution containing the test substance was applied to the apical side of a Caco-2 cell monolayer, and a transport buffer was applied to the lateral side of the substrate. To determine the permeability of the test substance from the lateral side of the substrate to the apex (P... app BA) was used to apply a solution containing the test substance to the basal side of a Caco-2 cell monolayer, while a transport buffer was applied to the apical side. At the start of the experiment, samples were taken from each donor compartment to ensure mass balance. After incubation at 37°C for two hours, samples were removed from both compartments. The samples were analyzed by LC-MS / MS, and the apparent permeability (P) was calculated. appFor each cell monolayer, the permeability of fluorescein was measured to ensure cell layer integrity. In each test run, the permeability of atenolol (a marker of low permeability) and sulfasalazine (a marker of active efflux) was measured as quality controls.

[0684] Determination of solubility of substances in pH 6.5 buffer solution B-8

[0685] Dissolve 2–4 mg of the analyte in DMSO to achieve a concentration of 50 g / L (Solution A, 515 µg / L). Add 960 µL of pH 6.5 PBS buffer to 10 µL of this solution; incubate the mixture in a 96-well plate and shake at room temperature for 24 hours. Centrifuge an aliquot of the sample at 42,000 rpm for 30 minutes. Dilute the supernatant with acetonitrile / water (8:2) at 1:10 and 1:1000, respectively. Analyze these diluted samples by LC-MS.

[0686] Calibration: 10 µl of solution A was diluted with 823 µl of DMSO (final concentration: 600 µg / ml), and then diluted 100 times with acetonitrile / water (8:2) (solution B).

[0687] Solution B was further diluted with acetonitrile / water (8:2) to obtain solutions with target concentrations of 1.2 - 12 - 60 - 600 ng / ml. These four solutions were then injected for mass spectrometry analysis to obtain calibration curves.

[0688] Mass spectrometry method optimization:

[0689] Solution B is used for mass spectrometry method optimization.

[0690] PBS-Puffer: Dissolve 6.18 g sodium chloride and 3.96 g sodium dihydrogen phosphate in 1 L of distilled water, and adjust the pH to 6.5 with 1 N sodium hydroxide.

[0691] LC-MSMS optimization:

[0692] The following configuration is for optimization.

[0693] 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.

[0694] Elution Buffer A: 0.5 ml formic acid (50% ig) / L water; Elution Buffer B: 0.5 ml formic acid (50% ig) / L acetonitrile

[0695]

[0696] Autosampler: No autosampler pre-set

[0697] Chromatographic column: Stainless steel capillary tube

[0698] Oven temperature: 22℃

[0699] Flow rate: flow gradient

[0700] Injection volume: 2 µl

[0701] Water Quattro Micro MS, Agilent 1100 (G1312A), degasser (G1322A), column oven (G1316A), CTC Analytics PAL injection system HTS, and eluent as above.

[0702] Time [min] Flow rate [µl / min] %B 0.00 250 70 1.50 250 70

[0705] Autosampler: Features pre-set autosampler settings

[0706] Chromatographic column: Stainless steel capillary tube

[0707] Oven temperature: 22℃

[0708] Flow rate: flow gradient

[0709] Injection volume: 5 µl

[0710] Mass spectrometry method: Flow injection analysis (FIA) for optimization (“MS-OPTI”);

[0711] Ionization modes: ABSciex-MS: ESI-pos / neg, Waters-MS: ESI-pos

[0712] HPLC method for MSMS quantification:

[0713] Eluents A and B are the same as above.

[0714] ABSciex-MS

[0715]

[0716] Autosampler: No autosampler pre-set

[0717] Column: Waters OASIS HLB, 2.1 x 20 mm, 25 µm

[0718] Column temperature: 30℃

[0719] Flow rate: 2.5 ml

[0720] Injection volume: 2 µl

[0721] Splitter (before MS) 1:20

[0722] Waters-MS

[0723]

[0724] Autosampler: Features pre-set autosampler settings

[0725] Column: Waters OASIS HLB, 2.1 x 20 mm, 25 µm

[0726] Column temperature: 30℃

[0727] Flow rate: 2.5ml

[0728] Injection volume: 5 µl

[0729] 1:20 splitter (before MS)

[0730] MS method: Multiple Response Monitoring (MRM)

