PYRAZOL PIPERIDINE-SUBSTITUTED CARBOXYLIC ACIDS, THEIR PREPARATION PROCESS AND MEDICINE

Description

1 / 152 PYRAZOL PIPERIDINE CARBOXYLIC ACIDS SUBSTITUTED, THEIR PREPARATION PROCESS, AND MEDICINE Separated from BR112023008374-5, filed on December 9, 2021.

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

[002] Furthermore, the same pathophysiological mechanisms mentioned above are effective when blood transfusions (e.g., by storage etc. with a high concentration of free Hb) are administered to patients with an indication for transfusion.

[003] Furthermore, in the future, the combination of an sGC activator with a synthetic Hb-based oxygen carrier may mitigate the side effects observed so far [Weiskopf, Anesthesia & Analgesia, 110:3; 659-661, 2010] that are caused by reduced NO availability, thus allowing clinical application.

[004] One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and Petition 870260054097, dated 03 / 06 / 2026, page 5 / 326 2 / 152 transmits hormonal and mechanical signals, forming the NO / cGMP system. Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The representatives of this family disclosed so far can be divided, both according to structural characteristics and according to the type of ligands, into two groups: particulate guanylate cyclases, which can be stimulated by natriuretic peptides, and soluble guanylate cyclases, which can be stimulated by NO. Soluble guanylate cyclases consist of two subunits and most likely contain a heme per heterodimer, which is part of the regulatory site. The latter is of central importance to the activation mechanism. NO is able to bind to the iron atom of the heme and thus markedly increase the enzyme's activity. Heme-free preparations, on the other hand, cannot be stimulated by NO.Carbon monoxide (CO) is also capable of binding to the central iron atom of heme, but the stimulation by CO is significantly less than by NO.

[005] Through the production of cGMP and the resulting regulation of phosphodiesterases, ion channels, and protein kinases, guanylate cyclase plays a crucial role in several physiological processes, particularly in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, and neuronal signal transmission, and in disorders caused by impairment of the aforementioned processes. Under pathophysiological conditions, the NO / cGMP system can be suppressed, which can lead, for example, to hypertension, platelet activation, increased cell proliferation and fibrosis, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke, and myocardial infarction.

[006] One possible way to treat such disorders that is independent of NO and aims to influence the cGMP signaling pathway Petition 870260054097, dated 03 / 06 / 2026, p. 6 / 326 3 / 152 in organisms is a promising approach due to its high efficiency and few expected side effects.

[007] Compounds, such as organic nitrates, whose effect is based on NO, have been used until now exclusively for therapeutic stimulation of soluble guanylate cyclase. NO is produced by bioconversion and activates soluble guanylate cyclase by binding to the central iron atom of heme. In addition to side effects, the development of tolerance is one of the crucial disadvantages of this treatment method [OV Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

[008] Substances that directly stimulate soluble guanylate cyclase, i.e., without prior release of NO, have been identified in recent years. The indazole derivative YC-1 was the first NO-independent, but hemo-dependent, sGC stimulator described [Evgenov et al., ibid.]. Based on YC-1, other substances that are more potent than YC-1 and do not exhibit relevant inhibition of phosphodiesterases (PDEs) have been found. This led to the identification of the pyrazolopyridine derivatives BAY 41-2272, BAY 41-8543, BAY 63-2521, and BAY 1021189. Together with the recently published structurally different substances CMF-1571 and A-350619, these compounds form the new class of sGC stimulators [Evgenov et al., ibid.]. A common characteristic of this class of substances is a selective and NO-independent activation of heme-containing sGCs.Furthermore, sGC stimulators in combination with NO have a synergistic effect on sGC activation based on the stabilization of the nitrosyl-heme complex. The exact binding site of sGC stimulators on sGC is still being debated. If the heme group is removed from soluble guanylate cyclase, the enzyme still possesses detectable basal catalytic activity, i.e., cGMP is still being formed. The remaining basal catalytic activity of the enzyme without heme cannot be stimulated by any of the stimulators mentioned above [Evgenov et al., ibid.]. Petition 870260054097, dated 03 / 06 / 2026, page 7 / 326 4 / 152

[009] Furthermore, NO- and heme-independent sGC activators have been identified, with BAY 58-2667 as the prototype of this class. The common characteristics of these substances are that, in combination with NO, they have only an additive effect on enzyme activation and that the activation of the oxidized or heme-free enzyme is markedly greater than that of the heme-containing enzyme [Evgenov et al., ibid.; JP Stasch et al., Br. J. Pharmacol. 136 (2002), 773; JP Stasch et al., J. Clin. Invest. 116 (2006), 2552]. Spectroscopic studies show that BAY 58-2667 displaces the oxidized heme group which, as a result of the weakening of the iron-histidine bond, is only weakly bound to sGC. It has also been shown that the characteristic heme binding motif sGC Tyr-x-Ser-x-Arg is absolutely essential for both the interaction of the negatively charged propionic acids of the heme group and for the action of BAY 58-2667.In this context, the BAY 58-2667 binding site in sGC is assumed to be identical to the heme group binding site [JP Stasch et al., J. Clin. Invest. 116 (2006), 2552].

[0010] The sGC activator Runcaciguat (Hahn et al., Drugs Future (2018), 738, WO 2012 / 139888) is in 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 treatment potential of sGC activators is not yet fully clear. However, since oxidative stress can render the heme enzyme sGC free of sGC activators, sGC activators may have even broader treatment potential that still needs to be identified and proven in the future.

[0011] The compounds described in the present invention are now equally capable of activating the heme-free form of soluble guanylate cyclase. This is also confirmed by the fact that these new activators, firstly, do not have synergistic action with NO in Petition 870260054097, dated 03 / 06 / 2026, page 8 / 326 5 / 152 heme-containing enzyme and, secondly, its action cannot be blocked by the heme-dependent inhibitor of soluble guanylate cyclase, 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but is still potentiated by this inhibitor [cf. OV Evgenov et al., Nature Rev. 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. In contrast to the compounds according to the present invention, these compounds have a heteroaromatic pyridine moiety that links the pyrazole carboxylic acid to the rest of the molecule. Furthermore, the pyridine nitrogen has a different position from the piperidine nitrogen of the compounds according to the present invention. However, these compounds exhibit only mediocre pharmacokinetic properties, such as moderate clearance (CL) and intermediate half-life and mean residence time (MRT) after intravenous (iv) administration in preclinical pharmacokinetic models.

[0013] It is therefore an objective of the present invention to provide novel sGC-activating compounds for the treatment and / or prophylaxis of diseases, in particular cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFrEF and HFpEF), hypertension (HTN), peripheral arterial disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic and diabetic kidney disease (CKD and CKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH) and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), wound healing disorders such as diabetic foot ulcer (DFU), in humans and animals, whose compounds exhibit a good Petition 870260054097, dated 03 / 06 / 2026, page 9 / 326 6 / 152 pharmacokinetic behavior with a good pharmacological activity profile, as well as beneficial physicochemical properties (e.g., solubility).

[0014] Surprisingly, it has now been found that certain substituted pyrazolopiperidine carboxylic acids, as well as salts thereof, represent highly potent sGC activators with good pharmacokinetic behavior with a good pharmacological activity profile, as well as beneficial physicochemical properties (e.g., solubility).

[0015] The invention provides compounds of Formula (I) OH (I) in which R1 represents hydrogen or halogen, R2 represents hydrogen or halogen. R3 stands for chlorine or trifluoromethyl. R4 represents hydrogen or C1-C4-alkyl R5 represents C1-C6-alkyl X1 represents nitrogen or carbon. X2 represents nitrogen or carbon and their salts, their solvates, and the solvates of their salts.

[0016] The term “substituted” means that one or more hydrogen atoms in the designated atom or group are replaced by a selection from the indicated group, provided the normal valence of the atom Petition 870260054097, dated 03 / 06 / 2026, p. 10 / 326 7 / 152, as designated under the existing circumstances, is not exceeded. Combinations of substituents and / or variables are permitted.

[0017] As used herein, the term “one or more”, for example, in the definition of the substituents of the compounds of General Formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2”.

[0018] In the context of the present invention, unless otherwise indicated, substituents are defined as follows:

[0019] The term “halogen” or “halogen” as in combinations, for example, in halogenoalkyl means an atom of fluorine, chlorine, bromine or iodine, particularly an atom of fluorine, chlorine or bromine, even more particularly fluorine or chlorine.

[0020] The term “C1-C4-alkyl”, “C1-C5-alkyl” and “C1-C6-alkyl” means a monovalent, saturated, linear or branched hydrocarbon group with 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, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl or an isomer thereof.Specifically, the said group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl or tert-butyl group, more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), for example, a methyl, ethyl, n-propyl or isopropyl group.

[0021] The terms “C1-C6-halogenalkyl”, “C2-C6-halogenalkyl”, “C1-C4-halogenalkyl”, “C2-C4-halogenalkyl”, “C1-C3-halogenalkyl alkyl” and “C1-C2-halo genoalkyl” represent a group of linear or branched, saturated, monovalent hydrocarbons in which the Petition 870260054097, dated 03 / 06 / 2026, p. 11 / 326 8 / 152 The term “alkyl” is as defined above and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. In particular, said halogen atom is a fluorine atom. Said C1-C6-halogenalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropan-1-yl, 1,1,1-trifluoropropan-2-yl, 1,3-difluoropropan-2-yl, 3-fluoropropan-1-yl, 1,1,1-trifluorobutan-2-yl and 3,3,3-trifluoro-1-methylpropan-1-yl.

[0022] The terms “C1-C4-halogenalkoxy” and “C1-C3-halogenalkoxy” represent a linear or branched, saturated, monovalent C1-C4-alkoxy or C1-C3-alkoxy group (wherein alkoxy represents a linear or branched monovalent alkoxy chain or radical with 1 to 4 or 1 to 3 carbon atoms, by way of example and preferably methoxy, ethoxy, n-propoxy, isopropoxy), in which one or more of the hydrogen atoms are replaced, identically or differently, by a halogen atom. In particular, said halogen atom is a fluorine atom. Said C1-C3-halogenalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

[0023] The term “C3-C6-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms. The said C3-C6 cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0024] The compounds according to the invention are the compounds of Formula (I) and the salts, solvates and solvates of the salts thereof, and also the compounds covered by Formula (I) and specified below as working example(s), and the salts, solvates and solvates of the salts thereof, insofar as the compounds covered by Formula (I) and specified below are not already salts, solvates and Petition 870260054097, dated 03 / 06 / 2026, p. 12 / 326 9 / 152 solvates of the salts.

[0025] The compounds of the invention may, depending on their structure, exist in different stereoisomeric forms, i.e., in the form of configurational isomers or, if applicable, conformational isomers (enantiomers and / or diastereomers, including rotamers and atropisomers). The present invention therefore encompasses enantiomers and diastereomers and their respective mixtures. Stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and / or diastereomers in a known manner; chromatographic processes are preferably used for this purpose, especially HPLC chromatography in an achiral or chiral phase.

[0026] The present invention includes all possible tautomers of the compounds of the present invention as simple tautomers, or as any mixture of said tautomers, in any proportion.

[0027] In the context of the present invention, the term “enantiomerically pure” is understood to mean that the compound in question, with respect to the absolute configuration of the chiral center, is present in an enantiomeric excess greater than 95%, preferably greater than 97%. The enantiomeric excess (ee value) is calculated in this case by evaluating the corresponding HPLC chromatogram in a chiral phase using the formula below: ee = [EA(area%) - EB(area%)] x 100% / [EA(area%) + EB (area%)] (EA: enantiomer in excess, EB: enantiomer in deficiency)

[0028] The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of an inventive compound is understood here to mean a compound in which at least one atom within the inventive compound has been replaced by another atom of the same number. Petition 870260054097, dated 03 / 06 / 2026, p. 13 / 326 10 / 152 atomic, but with an atomic mass different from the atomic mass that generally or predominantly occurs in nature. Examples of isotopes that can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I. Particular isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for examining the mechanism of action or distribution of the active ingredient in the body; Due to their comparatively easy preparability and detectability, compounds labeled with 3H or 14C isotopes are particularly suitable for this purpose.Furthermore, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example, an extension of the half-life in the body or a reduction in the required active dose; such modifications of the inventive compounds may, therefore, in some cases, also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by processes known to those skilled in the art, for example, by the methods described below and by the procedures described in the working examples, using corresponding isotopic modifications of the respective reagents and / or starting compounds.

[0029] The salts preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, the invention also covers salts that are not suitable for pharmaceutical applications but that can be used, for example, for the isolation or purification of the compounds according to the invention. Petition 870260054097, dated 03 / 06 / 2026, page 14 / 326 11 / 152

[0030] Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

[0031] Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, by way of example and preferably salts of alkali metals (e.g., sodium and potassium salts), salts of alkaline earth metals (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 carbon atoms, by way of example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

[0032] The present invention includes all possible salts of the compounds according to the invention as simple salts, or as any mixture of said salts, in any proportion.

[0033] Solvates in the context of the invention are described as those forms of the inventive compounds that form a complex in the solid or liquid state by coordination with solvent molecules. The compounds according to the invention may contain polar solvents, in particular water, methanol or ethanol for example, as a structural element of the crystalline lattice of the compounds. Hydrates are a specific form of solvates in which the coordination is with water. It is possible that the amount of polar solvents, in particular water, exists in a stoichiometric or non-stoichiometric ratio. In the case of Petition 870260054097, dated 03 / 06 / 2026, p. 15 / 326 12 / 152 stoichiometric solvates, for example, a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

[0034] Furthermore, the compounds according to the invention may exist as N-oxides, which are defined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized in a known manner. The present invention includes all such possible N-oxides.

[0035] The present invention also encompasses prodrugs of the inventive compounds. The term prodrugs encompasses compounds that, in turn, may be biologically active or inactive, but are converted during their residence time in the body into compounds according to the invention (for example, by metabolism or hydrolysis).

[0036] Preference is given to compounds of Formula (I) in which R1 represents hydrogen, fluorine R2 represents hydrogen, fluorine R3 represents chlorine or trifluoromethyl R4 represents hydrogen or methyl R5 represents C1-C5-alkyl X1 represents nitrogen or carbon. X2 represents nitrogen or carbon and their salts, their solvates, and the solvates of their salts.

[0037] Preference is also given to compounds of Formula (I) in which R1 represents hydrogen, fluorine R2 represents hydrogen, fluorine R3 represents chlorine or trifluoromethyl R4 represents hydrogen or methyl Petition 870260054097, dated 03 / 06 / 2026, page 16 / 326 13 / 152 R5 represents methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, isobutyl Xi represents nitrogen or carbon. X2 represents nitrogen or carbon and their salts, their solvates, and the solvates of their salts.

[0038] Preference is also given to compounds of Formula (I) in which R1 represents hydrogen. R2 represents hydrogen. R3 represents chlorine or trifluoromethyl R4 represents hydrogen or methyl R5 represents methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, isobutyl X1 represents carbon or nitrogen. X2 represents carbon and its salts, its solvates, and the solvates of its salts.

[0039] Preference is also given to compounds of Formula (I) where R1 represents hydrogen. R2 represents hydrogen. R3 represents chlorine or trifluoromethyl R4 represents hydrogen. R5 represents methyl, ethyl, n-propyl, i-propyl, 2,2-dimethylpropyl, isobutyl X1 represents carbon X2 represents carbon and its salts, its solvates, and the solvates of its salts. Petition 870260054097, dated 03 / 06 / 2026, p. 17 / 326 14 / 152

[0040] Preference is also given to compounds of Formula (I) where R1 represents hydrogen. R2 represents hydrogen. R3 represents chlorine. R4 represents hydrogen. R5 represents isobutyl X1 represents carbon X2 represents carbon and its salts, its solvates, and the solvates of its salts.

[0041] Preference is also given to the compound of the Formula and the salts thereof, solvates thereof or solvates of the salts thereof.

[0042] Preference is also given to the compound of the Formula Petition 870260054097, dated 03 / 06 / 2026, p. 18 / 326 15 / 152 enantiomer 1, and salts thereof, solvates thereof, or solvates of salts thereof.

[0043] Preference is also given to the compound of the Formula enantiomer 2, and salts thereof, solvates thereof, or solvates of salts thereof.

[0044] Preference is also given to the compound of the Formula and the salts thereof, solvates thereof, or solvates of the salts thereof.

[0045] Preference is also given to the compound of the Formula Petition 870260054097, dated 03 / 06 / 2026, p. 19 / 326 16 / 152 and the salts thereof, solvates thereof or solvates of the salts thereof.

[0046] Preference is especially given to the compound of Formula 0 L___ch3

[0047] Special preference is given to the compound of Formula, enantiomer 1

[0048] Special preference is given to the compound with Formula, enantiomer 2

[0049] Preference is especially given to the compound with Formula Petition 870260054097, dated 03 / 06 / 2026, p. 20 / 326 17 / 152 ch3

[0050] Preference is especially given to the compound with Formula Cl x 0.5 H2O

[0051] Preference is especially given to the compound of Formula

[0052] The invention further provides a process for preparing compounds of Formula (I), or salts thereof, solvates thereof or solvates of salts thereof, wherein in a first step [B] the compounds of Formula (IV) R3 (IV), Petition 870260054097, dated 03 / 06 / 2026, p. 21 / 326 18 / 152 where R1, R2, R3, R4 and Xi and X2 are defined as above, are reacted with compounds of Formula (III) R5a-CHO (III), wherein R5a represents C1-C3-alkyl, preferably isopropyl, in the presence of a reducing agent, a suitable base and a suitable solvent to give compounds of Formula (II) (II) wherein R1, R2, R3, R4, R5 and X1 and X2 are defined as above in a second step [A] compounds of Formula (II) are reacted with a base in a suitable solvent to give compounds of Formula (I), Petition 870260054097, dated 03 / 06 / 2026, p. 22 / 326 19 / 152 where R1, R2, R3, R4, R5 and Xi and X2 are defined as above.

[0053] Optionally, the compounds of Formula (I) are transferred in a third step [A]* into the corresponding salts of Formula (Ia) in the presence of a suitable acid in a suitable solvent wherein R1, R2, R3, R4, R5 and Xi and X2 are defined as above. or alternatively in a first step [D] the compounds of Formula (VIII) (VIII), where R1, R2 and R3 are defined as above, are reacted with compounds of Formula (VII) Petition 870260054097, dated 03 / 06 / 2026, p. 23 / 326 20 / 152 R9R9 II OOB' (5(VII), wherein R4, R5, and X ie X 2 are defined as above, and wherein R9 represents hydrogen, methyl or both R9 form through adjacent oxygen atoms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a palladium source, a suitable ligand and a base to provide compounds of Formula (II) (II) where R1, R2, R3, R4, R5 and X1 and X2 are defined as above in a second step [A] compounds of Formula (II) (II) are reacted with a base in a suitable solvent to provide Petition 870260054097, dated 03 / 06 / 2026, page 24 / 326 21 / 152 compounds of Formula (I), (I) where R1, R2, R3, R4, R5 and X1 and X2 are defined as above.

[0054] Optionally, the compounds of Formula (I) are transferred in a third step [A]* into the corresponding salts of Formula (Ia) x HCl (Ia) in the presence of a suitable acid in a suitable solvent. Reaction [A]* (salt formation)

[0055] Reaction [A]* is generally carried out in inert solvents in the presence of an acid, preferably in a temperature range of 0 °C to 60 °C at atmospheric pressure.

[0056] Suitable acids for salt formation are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Preference is given to hydrogen chloride, hydrogen bromide, toluenesulfonic acid, methanesulfonic acid or sulfuric acid. Petition 870260054097, dated 03 / 06 / 2026, page 25 / 326 22 / 152

[0057] Suitable inert solvents for salt formation are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, dimethyl glycol ether or diethylene glycol dimethyl ether or other solvents such as acetone, ethyl acetate, ethanol, n-propanol, isopropanol, acetonitrile, dimethyl sulfide oxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of the aforementioned solvents may also be used. Preference is given to diethyl ether, dioxane, tetrahydrofuran or mixtures of these solvents. Reaction [A] (ester hydrolysis)

[0058] The hydrolysis of the ester group in compounds of Formula II is carried out by the usual methods, treating the esters in inert solvents with acids or bases, where in the latter variant the salts initially formed are converted into free carboxylic acids by acid treatment. In the case of tert-butyl esters, ester hydrolysis is preferably carried out with acids.

[0059] Suitable inert solvents for these reactions are water or the usual organic solvents for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide or dimethyl sulfoxide. Mixtures of these solvents may also be used. In the case of basic ester hydrolysis, preference is given to the use of mixtures of water with dioxane, tetrahydrofuran, methanol, ethanol and / or dimethylformamide or mixtures of tetrahydrofuran and methanol or ethanol. In the case of the reaction with trifluoroacetic acid, dichloromethane is preferred, and in the case of the reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water is preferred. Petition 870260054097, dated 03 / 06 / 2026, p. 26 / 326 23 / 152

[0060] Suitable bases are the usual inorganic bases. These include especially hydroxides of alkali or alkaline earth metals, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, or carbonates of alkali or alkaline earth metals, such as sodium carbonate, potassium carbonate or calcium carbonate. Preference is given to lithium hydroxide, sodium hydroxide or potassium hydroxide.

[0061] Suitable acids for ester hydrolysis are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid is preferred for tert-butyl esters and hydrochloric acid for methyl esters.

[0062] Ester hydrolysis is generally carried out within a temperature range of -20 °C to +120 °C, preferably from 0 °C to +80 °C.

[0063] Compounds of Formula (II) r3 ÍJL r2SWR' O ^^Vch3 R5(II) where R1R2, R3, R4, R5 and Xi and X2 are defined as above are new.

[0064] The compounds of Formula (II) can be synthesized from the corresponding starting compounds of Formula (IV) by [B] reacting the compounds of Formula (IV) Petition 870260054097, dated 03 / 06 / 2026, p. 27 / 326 24 / 152 x 2 HCl (IV), where R1-R2, R3-R4 and Xi and X2 are defined as above, with compounds of Formula (III) R5a-CHO (III), wherein R5a represents C1-C3-alkyl, preferably isopropyl, in the presence of a reducing agent, a suitable base and a suitable solvent to provide compounds of Formula (II) where R1R2, R3, R4, R5 and Xi and X2 are defined as above. Reaction [B] (reductive amination)

[0065] The reaction in step [B] is generally carried out in inert solvents in the presence of a reducing agent, if appropriate in the presence of a base and / or a dehydrating agent, preferably in a temperature range of 0°C to 60°C at atmospheric pressure.