[0731] B-9 Determination of the solubility of solids

[0732] For each solvent, place 0.5–1 mg of the analyte (accurate weight), 2–3 glass beads (3 mm in diameter), and 1.0 ml of the corresponding solvent into an Eppendorf plastic vial. Seal the vial and shake at room temperature for 24 hours (1400 rpm; Thermomixer, Eppendorf). Afterward, transfer 230 µl of each solution / suspension to one or more centrifuge tubes (Beckman Coulter) and centrifuge at 42,000 rpm for 30 minutes (Beckman Coulter Optima L90). Extract at least 100 µl of the supernatant and further dilute with DMSO at two dilution strengths: 1:5 and 1:50 (the latter is obtained by adding DMSO after the 1:5 dilution step). This liquid handling can be done manually or with the assistance of a pipetting robot (Lissy, Zinsser Analytic).

[0733] For HPLC quantification, DMSO calibration solutions of the analyte compounds were prepared. Starting from 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 via Lissy).

[0734] Both the calibration solution and the supernatant were analyzed by HPLC / UV detector at an appropriate wavelength. Solubility was determined using a linear calibration curve.

[0735] HPLC system:

[0736] Hewlett Packard / Agilent HPLC systems, G1311A+G1316A+G1315B and G1312A+G1316A+G1315A

[0737] Injector system: CTC-Analytik HTC PAL

[0738] Alternatively, use an Agilent HPLC system (G7117C, G7116B, G7167B, and G7120).

[0739] Oven temperature: 30℃, detection: 210 and / or 254 nm, injection volume: 20 µl

[0740] Elution buffer A: 0.1% TFA aqueous solution; Elution buffer B: 0.1% TFA acetonitrile solution

[0741] Column: ZORBAX Extend-C18, 3.0 x 50 mm, 3.5 µm

[0742] gradient:

[0743]

[0744] C. Working Examples of Pharmaceutical Compositions

[0745] The compounds of this invention can be converted into the following pharmaceutical formulations:

[0746] tablet:

[0747] Element:

[0748] 100 mg of the compound of the present invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

[0749] The tablet weighs 212 mg. It has a diameter of 8 mm and a radius of curvature of 12 mm.

[0750] preparation:

[0751] The mixture of the compound, lactose, and starch of this invention was granulated using a 5% (w / w) aqueous solution of PVP. The granules were dried and then mixed with magnesium stearate for 5 minutes. The mixture was then compressed into tablets using a conventional tableting machine (tablet specifications are described above). The guideline for compression was a pressure of 15 kN.

[0752] Suspension formulations for oral administration:

[0753] Element:

[0754] 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.

[0755] 10 ml of oral suspension is equivalent to a single dose of 100 mg of the compound of the present invention.

[0756] preparation:

[0757] Rhodigel was suspended in ethanol; the compound of the present invention was added to the suspension. Water was added while stirring. The mixture was stirred for about 6 hours until the Rhodigel was completely swollen.

[0758] Solutions for oral administration:

[0759] Element:

[0760] 500 mg of the compound of the present invention, 2.5 g of polysorbate, and 97 g of polyethylene glycol 400. 20 g oral solution are equivalent to a single dose of 100 mg of the compound of the present invention.

[0761] preparation:

[0762] The compound of the present invention is suspended in a mixture of polyethylene glycol and polysorbate under stirring. Stirring continues until the compound of the present invention is completely dissolved.

[0763] Intravenous injection solution:

[0764] The compounds of the present invention are dissolved at concentrations below saturation solubility in physiologically acceptable solvents (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution). The solutions are filtered and sterilized for filling sterile and pyrogen-free injection containers.

Claims

1. A compound or a salt thereof, said compound having the following formula: 。 2. The compound according to claim 1 or a salt thereof, wherein it is enantiomer 1 of 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, and its specific rotation is: [a]D20 = -68.23°, c = 0.49 g / 100 cm 3 , chloroform.

3. Use of the compound or salt thereof according to claim 1 or 2 in the preparation of medicaments for the treatment and / or prevention of heart failure, hypertension (HTN), chronic kidney disease (CKD) and diabetic kidney disease (DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcers (DFU).

4. The use of claim 3, wherein the heart failure is HFrEF, HFmrEF, or HFpEF.

5. A pharmaceutical product comprising the compound of claim 1 or 2 or a salt thereof, and an inert, non-toxic, pharmaceutically suitable excipient.

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