[0066] Suitable reducing agents for reducing aminations are alkali metal borohydrides commonly used for such purposes, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; preference is given to the use of sodium triacetoxyborohydride. Petition 870260054097, dated 03 / 06 / 2026, page 28 / 326 25 / 152

[0067] The addition of an acid, such as acetic acid in particular, and / or a dehydrating agent, for example molecular sieve or trimethyl orthoformate or triethyl orthoformate, can be advantageous in these reactions.

[0068] Bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine or pyridine. Bases, such as N,N-diisopropylethylamine and triethylamine in particular, can be advantageous in these reactions.

[0069] Suitable solvents for these reactions are especially 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.

[0070] The reactions are generally carried out within a temperature range of 0°C to +60°C.

[0071] Aldehydes of Formula (III) are commercially available, are known, or can be synthesized from known starting materials by known processes.

[0072] Compounds of Formula (IV) x 2 HCl (IV), where R1- R2, R3- R4 and X1 and X2 are defined as above are new.

[0073] The compounds of Formula (IV) can be synthesized to Petition 870260054097, dated 03 / 06 / 2026, p. 29 / 326 26 / 152 of the corresponding compounds of Formula (V) [C] reacting the compounds of Formula (V) (V), where R1- R2, R3- R4 and Xi and X2 are defined as above, in the presence of a suitable acid and a suitable solvent. Reaction [C] (Deprotection)

[0074] Reaction [C] is generally carried out in inert solvents in the presence of a suitable acid, preferably in a temperature range of 0°C to 60°C at atmospheric pressure.

[0075] Acids are, for example, organic or inorganic acids, 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 mixtures thereof, optionally with the addition of water. Preference is given to hydrogen chloride or trifluoroacetic acid.

[0076] Suitable solvents for these reactions are especially 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.

[0077] The reactions are generally carried out within a temperature range of 0°C to +60°C. Petition 870260054097, dated 03 / 06 / 2026, page 30 / 326 27 / 152

[0078] Formula Compounds (V) (V), where R1- R2, R3- R4 and Xi and X2 are defined as above are new.

[0079] The compounds of Formula (V) can be synthesized from the corresponding compounds of Formula (VIII) [G] through the reaction of compounds of Formula (VIII) (VIII), wherein R1, R2 and R3 are defined as above, in the presence of a suitable palladium catalyst, base and a suitable solvent with compounds of Formula (VI) (VI). where R1, R2 and R3 are defined as above, Reaction [G] (Suzuki coupling)

[0080] The reaction [G] is generally carried out in the presence of a Petition 870260054097, dated 03 / 06 / 2026, page 31 / 326 28 / 152 suitable palladium catalyst and a suitable base in inert solvents, preferably in the temperature range from room temperature to solvent reflux at atmospheric pressure.

[0081] Inert solvents for the reaction step [G] are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyleneglycoldimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum oil, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or also water. Mixtures of the above-mentioned solvents can also be used. Pse refers to a mixture of dimethylformamide / water and toluene / ethanol.

[0082] Suitable bases for reaction steps are the usual inorganic bases. These include especially hydroxides of alkali or alkaline earth metals, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrogen carbonates, such as sodium or potassium hydrogen carbonate, or alkali or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogen phosphate. The bases preferably used are sodium or potassium carbonate.

[0083] Examples of suitable palladium catalysts for reaction steps [Suzuki Coupling] are, for example, palladium on charcoal, palladium(II)-acetate, tetrakis-(triphenylphosphine)-palladium(II), bis(triphenylphosphine)-palladium(II)-chloride, bis-(acetonitrile)-palladium(II) chloride and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichlormethane complex [cf. for example, Hassan J. et al., Chem. Rev. 102, 13591469 (2002)].

[0084] The reaction steps are generally carried out within Petition 870260054097, dated 03 / 06 / 2026, page 32 / 326 29 / 152 a temperature range of +20 °C to +150 °C, preferably from +50 °C to +100 °C.

[0085] The compounds of Formula (VI) are novel, commercially available or available through known processes.

[0086] Compounds of Formula (VIII) (VIII), where R1, R2 and R3 are defined as above are new.

[0087] Compounds of Formula (VIII) can be prepared [H] through the reaction of compounds of Formula (IX) (IX), wherein R1- R2 and R3 are as defined above, with triflic acid anhydride in the presence of base and an inert solvent. [H] reaction (triflatation)

[0088] The [H] reaction is generally carried out with triflic acid anhydride in the presence of base in inert solvents, preferably in a temperature range from room temperature to reflux of solvents at atmospheric pressure.

[0089] Bases are, for example, organic bases such as alkaline amines or pyridines, or inorganic bases such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, or carbonates of alkali metals such as cesium carbonate, sodium carbonate, or potassium carbonate, or alkoxides such as potassium tert-butoxide or tert-butoxide. Petition 870260054097, dated 03 / 06 / 2026, page 33 / 326 30 / 152 sodium butoxide, or pyridines such as pyridine or 2,6-lutidine, or alkaline amines such as triethylamine or N,N-diisopropylethylamine; triethylamine is preferred.

[0090] Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents; preference is given to dichloromethane.

[0091] Compounds of Formula (IX) X—ch3(IX), where R1, R2, and R3 are defined as above, are new.

[0092] The compounds of Formula (IX) can be prepared [I] by means of the reaction of compounds of Formula (X) r3° ... (X) wherein R1, R2 and R3 are as defined above, with an acid optionally in an inert solvent. Reaction [I] (acid deprotection)

[0093] Reaction [I] is generally carried out with an acid in inert solvents or without a solvent, preferably in a range Petition 870260054097, dated 03 / 06 / 2026, page 34 / 326 31 / 152 temperature from 0°C until the solvents reflux at atmospheric pressure.

[0094] Inert solvents are, 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; preference is given to dichloromethane or dioxane.

[0095] Suitable acids for acid deprotection are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0096] Compounds of Formula (X) R ... (X) where R1- R2 and R3 are as defined above are new.

[0097] Compounds of Formula (X) can be prepared [J] through the reaction of compounds of Formula (XII) Petition 870260054097, dated 03 / 06 / 2026, page 35 / 326 32 / 152 (XII), where R1 and R2 are as defined above, with compounds of Formula (XI) ch3em que R3 is as defined above, in the presence of a palladium source, a suitable ligand, and a base. Reaction [J] (Buchwald-Hartwig coupling)

[0098] The reaction [J] is generally carried out in the presence of a palladium source, a suitable ligand and a base in inert solvents, preferably in a temperature range from room temperature to reflux of solvents at atmospheric pressure.

[0099] The palladium source and a suitable ligand are, for example, palladium in charcoal, palladium (II)-acetate, tris(dibenzylideneacetone)palladium(II), tetrakis-(triphenylphosphine)palladium(II), bis-(triphenylphosphine)-palladium(II) chloride, bis(acetonitrile)-palladium(II) chloride, [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in conjunction with additional phosphane ligands such as, for example, 2,2'Bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), (2-dicyclohexylphosphine-2',4',6'-triisopropylI-1,1'-biphenyl)[2-(2'-amino-1,1 Palladium(II) methanesulfonate (XPhos-Pd-G3, CAS No.: 1445085-55-1), (2-biphenyl)di-tert-Petition 870260054097, dated 03 / 06 / 2026, page 36 / 326 33 / 152 butylphosphine, dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphane (XPhos, CAS-No: CAS-No: 564483-18-7), Bis(2-phenylphosphinophenyl) ether (DPEphos), or 4,5-bis (diphenyl phosphino)-9,9-dimethyl xanthene (Xantphos: CAS-No: 161265-03-8) [cf. 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), 2dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, CAS-No: 78761822-8), 2-(di-tert-butylphosphine)-3-methoxy-6-methyl-2',4',6'-tri-i-propyl-1,1'biphenyl (RockPhos) and 2-di-tert-butylphosphino-2',4',6'-tri-isopropylbiphenyl (tertButylXPhos). It is also possible to use corresponding precatalysts, such as chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy2',4',6'-tri-isopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalysts) [cf. for example, SL Buchwald et al., Chem. Sci.[2013, 4, 916] can optionally be used in conjunction with additional phosphine binders, such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos).

[00100] Preference is given to 2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), tris(dibenzylideneacetone)palladium (0), or in combination with 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) or dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphane (Xphos).

[00101] Bases are, for example, suitable inorganic or organic bases, such as, for example, carbonates of alkali or alkaline earth metals, such as lithium, sodium, potassium, calcium or cesium carbonate, or sodium bicarbonate or potassium bicarbonate; hydrogen carbonates of alkali metals, such as sodium hydrogen carbonate or potassium hydrogen carbonate; hydroxides of alkali or alkaline earth metals such as sodium, barium or potassium hydroxide; phosphates of alkali or alkaline earth metals such as potassium phosphate; alcoholates of alkali metals such as sodium tert-butylate. Petition 870260054097, dated 03 / 06 / 2026, page 37 / 326 34 / 152 or potassium and sodium methanolate, alkali metal phenolates such as sodium phenolate, potassium acetate, amides such as sodium amide, lithium bis(trimethylsilyl)amide, sodium or potassium 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 is preferred.

[00102] Inert solvents are, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, di-n-butyl ether, cyclopentylmethyl ether, dimethyl glycol ether or diethyleneglycoldimethyl ether, alcohols such as tert-butanol or amyl alcohols or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene or acetonitrile, or mixtures of solvents; preference is given to tert-butanol, 1,4-dioxane and toluene.

[00103] The compounds of Formula (XI) are known or can be synthesized from the corresponding commercially available starting compounds by known processes.

[00104] The compounds of Formula (XII) are new (XII), where R1 and R2 are as defined above.

[00105] The compounds of Formula (XII) can be prepared [K] through the reaction of compounds of Formula (XIII) Petition 870260054097, dated 03 / 06 / 2026, page 38 / 326 35 / 152 (XIII), where R1 and R2 are as defined above, with an acid in an inert solvent. Reaction [K] (decoiling)

[00106] The [K] reaction is generally carried out in inert solvents in the presence of a suitable acid, preferably in a temperature range of 0°C to 60°C at atmospheric pressure.

[00107] Acids are, for example, organic or inorganic acids, 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 mixtures thereof, optionally with the addition of water. Preference is given to hydrogen chloride or trifluoroacetic acid.

[00108] Inert solvents are 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; preference is given to the use of 1,4-dioxane.

[00109] Compounds of Formula (XIII) Petition 870260054097, dated 03 / 06 / 2026, page 39 / 326 36 / 152 in which

[00110] (XIII) R1 and R2 are as defined above; they are new. The compounds of Formula (XIII) can be prepared [L] through the reaction of compounds of Formula (XV) (XV), in which R1 and R2 are as defined above, with compounds of Formula (XIV) (XIV) in a solvent. Reaction [L] (pyrazole formation)

[00111] The reaction [L] is generally carried out in a solvent at temperatures from room temperature to reflux.

[00112] Suitable solvents are 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; ethanol is preferred. Petition 870260054097, dated 03 / 06 / 2026, p. 40 / 326 37 / 152

[00113] The compounds of Formula (XIV) are known, are commercially available, or can be synthesized from the corresponding starting compounds by known processes.

[00114] The compounds of Formula (XV) (XV), where R1 and R2 are as defined above and are new.

[00115] The compounds of Formula (XV) can be prepared [M] by means of the reaction of compounds of Formula (XVI) (XVI), wherein R1 and R2 are as defined above with hydrogen in the presence of palladium on charcoal in a suitable solvent. Reaction [M] (Z-deprotection)

[00116] The reaction [M] is generally carried out in the presence of palladium on charcoal in a suitable solvent from room temperature to reflux, preferably at 1 bar.

[00117] Suitable solvents are 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 solvents such as acetonitrile, N,N-dimethylformamide (DMF), NMP, acetic acid or water or mixtures of these solvents; preference is given to ethanol / acetic acid. Petition 870260054097, dated 03 / 06 / 2026, page 41 / 326 38 / 152

[00118] The compounds of Formula (XVI) (XVI), where R1 and R2 are as defined above are new.

[00119] The compounds of Formula (XVI) can be prepared [N] through the reaction of compounds of Formula (XVII) (XVII) in which R1 and R2 are as defined above with a compound of Formula (XVIII) (XVIII) in the presence of a reducing agent and a suitable solvent. Reaction [N] (reductive hydrazination)

[00120] The reaction [N] is generally carried out in the presence of a reducing agent and a suitable solvent in a temperature range from room temperature to reflux of solvents at atmospheric pressure.

[00121] Suitable solvents are 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, solvents Petition 870260054097, dated 03 / 06 / 2026, p. 42 / 326 39 / 152 polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of these solvents; tetrahydrofuran / methanol is preferred.

[00122] Suitable reducing agents are alkali metal borohydrides such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; sodium borohydride is preferred.

[00123] The compound of Formula (XVIII) is known and commercially available or can be synthesized from the corresponding starting compounds by known processes.

[00124] The compound of Formula (XVII) is known and commercially available or can be synthesized from the corresponding starting compounds by known processes.

[00125] The compound of Formula (XVII) is known and commercially available or can be synthesized from the corresponding starting compounds by known processes.

[00126] Alternatively, compounds of Formula (II) are obtained by [D] reaction of compounds of Formula (VIII) (VIII) where R1- R2e R3 are defined as above with compounds of Formula (VII) r9r9I (VII) Petition 870260054097, dated 03 / 06 / 2026, p. 43 / 326 40 / 152 where R4' R5' R9e Xi and X2 are defined as above, in the presence of a suitable palladium catalyst, a base and a suitable solvent. Reaction [D] (Suzuki coupling)

[00127] Reaction [D] is generally carried out in the presence of a suitable palladium catalyst, a base and in inert solvents, preferably in the temperature range from room temperature to reflux of solvents at atmospheric pressure.

[00128] Inert solvents for reaction [D] are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyleneglycoldimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum oil, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or also water. Mixtures of the above-mentioned solvents can also be used. Pse refers to a mixture of dimethylformamide / water and toluene / ethanol.

[00129] Suitable bases for reaction steps are the usual inorganic bases. These include especially hydroxides of alkali or alkaline earth metals, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrogen carbonates, such as sodium or potassium hydrogen carbonate, or alkali or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogen phosphate. The bases preferably used are sodium or potassium carbonate.

[00130] Examples of palladium catalysts suitable for reaction steps [Suzuki Coupling] are, for example, palladium in charcoal, palladium (II)-acetate, tetrakis-(triphenylphosphine)-palladium(0), bis Petition 870260054097, dated 03 / 06 / 2026, page 44 / 326 41 / 152 (triphenylphosphine)-palladium(II)-chloride, bis-(acetonitrile)-palladium(II)-chloride and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II)dichlormethane complex [cf. for example, Hassan J. et al., Chem. Rev. 102, 13591469 (2002)].

[00131] The reaction steps are generally carried out within a temperature range of +20 °C to +150 °C, preferably from +50 °C to +100 °C.

[00132] Compounds of Formula (VIII) (VIII), where R1- R2 and R3 are defined as above are new.

[00133] The synthesis of compounds of Formula (VIII) is described above.

[00134] The compounds of Formula (VII) II OO 'Bx X1 < / X2 THE <vii>ά5em where R4, R5, and R9, X1 and X2 are defined as above, are new.

[00135] Compounds of Formula (VII) are obtained by [E] reaction of compounds of Formula (XIX) Petition 870260054097, dated 03 / 06 / 2026, page 45 / 326 42 / 152 (XIX) where R4' R5e R9e Xi and X2 are defined as above with compounds of Formula (III) R5a-CHO (III) wherein R5a is defined as above in the presence of a reducing agent, a suitable base and a suitable solvent. Reaction [E] (reductive amination)

[00136] Reaction [E] is generally carried out in inert solvents in the presence of a reducing agent, if appropriate in the presence of a base and / or a dehydrating agent, preferably in a temperature range of 0°C to 60°C at atmospheric pressure.

[00137] Suitable reducing agents for reducing aminations are alkali metal borohydrides commonly used for such purposes, such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; preference is given to the use of sodium triacetoxyborohydride.

[00138] The addition of an acid, such as acetic acid in particular, and / or a dehydrating agent, for example molecular sieve or trimethyl orthoformate or triethyl orthoformate, can be advantageous in these reactions.

[00139] The bases are, for example, organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine or pyridine. Bases, such as N,N-diisopropylethylamine and triethylamine in particular, can be advantageous in these reactions. Petition 870260054097, dated 03 / 06 / 2026, page 46 / 326 43 / 152

[00140] Suitable solvents for these reactions are especially 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 A / ,A / -dimethylformamide (DMF) or mixtures of such solvents; tetrahydrofuran is preferred.

[00141] The reactions are generally carried out within a temperature range of 0 °C to +60 °C.

[00142] Aldehydes of Formula (III) are commercially available or can be synthesized from known starting materials by known processes.

[00143] The starting material for Formula (XIX) is commercially available, known or available by known processes.

[00144] The preparation of the starting compounds and the compounds of Formula (I) can be illustrated by synthesis schemes 1 to 5 below. Scheme 1 Scheme 2 Petition 870260054097, dated 03 / 06 / 2026, p. 47 / 326 44 / 152 Scheme 3 INLiOH THF / HeOH Petition 870260054097, dated 03 / 06 / 2026, p. 48 / 326 45 / 152 Scheme 5 VI 4N HCl, dioxane RSi-CHO111 NaH{OAc);, DIPEA THF VII

[00145] The compounds of the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[00146] The compounds according to the invention are potent activators of soluble guanylate cyclase. They lead to vasorelaxation, Petition 870260054097, dated 03 / 06 / 2026, p. 49 / 326 46 / 152 inhibition of platelet aggregation and decrease in blood pressure and increase in coronary and renal blood flow. These effects are mediated via direct heme-independent activation of soluble guanylate cyclase and increased intracellular cGMP.

[00147] Furthermore, the compounds according to the invention exhibit advantageous pharmacokinetic properties, particularly with regard to their bioavailability and / or duration of action after intravenous or oral administration.

[00148] The compounds according to the present invention exhibit superior pharmacokinetic (PK) properties compared to compounds disclosed in the prior art (WO 2012 / 058132) (see experimental section, tables 3 to 6). For example, Example 2 of the present invention shows a lower plasma clearance (CLplasma) (up to 10 times) and therefore a much higher exposure (AUCnorm) compared to the prior art compound disclosed as Example 174 in WO 2012 / 058132 in rats as well as in dogs. Example 2 also shows a long half-life and a mean residence time (MRT) in all species tested after postoperative (oral) administration. Due to the significantly lower plasma clearance of Example 2 and the resulting very high exposure (AUCnorm, exposure, area under the normalized curve) with good bioavailability after postoperative administrationIn all species tested, we observed a clear superiority of pharmacokinetic (PK) properties versus example 174 disclosed in WO 2012 / 058132.

[00149] The compounds according to the invention have an unpredictable spectrum of useful pharmacological activity and good pharmacokinetic behavior, in particular sufficient exposure of such compound in the blood above the minimum effective concentration within a given dosage range after oral administration. Such Petition 870260054097, dated 03 / 06 / 2026, page 50 / 326 The 47 / 152 profile results in an improved peak-to-valley ratio (quotient of maximum to minimum concentration) within a given dosage range, which has the advantage that the compound can be administered less frequently and at a significantly lower dose to achieve an effect. These are compounds that activate soluble guanylate cyclase.

[00150] In the context of the present invention, the term treatment or treatable includes inhibition, delay, control, relief, attenuation, restriction, reduction, suppression, repellency or cure of a disease, condition, disorder, injury or health problem, or the development, course or progression of such states and / or the symptoms of such states. The term therapy is understood here as synonymous with the term treatment.

[00151] In the context of the present invention, the terms prevention, prophylaxis and preclusion are used synonymously and refer to preventing or reducing the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or the development or progression of such states and / or the symptoms of such states.

[00152] The treatment or prevention of a disease, condition, disorder, injury, or health problem can be partial or complete.

[00153] In addition, the compounds according to the invention have other advantageous properties, in particular with regard to their pulmoselective action (as opposed to a systemic action), their pulmonary retention time and / or their duration of action after intrapulmonary administration.

[00154] The compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular and heart diseases, cardiorenal and renal diseases, cardiopulmonary and pulmonary diseases, diseases Petition 870260054097, dated 03 / 06 / 2026, page 51 / 326 48 / 152 neurodegenerative diseases, thromboembolic diseases, fibrotic disorders and / or wound healing disorders.

[00155] The compounds according to the 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 arterial disease (PAD, PAD), cardiorenal and renal diseases, preferably chronic and diabetic kidney disease (CKD and CKD), 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), wound healing disorders such as diabetic foot ulcer (DFU).

[00156] Consequently, the compounds according to the invention can be used in medicaments for the treatment and / or prevention of cardiovascular, cardiopulmonary and cardiorenal disorders, such as, for example, high blood pressure (hypertension), heart failure, coronary heart disease, stable and unstable angina pectoris, pulmonary arterial hypertension (PAH) and secondary forms of pulmonary hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal, renovascular and treatment-resistant hypertension, peripheral and cardiac vessel disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction, such as, for example, first- to third-degree atrioventricular blocks, supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junction extrasystoles, sick sinus syndrome, syncope,AV node reentrant tachycardia, Wolff-Parkinson-White syndrome, Petition 870260054097, dated 03 / 06 / 2026, page 52 / 326 49 / 152 Acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathies), boxer cardiomyopathy, erythematosus, shock such as cardiogenic shock, septic shock and anaphylactic shock, in addition to the treatment and / or prevention of thromboembolic and ischemic disorders such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient ischemic attacks, pre-eclampsia, cardiovascular disorders, spasms of the coronary and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or edema induced by heart failure, impaired peripheral perfusion, reperfusion injury, arterial and venous thromboses, microalbuminuria, heart failure, endothelial dysfunction, micro and macrovascular damage (vasculitis) and also to prevent restenosis, for example, after thrombolysis therapies, percutaneous transluminal angioplasty (PTA),Percutaneous transluminal coronary angioplasty (PTCA), heart transplants and heart surgery operations.

[00157] In the context of the present invention, the term pulmonary hypertension encompasses its primary and secondary subforms, as defined below by the Dana Point classification according to their respective etiology [see D. Montana and G. Simonneau, in: 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. Col. Cardiol. 2009, 54 (1), S85-S96]. These include, in particular, Pulmonary Arterial Hypertension (PAH) of group 1, which encompasses, among others, the idiopathic and familial forms (PAH and FPAH, respectively). Furthermore, PAH also encompasses persistent pulmonary hypertension of the newborn and pulmonary arterial hypertension (PAH) associated with collagenoses, congenital systemic pulmonary shunt lesions, portal hypertension, HIV infections, and the ingestion of certain drugs. Petition 870260054097, dated 03 / 06 / 2026, page 53 / 326 50 / 152 medications (e.g., appetite suppressants), with disorders with a significant venous / capillary component, such as pulmonary veno-occlusive disorder and pulmonary capillary hemangiomatosis, or with other disorders, such as thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. Group 2 of the Dana Point classification comprises patients with PH who present with a causative left heart disorder, such as ventricular, atrial, or valvular disorders. Group 3 comprises forms of pulmonary hypertension associated with a pulmonary disorder, for example, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (PFI), and / or hypoxemia (e.g., sleep apnea syndrome, hypoventilation, chronic high-altitude disease, hereditary deformities).Group 4 includes patients with pulmonary hypertension (PH) with chronic thrombotic and / or embolic disorders, for example, in the case of thromboembolic obstruction of the proximal and distal pulmonary arteries (CTEPH) or non-thrombotic embolisms (e.g., as a result of tumors, parasites, foreign bodies). Less common forms of pulmonary hypertension, such as in patients with sarcoidosis, histiocytosis X, or lymphangiomatosis, are summarized in group 5.

[00158] In the context of the present invention, the term heart failure encompasses acute and chronic forms of heart failure and also more specific or related disease types, such as acute decompensated heart failure, right heart failure, left heart failure, global heart failure, also diastolic heart failure and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with ejection fraction Petition 870260054097, dated 03 / 06 / 2026, page 54 / 326 51 / 152 intermediate (HFmEF), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects and cardiomyopathies, heart valve defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, and also diastolic heart failure and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF).

[00159] In addition, the compounds according to the invention can also be used for the treatment and / or prevention of arteriosclerosis, disturbed lipid metabolism, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, combined hyperlipidemias, hypercholesterolemias, abetalipoproteinemia, sitosterolemia, xanthomatosis, Tangier disease, adiposity, obesity and also metabolic syndrome.

[00160] In addition, the compounds according to the invention can be used for the treatment and / or prevention of primary and secondary Raynaud's phenomenon, microcirculation disorders, claudication, hearing disorders, tinnitus, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis and rheumatic disorders.

[00161] In addition, the compounds according to the invention may Petition 870260054097, dated 03 / 06 / 2026, p. 55 / 326 52 / 152 can be used for the treatment of sickle cell disease (SCD), sickle cell anemia, and also other symptoms of SCD-related diseases (e.g., end-organ damage affecting the lung, brain, kidney, or heart), but also vaso-occlusive events or pain crises, achalasia, hemolysis-induced vasculopathies for the treatment of malaria, thalassemia, hemolytic-uremic syndrome, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemias, or rhabdomyolysis. Furthermore, since similar pathophysiological mechanisms mentioned above are effective when blood transfusions (e.g., by storage, etc., with a high concentration of free Hb) are administered to patients requiring transfusion, these compounds can be used for patients receiving a blood transfusion.Finally, in the future, the combination of an sGC activator with a synthetic Hb-based oxygen carrier may mitigate the side effects observed so far [Weiskopf, Anesthesia & Analgesia, 110:3; 659-661, 2010] that are caused by reduced NO availability, thus allowing new clinical applications.

[00162] The compounds according to the invention can also be used additionally to prevent ischemic and / or reperfusion-related damage in organs or tissues and also as additives for perfusion and preservation solutions for organs, parts of organs, tissues or parts of tissues of human or animal origin, in particular for surgical interventions or in the field of transplant medicine.

[00163] Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of renal disorders, especially renal failure and renal insufficiency. In the context of the present invention, the terms renal failure and renal insufficiency encompass acute and chronic manifestations (chronic kidney disease; Petition 870260054097, dated 03 / 06 / 2026, page 56 / 326 53 / 152 CKD), as well as underlying or related kidney diseases, such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal graft rejection and immune complex-induced kidney diseases, toxic substance-induced nephropathy, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, diabetic kidney disease (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome, which can be diagnostically characterized, for example, by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as, for example, glutamyl synthase,Altered urinary osmolarity or volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia and / or need for dialysis. The present invention also encompasses the use of the compounds according to the invention for the treatment and / or prophylaxis of sequelae of renal failure, for example hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g. hyperkalemia, hyponatremia) and disturbances in bone and carbohydrate metabolism.

[00164] In addition, the compounds according to the invention are suitable for the treatment and / or prevention of urological disorders, for example, 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), incontinence, for example. Petition 870260054097, dated 03 / 06 / 2026, page 57 / 326 54 / 152 example, mixed, urge, stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC) and also rectal dysfunction and female sexual dysfunction.

[00165] The compounds according to the invention are also suitable for the treatment and / or prevention of asthmatic disorders, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), alpha-1 antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (e.g., cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF).

[00166] The compounds described in the present invention are also active compounds for controlling central nervous system disorders characterized by NO / cGMP system disorders. They are particularly suitable for improving perception, concentration, learning or memory after cognitive impairments, such as those occurring in particular in association with situations / diseases / syndromes such as mild cognitive impairment, age-related learning and memory impairments, age-related memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia, post-traumatic brain injury, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies, dementia with frontal lobe degeneration including Pick's syndrome, Parkinson's disease, progressive nuclear palsy,Dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeldt-Jakob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's disease psychosis. They are also suitable for... Petition 870260054097, dated 03 / 06 / 2026, page 58 / 326 55 / 152 treatment and / or prevention of central nervous system disorders, such as states of anxiety, tension and depression, sexual dysfunctions related to the CNS and sleep disorders, and to control pathological disorders of food intake, stimulants and addictive substances.

[00167] Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are therefore effective agents for controlling migraines. They are also suitable for the prophylaxis and control of sequelae of cerebral infarction (Apoplexy cerebri), such as stroke, cerebral ischemia and craniocerebral trauma. The compounds according to the invention can also be used to control pain states.

[00168] Furthermore, the compounds according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatories for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disorders, chronic inflammatory bowel diseases (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin disorders and inflammatory eye disorders.

[00169] Furthermore, the compounds according to the invention are suitable for the treatment and / or prevention of fibrotic disorders of internal organs, for example, of the lung, heart, kidneys, bone marrow and especially the liver, and also of dermatological fibroses and fibrotic disorders of the eye. In the context of the present inventions, the term fibrotic disorders especially encompasses disorders such as hepatic fibrosis, hepatic cirrhosis, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, renal interstitial fibrosis, fibrosis resulting from diabetes, myelofibrosis and disorders Petition 870260054097, dated 03 / 06 / 2026, page 59 / 326 56 / 152 similar fibrotic conditions, scleroderma, systemic sclerosis, morphea, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue disorders (e.g., sarcoidosis). The compounds according to the invention can also be used to promote wound healing, including the healing of digital ulcers and diabetic foot ulcers, to control postoperative scars, for example, resulting from glaucoma operations, and cosmetically for aged and keratinized skin.

[00170] Due to their activity profile, the compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular diseases and cardiopulmonary disorders, such as primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris and hypertension, and also for the treatment and / or prevention of thromboembolic disorders, ischemia, vascular disorders, impaired microcirculation, renal failure, fibrotic disorders and arteriosclerosis.

[00171] The present invention also provides for the use of the compounds according to the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[00172] The present invention further provides for the use of the compounds according to the invention for the preparation of a medicament for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[00173] The present invention also provides a medicament comprising at least one of the compounds according to the invention for the treatment and / or prevention of disorders, in particular the disorders mentioned above.

[00174] The present invention further provides for the use of the compounds according to the invention in a method for treatment Petition 870260054097, dated 03 / 06 / 2026, page 60 / 326 57 / 152 and / or prevention of disorders, in particular the disorders mentioned above.

[00175] The present invention further provides a method for the treatment and / or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.

[00176] They are therefore suitable for use as medicines for the treatment and / or prophylaxis of diseases in humans and animals.

[00177] The present invention also provides the use of the compounds according to the invention for the treatment and / or prophylaxis of disorders, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders and / or thrombotic or thromboembolic complications, such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral occlusive arterial disease and / or diabetes and / or urogenital disorders, in particular those associated with.

[00178] For the purposes of the present invention, thrombotic or thromboembolic disorders include disorders that preferentially occur in the arterial vasculature and that can be treated with the compounds according to the invention, in particular disorders that lead to peripheral arterial occlusive disorders and in 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 pectoris, unstable angina pectoris, re-occlusions and restenosis after coronary interventions such as angioplasty, stent implantation or aortocoronary heart surgery, but also thrombotic or thromboembolic disorders in cerebrovascular arteries, such as transient ischemic attacks (TIAs), strokes Petition 870260054097, dated 03 / 06 / 2026, page 61 / 326 58 / 152 ischemic strokes, including cardioembolic strokes, such as strokes due to atrial fibrillation, non-cardioembolic strokes, such as lacunar strokes, strokes due to large or small artery disease or strokes due to diseases of undetermined cause, cryptogenic stroke, embolic stroke, embolic stroke of undetermined origin or thrombotic and / or thromboembolic events leading to stroke or TIA.

[00179] Furthermore, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of disorders in which the pro-inflammatory component plays an essential role, including vasculitis such as Kawasaki disease, Takayasu arteritis and thrombangiitis obliterans (Buerger's disease), as well as inflammatory disorders such as myocarditis.

[00180] In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of urogenital tract disorders such as overactive bladder, interstitial cystitis and bladder pain syndrome.

[00181] Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of diabetes mellitus, including its manifestations in target organs such as diabetic retinopathy and diabetic nephropathy.

[00182] Furthermore, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of neurological disorders such as neuropathic pain, neurodegenerative disorders and dementias such as vascular dementia or Alzheimer's disease and Parkinson's disease.

[00183] In addition, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary disorders such as chronic cough, asthma and COPD. Petition 870260054097, dated 03 / 06 / 2026, page 62 / 326 59 / 152

[00184] The present invention also provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above.

[00185] The present invention also provides for the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above.

[00186] The present invention further provides a method for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.

[00187] The present invention further provides the compounds according to the invention for use in a method for the treatment and / or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.

[00188] In particular, the present invention provides the compounds according to the invention for use in a method for the treatment and / or prophylaxis of thrombotic or thromboembolic disorders, in particular atherothrombotic disorders, using a therapeutically effective amount of a compound according to the invention.

[00189] The present invention also provides medicaments comprising a compound according to the invention and one or more other active compounds.

[00190] In addition, the compounds according to the invention can also be used to prevent ex vivo coagulation, for example, to protect organs to be transplanted against organ damage caused by clot formation and to protect the recipient organ against thromboembolism of the transplanted organ, for preservation of blood and plasma products, for cleaning / pre- Petition 870260054097, dated 03 / 06 / 2026, page 63 / 326 60 / 152 treatment of catheters and other medical devices and instruments, for coating synthetic surfaces of medical devices and instruments used in vivo or ex vivo or for biological samples that may contain factor XIa or plasma kallikrein.

[00191] The present invention further provides a method for preventing blood coagulation in vitro, in particular in stored blood or biological samples which may comprise factor XIa or plasma kallikrein or both enzymes, the method being characterized in that an effective anticoagulant amount of the compound according to the invention is added.

[00192] The compounds of the invention can act systemically and / or locally. For this purpose, they can be appropriately administered, for example, orally, parenterally, pulmonaryly, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally or otically, or as an implant or stent.

[00193] For these routes of administration, it is possible that the compounds according to the invention may be administered in suitable administration forms.

[00194] For oral administration, it is possible to formulate the compounds according to the invention in pharmaceutical forms known in the art that deliver the compounds of the invention rapidly and / or in a modified form, such as, for example, tablets (uncoated or coated tablets, for example, with enteric coatings or delayed-release or insoluble controlled-release coatings), orally disintegrating tablets, films / wafers, lyophilized films, capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and / or amorphized and / or dissolved form into said dosage forms. Petition 870260054097, dated 03 / 06 / 2026, page 64 / 326 61 / 152

[00195] Parenteral administration can be performed by avoiding an absorption step (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or by including absorption (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable forms of administration for parenteral use include, among others, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized powders, or sterile powders.

[00196] Suitable for extraocular (topical) administration are forms of administration that operate according to the previous technique, that release the active compound rapidly and / or in a modified or controlled manner and that contain the active compound in a crystalline and / or amorphized and / or dissolved state, such as, for example, eye drops, sprays and lotions (e.g., solutions, suspensions, vesicular / colloidal systems, emulsions, aerosols), powders for eye drops, sprays and lotions (e.g., ground active compound, mixtures, lyophilized, precipitated active compound), semi-solid ocular preparations (e.g., hydrogels, in situ hydrogels, creams and ointments), ocular inserts (solid and semi-solid preparations, e.g., bioadhesives, films / wafers, tablets, contact lenses).

[00197] Intraocular administration includes, for example, intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar, and subtenon injections. Suitable for intraocular administration are dosage forms that operate according to the previous technique, that release the active compound rapidly and / or in a modified or controlled manner, and that contain the active compound in crystalline and / or amorphized and / or dissolved form, such as, for example, preparations for injection and concentrates for preparations for injection (e.g., solutions, suspensions, vesicular / colloidal systems, emulsions), powders for preparations for injection (e.g., ground active compound, mixtures, lyophilized powders, Petition 870260054097, dated 03 / 06 / 2026, page 65 / 326 62 / 152 precipitated active compound), gels for injection preparations (semi-solid preparations, for example, hydrogels, in situ hydrogels) and implants (solid preparations, for example, biodegradable and non-biodegradable implants, implantable pumps).

[00198] Oral administration is preferred.

[00199] Examples that are suitable for other routes of administration are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear rinse solutions, earplugs; vaginal capsules, aqueous suspensions (lotions, agitated mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, powders for dusting, implants or stents.

[00200] The compounds according to the invention can be incorporated into the indicated dosage forms. This can be accomplished in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (e.g., cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), • ointment bases (e.g., petrolatum, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • suppository bases (e.g., polyethylene glycols, cocoa butter, hard fat), Petition 870260054097, dated 03 / 06 / 2026, page 66 / 326 63 / 152 • solvents (for example, water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglycerides, fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetting agents (for example, sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), • buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonic agents (e.g., glucose,sodium chloride), • adsorbents (e.g., highly dispersed silicas), • viscosity-increasing agents, gel formers, thickeners and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as Carbopol®); alginates, gelatin), • disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (such as Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (such as AcDiSol®)), • flow regulators, lubricants, slip agents and mold release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silicas (such as Aerosil®)), Petition 870260054097, dated 03 / 06 / 2026, page 67 / 326 64 / 152 • Coating materials (e.g., sugar, shellac) and film formers for diffusion films or membranes that dissolve rapidly or in a modified manner (e.g., polyvinylpyrrolidones (such as Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as Eudragit®)), • Capsule materials (e.g., gelatin, hydroxypropylmethylcellulose), • Synthetic polymers (e.g., polylactides, polyglycolides, polyacrylates, polymethacrylates (such as Eudragit®), polyvinylpyrrolidones (such as Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers), • plasticizers (e.g., polyethylene glycols, propylene glycol, glycerol, triacetin, triacetyl citrate,• dibutyl phthalate), • penetration enhancers, • stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate), • preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colorants (e.g., inorganic pigments such as iron oxides, titanium dioxide), • flavorings, sweeteners, and / or odor-masking agents.

[00201] The present invention also relates to a pharmaceutical composition comprising at least one compound according to the invention, conventionally in conjunction with one or more Petition 870260054097, dated 03 / 06 / 2026, page 68 / 326 65 / 152 pharmaceutically suitable excipients, and their use in accordance with the present invention.

[00202] One embodiment of the invention is pharmaceutical compositions comprising at least one compound of Formula (I) according to the invention, preferably in conjunction with at least one inert, non-toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the aforementioned purposes.

[00203] According to another aspect, the present invention encompasses pharmaceutical combinations, in particular medicaments, comprising at least one compound of General Formula (I) of the present invention and at least one or more additional active ingredients, in particular for the treatment and / or prophylaxis of cardiovascular disorders, preferably thrombotic or thromboembolic disorders and diabetes, and also urogenital and ophthalmic disorders.

[00204] The term "combination" in the present invention is used as is known to those skilled in the art, and said combination may be a fixed combination, a non-fixed combination or a kit of parts.

[00205] A fixed combination in the present invention 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) of the present invention, and another active ingredient are present together in a unit dosage or in a single entity. An example of a fixed combination is a pharmaceutical composition in which a first active ingredient and another active ingredient are present in a mixture for simultaneous administration, as in a formulation. Another example of a fixed combination is a pharmaceutical combination in which a first active ingredient and another active ingredient are present in Petition 870260054097, dated 03 / 06 / 2026, page 69 / 326 66 / 152 one unit without being mixed.

[00206] A non-fixed combination or kit of parts in the present invention is used as known to those skilled in the art and is defined as a combination in which a first active ingredient and another active ingredient are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the other active ingredient are present separately. The components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered.

[00207] The compounds of the invention can be used alone or, if necessary, in combination with other active ingredients. The present invention also provides medicaments comprising at least one of the compounds of the invention and one or more additional active ingredients, especially for the treatment and / or prophylaxis of the disorders mentioned above. Preferred examples of suitable combinations of active ingredients include: • organic nitrates and NO donors, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 and inhaled NO; • compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP), for example, phosphodiesterase (PDE) inhibitors 1, 2, 5 and / or 9, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, mirodenafil, lodenafil or PF-00489791; • compounds that inhibit the degradation of cyclic adenosine monophosphate (cAMP), for example, phosphodiesterase (PDE) 3 and 4 inhibitors, especially cilostatzole, milrinone, roflumilast, apremilast or crisaborole; Petition 870260054097, dated 03 / 06 / 2026, page 70 / 326 67 / 152 • Antihypertensive active ingredients, by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, rhokinase inhibitors and diuretics; • Antiarrhythmic agents, including, for example, and preferably, sodium channel blockers, beta-receptor blockers, potassium channel blockers, calcium antagonists, If channel blockers, digitalis, parasympatholytics (vagolytics), sympathomimetics, and other antiarrhythmics such as adenosine, adenosine receptor agonists, as well as vernacalant; • positive inotropic agents, for example, cardiac glycoside (Dogoxin), beta-adrenergic and dopaminergic agonists, such as isoprenaline, adrenaline, noradrenaline, dopamine or dobutamine; • Vasopressin receptor antagonists, by way of example and preferably from the group of conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, pecavaptan, SR-121463, RWJ 676070 or BAY 86-8050, as well as the compounds described in WO 2010 / 105770, WO2011 / 104322 and WO 2016 / 071212; • active ingredients that alter lipid metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors, such as, for example and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists. Petition 870260054097, dated 03 / 06 / 2026, page 71 / 326 68 / 152 • bronchodilators, for example and preferably from the group of beta-adrenergic receptor agonists, such as, by way of example and preferably, albuterol, isoproterenol, metaproterenol, terbutaline, formoterol or salmeterol, or from the group of anticholinergics, such as, by way of example and preferably, ipratropium bromide; • anti-inflammatory agents, for example and preferably from the glucocorticoid group, such as, by way of example and preferably, prednison, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolid, budesonide or fluticason, as well as non-steroidal anti-inflammatory drugs (NSAIDs), by way of example and preferably, acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminosalicylic acid derivatives, leukotriene antagonists, TNF-alpha inhibitors and chemokine receptor antagonists, such as CCR1, 2 and / or 5 inhibitors; • Immune system modulators, for example, immunoglobulins; • agents that inhibit the signal transduction cascade, for example and preferably from the group of kinase inhibitors, specifically from the group of tyrosine kinase and / or serine / threonine kinase inhibitors; • Agents that inhibit the degradation and modification of the extracellular matrix, for example and preferably from the group of matrix metalloproteinase (MMP) inhibitors, such as, for example and preferably, chymase, stromelysin, collagenase, gelatinase and aggrecanase inhibitors (preferably from the MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13 groups) as well as metalloelastase (MMP-12) and neutrophil-elastase (HNE) inhibitors, such as sivelestat or DX-890; • agents that block the binding of serotonin to its receptor, for example and preferably 5- receptor antagonists Petition 870260054097, dated 03 / 06 / 2026, page 72 / 326 69 / 152 HT2b; • organic nitrates and NO donors, for example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, as well as inhaled NO; • NO-independent but heme-dependent stimulators of soluble guanylate cyclase, for example and preferably the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; • NO-independent and heme-independent activators of soluble guanylate cyclase, for example and preferably the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510 written Verbindungen; • agents that stimulate cGMP synthesis, such as sGC modulators, for example and preferably riociguat, cinaciguat, vericiguat or runcaciguat; • Prostacyclin analogues, for example and preferably iloprost, beraprost, treprostinil or epoprostenol; • agents that inhibit soluble epoxyhydrolase (sEH), for example and preferably N,N'-Dicyclohexyl urea, 12-(3-Adamantan-1-yl-ureido)-dodecanic acid or 1-Adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea; • agents that interact with glucose metabolism, for example and preferably insulin, biguanide, thiazolidinedione, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-2 inhibitors, for example empagliflozin, dapagliflozin, canagliflozin, sotagliflozin; • natriuretic peptides, for example and preferably atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Petition 870260054097, dated 03 / 06 / 2026, page 73 / 326 70 / 152 Nesiritid), C-type natriuretic peptide (CNP) or urodilatin; • activators of cardiac myosin, for example and preferably omecamtiv mecarbil (CK-1827452); • calcium sensitizers, for example, and preferably levosimendan; • agents that affect the energy metabolism of the heart, for example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine, full or partial agonists of adenosine A1 receptors, such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate; • agents that affect heart rate, for example and preferably ivabradine; • Cyclooxygenase inhibitors such as, for example, bromfenac and nepafenac; • Inhibitors of the kallikrein-kinin system, such as safotibant and ecallantide; • inhibitors of sphingosine 1-phosphate signaling pathways, such as sonepcizumab; • complement-C5a receptor inhibitors such as eculizumab; • Plasminogen activators (thrombolytics / fibrinolytics) and compounds that promote thrombolysis / fibrinolysis, such as plasminogen activator inhibitors (PAI inhibitors) or thrombin-activated fibrinolysis inhibitors (TAFI inhibitors), such as tissue plasminogen activator (t-PA, e.g., Actilyse®), streptokinase, reteplase, and urokinase, or plasminogen modulating substances that cause increased plasmin formation; • anticoagulant substances (anticoagulants) such as, for example, heparin (UFH), low molecular weight (LMW) heparins, for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, Petition 870260054097, dated 03 / 06 / 2026, page 74 / 326 71 / 152 enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675 / ORG42675; Direct thrombin inhibitors (DTIs), such as, for example, Pradaxa (dabigatran), atecegatran (AZD-0837), DP-4088, SSR182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT-1011) and hirudin; Direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux; Inhibitors of coagulation factors XI and XIa, such as, for example, FXI ASO-LICA, fesomersen, BAY 121-3790, MAA868, BMS986177, EP-7041 and AB-022; Substances that inhibit platelet aggregation (platelet aggregation inhibitors, platelet aggregation inhibitors), such as acetylsalicylic acid (such as aspirin), P2Y12 antagonists, such as ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor and elinogrel, and PAR-1 antagonists such as vorapaxar, and PAR-4 antagonists; • platelet adhesion inhibitors, such as GPVI and / or GPIB antagonists, such as Revacept or caplacizumab; • Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists) such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban; • Recombinant human activated protein, such as Xigris or recombinant thrombomodulin.

[00208] Antithrombotic agents are preferably understood as compounds from the group of platelet aggregation inhibitors, of Petition 870260054097, dated 03 / 06 / 2026, page 75 / 326 72 / 152 anticoagulants or profibrinolytic substances.

[00209] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, for example and preferably aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine or dipyridamole.

[00210] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, for example and preferably ximelagatran, dabigatran, melagatran, bivalirudin or clexane.

[00211] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb / IIIa antagonist such as, by way of example and preferably, tirofiban or abciximab.

[00212] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor, by way of example and preferably rivaroxaban (BAY 59-7939), DU176b, apixaban, betrixaban, otamixaban, fidexaban, razaxaban, letaxaban, eribaxaban, fondaparinux, idraparinux, PMD-3112, darexaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV 803, SSR-126512 or SSR-128428.

[00213] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor XI or factor XIa inhibitor, for example and preferably FXI ASO-LICA, fesomersen, BAY 121-3790, MAA868, BMS986177, EP-7041 or AB022.

[00214] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or with a low molecular weight (LMW) heparin derivative.

[00215] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, for example and preferably coumarin. Petition 870260054097, dated 03 / 06 / 2026, page 76 / 326 73 / 152

[00216] Hypotensive agents are preferably understood to be compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, chloroquine inhibitors and diuretics.

[00217] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist, for example and preferably nifedipine, amlodipine, verapamil or diltiazem.

[00218] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1 receptor blocker, for example, and preferably with prazosin.

[00219] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-blocker, by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[00220] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist, for example and preferably losartan, candesartan, valsartan, telmisartan or embusartan or a dual angiotensin AII antagonist / neprilysin inhibitor, for example and preferably LCZ696 (valsartan / sacubitril).

[00221] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE inhibitor, for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril. Petition 870260054097, dated 03 / 06 / 2026, page 77 / 326 74 / 152

[00222] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.

[00223] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, for example and preferably aliskiren, SPP-600 or SPP-800.

[00224] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably spironolactone, AZD9977, finerenone or eplerenone.

[00225] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a loop diuretic, for example, furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics, for example, amiloride and triamterene, with aldosterone antagonists, for example, spironolactone, potassium canrenoate and eplerenone, and also thiazide diuretics, for example, hydrochlorothiazide, chlorthalidone, xipamide and indapamide.

[00226] Lipid metabolism modifiers are preferably understood as compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[00227] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a CETP inhibitor, for example and preferably dalcetrapib, anacetrapib, torcetrapib Petition 870260054097, dated 03 / 06 / 2026, page 78 / 326 75 / 152 (CP-529 414), JJT-705 or CETP vaccine (Avant).

[00228] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist, for example and preferably D-thyroxine, 3,5,3'triiodothyronine (T3), CGS 23425 or axithyrome (CGS 26214).

[00229] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an HMGCoA reductase inhibitor from the statin class, for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[00230] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an inhibitor of squalene synthesis, for example and preferably BMS-188494 or TAK-475.

[00231] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor, for example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[00232] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, for example and preferably an implitapide, BMS-201038, R-103757 or JTT-130.

[00233] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPARgamma agonist, for example and preferably pioglitazone or rosiglitazone.

[00234] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a PPARdelta agonist, for example and preferably GW 501516 or BAY 68-5042.

[00235] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an absorption inhibitor. Petition 870260054097, dated 03 / 06 / 2026, page 79 / 326 76 / 152 cholesterol, for example, and preferably ezetimibe, tiqueside or pamaqueside.

[00236] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a lipase inhibitor, a preferred example being orlistat.

[00237] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent, for example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

[00238] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a bile acid reabsorption inhibitor, for example and preferably with ASBT inhibitors (= IBAT), for example AZD-7806, S-8921, AK-105, BARI1741, SC-435 or SC-635.

[00239] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein(a) antagonist, for example and preferably gemcabene calcium (CI-1027) or nicotinic acid.

[00240] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein(a) antagonist, for example and preferably gemcabene calcium (CI-1027) or nicotinic acid.

[00241] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with sGC modulators, for example and preferably, riociguat, cinaciguat or vericiguat.

[00242] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an agent that affects glucose metabolism, for example and preferably, insulin, a sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors empagliflozin, dapagliflozin, canagliflozin, Petition 870260054097, dated 03 / 06 / 2026, p. 80 / 326 77 / 152 sotagliflozin.

[00243] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TGFbeta antagonist, for example and preferably pirfenidone or fresolimumab.

[00244] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CCR2 antagonist, for example and preferably CCX-140.

[00245] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TNF-alpha antagonist, for example and preferably adalimumab.

[00246] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a galectin-3 inhibitor, for example and preferably GCS-100.

[00247] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an Nrf-2 inhibitor, for example and preferably bardoxolone.

[00248] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a BMP-7 agonist, for example and preferably THR-184.

[00249] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a NOX1 / 4 inhibitor, for example and preferably GKT-137831.

[00250] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a drug that affects vitamin D metabolism, for example and preferably calcitriol, alfacalcidol, doxercalciferol, maxacalcitol, paricalcitol, cholecalciferol or paracalcitol.

[00251] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an agent Petition 870260054097, dated 03 / 06 / 2026, page 81 / 326 78 / 152 cytostatic, as an example and preferably cyclophosphamide.

[00252] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an immunosuppressive agent, for example and preferably cyclosporine.

[00253] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a phosphate binder, for example and preferably colestilane, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[00254] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with the renal proximal tubule sodium-phosphate cotransporter, for example and preferably, niacin or nicotinamide.

[00255] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcimimetic for hyperparathyroidism therapy.

[00256] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with agents for iron deficiency therapy, for example and preferably with iron products.

[00257] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with agents for the therapy of hyperuricemia, for example and preferably allopurinol or rasburicase.

[00258] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with glycoprotein hormone for the therapy of anemia, by way of example and preferably erythropoietin, daprodustat, molidustat, roxadustat, vadadustat, desidustat.

[00259] In a preferred embodiment of the invention, the compounds of Petition 870260054097, dated 03 / 06 / 2026, page 82 / 326 79 / 152 according to the invention are administered in combination with biological products for immunotherapy, by way of example and preferably abatacept, rituximab, eculizumab or belimumab.

[00260] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with vasopressin antagonists (vaptan group) for the treatment of heart failure, by way of example and preferably tolvaptan, conivaptan, lixivaptan, mozavaptan, satavaptan, pecavaptan or relcovaptan.

[00261] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with JAK inhibitors, by way of example and preferably ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) or TG101348.

[00262] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with prostacyclin analogues for microthrombus therapy.

[00263] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alkaline therapy, for example and preferably sodium bicarbonate.

[00264] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an mTOR inhibitor, for example and preferably everolimus or rapamycin.

[00265] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an NHE3 inhibitor, for example and preferably AZD1722 or tenapanor.

[00266] In a preferred embodiment of the invention, the compounds according to the invention are delivered in combination with a Petition 870260054097, dated 03 / 06 / 2026, p. 83 / 326 80 / 152 eNOS modulator, for example and preferably sapropterin.

[00267] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CTGF inhibitor, for example and preferably FG-3019.

[00268] The present invention also provides medicaments comprising at least one compound according to the invention, typically in conjunction with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the aforementioned purposes.

[00269] The compounds according to the invention can act systemically and / or locally. For this purpose, they can be appropriately administered, for example, orally, parenterally, pulmonaryly, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically, or as an implant or stent.

[00270] The compounds according to the invention can be administered in dosage forms suitable for these routes of administration.

[00271] Suitable dosage forms for oral administration are those that function in accordance with the prior art, that release the compounds according to the invention rapidly and / or in a modified manner, and that contain the compounds according to the invention in crystalline and / or amorphous and / or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed-dissolving or insoluble coatings that control the release of the compound according to the invention), tablets or films / wafers that disintegrate rapidly in the oral cavity, films / lyophilized products or capsules (for example, hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. Petition 870260054097, dated 03 / 06 / 2026, p. 84 / 326 81 / 152

[00272] Parenteral administration may bypass an absorption step (e.g., intravenously, intra-arterially, intracardially, intraspinally, or intralumbarly) or include absorption (e.g., intramuscularly, subcutaneously, intradermally, percutaneously, or intraperitoneally). Suitable forms of administration for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized powders, or sterile powders.

[00273] For other routes of administration, suitable examples are inhalable forms of medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films / wafers or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g., patches), milk, pastes, foams, powders for sprinkling, implants or stents.

[00274] Oral or parenteral administration is preferred, especially oral and intravenous administration.

[00275] The compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se, by mixing with pharmaceutically suitable, inert, non-toxic excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbite oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxides) and flavor correctors and / or Petition 870260054097, dated 03 / 06 / 2026, page 85 / 326 82 / 152 odor.

[00276] In general, it has been found to be advantageous in the case of parenteral administration to administer amounts of approximately 0.001 to 1 mg / kg, preferably approximately 0.01 to 0.5 mg / kg of body weight to achieve effective results. In the case of oral administration, the dosage is approximately 0.01 to 100 mg / kg, preferably approximately 0.01 to 20 mg / kg and more preferably 0.1 to 10 mg / kg of body weight.

[00277] However, it may be necessary, when appropriate, to deviate from the indicated amounts, specifically depending on body weight, route of administration, individual response to the active compound, nature of the preparation, and the time or interval during which administration occurs. For example, in some cases, less than the minimum amount mentioned above may be sufficient, while in other cases the maximum limit mentioned should be exceeded. In the case of administering relatively large amounts, it may be advisable to divide them into several individual doses throughout the day.

[00278] The total amount of active ingredient to be administered generally ranges from about 0.001 mg / kg to about 200 mg / kg of body weight per day, and preferably from about 0.01 mg / kg to about 50 mg / kg of body weight per day, and more preferably from about 0.01 mg / kg to about 20 mg / kg of body weight per day. Clinically useful dosing schedules will range from one to three times daily to once every four weeks. In addition, "medication holidays," during which a patient does not receive medication for a specified period of time, may be beneficial for the overall balance between pharmacological effect and tolerability. A single dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more times daily or less than once daily. The average daily dosage Petition 870260054097, dated 03 / 06 / 2026, p. 86 / 326 83 / 152 for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques, will preferably be 0.01 to 200 mg / kg of total body weight. The average daily rectal dosage regimen will preferably be 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosage regimen will preferably be 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen will preferably be 0.1 to 200 mg administered one to four times a day. The transdermal concentration will preferably be that necessary to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be 0.01 to 100 mg / kg of total body weight.

[00279] It is clear that the initial and ongoing dosage regimen specific to each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, drug excretion rate, drug combinations and the like. The desired treatment regimen and the number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional treatment tests.

[00280] However, it may be necessary to deviate from the indicated quantities, particularly depending on body weight, route of administration, individual response to the active substance, type of preparation and timing or interval of application. Thus, in some cases it may be sufficient to use less than the minimum quantity mentioned above, while in other cases the stated maximum limit must be exceeded. When applying larger quantities, it may be Petition 870260054097, dated 03 / 06 / 2026, p. 87 / 326 84 / 152 It is advisable to distribute them in several individual doses throughout the day.

[00281] According to another embodiment, the compounds of Formula (I) according to the invention are administered orally once or twice or three times a day. According to another embodiment, the compounds of Formula (I) according to the invention are administered orally once or twice a day. According to another embodiment, the compounds of Formula (I) according to the invention are administered orally once a day. For oral administration, a rapid-release or modified-release dosage form may be used.

[00282] Unless otherwise indicated, percentages in the following tests and examples are weight percentages; parts are weight parts. Solvent ratios, dilution ratios, and concentration data for liquid / liquid solutions are based in each case on volume. "w / v" means "weight / volume". For example, "10% w / v" means: 100 mL of solution or suspension comprise 10 g of substance. EXPERIMENTAL SECTION Table 1: Abbreviations

[00283] The following table lists the abbreviations used here. Abbreviation Meaning BH3^THF Borane-tetrahydrofuran BINAP 2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl br broad (1H-NMR signal) CI chemical ionization d doublet (1H-NMR signal) d Day(s) PAI diode array detector dd Double-duplet DMF N,N-dimethylformamide DMSO dimethyl sulfoxide ESI electrospray ionization (ES) Petition 870260054097, dated 03 / 06 / 2026, p. 88 / 326 85 / 152 EtOAc ethyl acetate h hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- HPLC b]pyridinium3-oxide hexafluorophosphate, CAS 148893-10-1 High-performance liquid chromatography LC-MS Liquid chromatography-mass spectrometry m multiplet (1H-NMR signal) M molar min minute(s) EM mass spectrometry MTBE Methyl tert-butyl ether NaBH4 Sodium borohydride, sodium tetrahydroborate NaHCO3 Sodium hydrogen carbonate Na2SO4 Sodium sulfate NMR nuclear magnetic resonance spectroscopy: chemical shifts (δ) are given in ppm. Chemical shifts were corrected by adjusting the DMSO signal to 2.50 ppm, unless otherwise indicated. PDA Photo Diode Array Pd2dba3 Tris(dibenzylideneacetone)dipalladium (0), CAS 51364-51-3 Pd(PPh3)4 quant.Tetrakis(triphenylphosphane)palladium(0), CAS 14221-01-3 quantitative racemic Rt, Rt retention time (as measured with HPLC or UPLC) in minutes RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]methanesulfonate palladium(II), CAS 1445085-77-7 s singlet (1H-NMR signal) SFC Supercritical Fluid Chromatography SQD Detector Quadrupole Single t triplet (1H-NMR signal) td triple-double (1H-NMR signal). Petition 870260054097, dated 03 / 06 / 2026, p. 89 / 326 86 / 152 TFA trifluoroacetic acid THF Tetrahydrofuran UPLC ultra-high performance liquid chromatography X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, CAS 564483-18-7

[00284] Other abbreviations not specified in this document have their usual meanings for those skilled in the art.

[00285] The various aspects of the invention described in this application are illustrated by the following examples, which are in no way intended to limit the invention. All publications mentioned herein are incorporated by reference in their entirety.

[00286] The examples of test experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given. EXPERIMENTAL SECTION - GENERAL PART

[00287] All reagents for which the synthesis is not described in the experimental part are commercially available or are known compounds or can be formed from known compounds by methods known to one skilled in the art.

[00288] The compounds and intermediates produced according to the methods of the invention may require purification. The purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using, for example, pre-packaged silica gel cartridges, for example Biotage SNAP KP-Sil® or KP-NH® cartridges in combination with a Biotage self-purification system (SP4® or Isolera Four®) and eluents such as Petition 870260054097, dated 03 / 06 / 2026, page 90 / 326 87 / 152 hexane / ethyl acetate or DCM / methanol gradients. In some cases, the compounds can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and / or online electrospray ionization mass spectrometer in combination with a suitable pre-packed reversed-phase column and eluents such as water and acetonitrile gradients which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[00289] In some cases, the purification methods described above may provide compounds of the present invention possessing sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention that is sufficiently basic, a trifluoroacetate or formate salt, for example, or, in the case of a compound of the present invention that is sufficiently acidic, an ammonium salt, for example. A salt of this type may be transformed into its free base or free acid form, respectively, by various methods known to those skilled in the art, or be used as salts in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, etc.) of a compound of the present invention, as isolated and described herein, is not necessarily the only form in which said compound may be applied to a biological assay to quantify specific biological activity.

[00290] In the case of the synthesis intermediates and working examples of the invention described below, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and / or purification process. Unless specified in more detail, additions to names and structural formulas, such as "hydrochloride", "trifluoroacetate", "salt" Petition 870260054097, dated 03 / 06 / 2026, p. 91 / 326 88 / 152 of sodium” or “x HCl”, “x CF3COOH”, “xNa+” should therefore not be understood in a stoichiometric sense in the case of such salts, but are merely descriptive in relation to the salt-forming components present in them.

[00291] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and / or purification processes described.

[00292] NMR peak shapes are indicated as they appear in the spectrum; possible higher-order effects were not considered.

[00293] The 1H-NMR data of selected compounds are listed in the form of 1H-NMR peak lists. For each signal peak, the δ value in ppm is given, followed by the signal intensity, reported in parentheses. Pairs of signal intensity δ values ​​from different peaks are separated by commas. Therefore, a peak list is described by the general form: δ1 (intensity^, δ2 (intensity2),..., δi (intensityi),..., δn (intensityn).

[00294] The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated with the actual ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with its relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A 1H-NMR peak list is similar to a classical 1H-NMR reading and therefore usually contains all the peaks listed in a classical NMR interpretation. Furthermore, similar to classical 1H-NMR prints, peak lists can show solvent signals, signals derived from stereoisomers. Petition 870260054097, dated 03 / 06 / 2026, page 92 / 326 89 / 152 of target compounds (also the subject of the invention) and / or impurity peaks. Stereoisomer peaks and / or impurity peaks are typically displayed with lower intensity compared to target compound peaks (e.g., with purity > 90%). Such stereoisomers and / or impurities may be typical for the specific manufacturing process, and therefore their peaks can help identify the reproduction of our manufacturing process based on byproduct fingerprints. A versadp who calculates the target compound peaks by known methods (MestReC, ACD simulation, or by using empirically evaluated expectation values) can isolate the target compound peaks as needed, optionally using additional intensity filters. Such an operation would be similar to peak selection in classical 1H-NMR interpretation.A detailed description of the NMR data report in peaklist form can be found in the publication Citation of NMR Peaklist Data within Patent Applications (cf. Research Disclosure Database Number 605005, 2014, August 1, 2014, or http: / / www.researchdisclosure.com / searching-disclosures). In the peak collection routine, as described in Research Disclosure Database Number 605005, the MinimumHeight parameter can be adjusted between 1% and 4%. Depending on the chemical structure and / or depending on the concentration of the compound being measured, it may be reasonable to set the MinimumHeight parameter <1%.

[00295] In NMR spectra of mixtures of stereoisomers, the numbers mentioned with " / " indicate that the stereoisomers show separate signals for the respective hydrogen atom, i.e., ".... / (2s, 1H)" means that a hydrogen atom is represented by 2 singlets, each singlet of one or more different stereoisomer(s).

[00296] The IUPAC names of the following intermediates and compounds Petition 870260054097, dated 03 / 06 / 2026, page 93 / 326 Examples 90 / 152 were generated using ACD / Name software (batch version 14.00; Advanced Chemistry Development, Inc.) or the naming tool implemented in BIOVIA Draw software (version 4.2 SP1; Dassault Systèmes SE). LC-MS Analytical Methods: Method 1

[00297] MS instrument type: SHIMADZU LCMS-2020, Column: Kinetex EVO C18 30*2.1 mm, 5µm, Mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in acetonitrile (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°C; UV detection: 220 nm and 254 nm. Method 2

[00298] HPLC instrument type: SHIMADZU LCMS-2020, Column: Kinetex EVO C18 50*4.6 mm, 5µm, mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in acetonitrile (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°C; UV detection: 220 nm and 215 nm and 254 nm. Method 3 (LC-MS)

[00299] MS Instrument: Thermo Scientific FT-MS; UHPLC+ Instrument Type: 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: 50 °C; Flow rate: 0.90 mL / min; UV Detection: 210 nm / Ideal integration path 210-300 nm. Method 4 (LC-MS)

[00300] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLCHSS T3 1.8 µm 50 x 1 mm; Eluent A: 1 l of water Petition 870260054097, dated 03 / 06 / 2026, p. 94 / 326 91 / 152 + 0.25 mL of formic acid, Eluent B: 1 L of acetonitrile + 0.25 mL of formic acid; Gradient: 0.0 min 90% A ^ 1.2 min 5% A ^ 2.0 min 5% A; Oven: 50 °C; Flow rate: 0.40 mL / min; UV detection: 210 nm. Method 5 (LC-MS)

[00301] Instrument: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLCHSS 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 95% A ^ 6.0 min 5% A ^ 7.5 min 5% A; Oven: 50 °C; Flow rate: 0.35 mL / min; UV detection: 210 nm. Method 6 (LC-MS)

[00302] Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLCHSS 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 °C; Flow rate: 1.20 mL / min; UV detection: 205 - 305 nm. Method 7 (LC-MS)

[00303] Instrument: Waters Single Quad MS System; UPLC acquisition by Instrument Waters; Column: Waters BEH C18 1.7 μ 50 x 2.1 mm; Eluent A: 1 L water + 1.0 mL (25% aqueous ammonia) / L, Eluent B: 1 L acetonitrile; Gradient: 0.0 min 92% A ^ 0.1 min 92% A ^ 1.8 min 5% A ^ 3.5 min 5% A; Oven: 50 °C; Flow rate: 0.45 mL / min; UV detection: 210 nm. Method 8 (LC-MS)

[00304] MS System: Waters TOF Instrument; UPLC System: Waters Acquity I-CLASS; Column: Waters Acquity UPLCHSS T3 1.8 μm 50 x 1 mm; Eluent A: 1 l Water + 0.100 mL 99% IgE Formic Acid, Eluent B: 1 l Acetonitrile + 0.100 mL 99% IgE Formic Acid; Gradient: 0.0 min 90% A ^ 1.2 min 5% A ^ 2.0 min 5% A; Oven: 50 °C; Flow: 0.40 mL / min; UV Detection: 210 nm. Petition 870260054097, dated 03 / 06 / 2026, p. 95 / 326 92 / 152 Method 9 (LC-MS)

[00305] MS System: Waters TOF Instrument; UPLC System: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3 1.8 µm 50 x 1 mm; Eluent A: 1 l Water + 0.100 mL 99% IgE Formic Acid, Eluent B: 1 l Acetonitrile + 0.100 mL 99% IgE Formic Acid; Gradient: 0.0 min 95% A ^ 6.0 min 5% A ^ 7.5 min 5% A; Oven: 50 °C; Flow: 0.35 mL / min; UV Detection: 210 nm. HPLC preparatory methods

[00306] Instrument: Waters Prep LC / MS System, column: Phenomenex Kinetex C18 5pm 100x30 mm, UV detection 200-400 nm, room temperature, column injection (complete injection), eluent A: water, eluent B: acetonitrile, eluent C: 2% formic acid in water, eluent D: acetonitrile / water (80% vol. / 20% vol.); flow rate: 80 mL / min, gradient profile: 0 to 2 min: eluent A 47 mL / min, eluent B 23 mL / min; 2 to 10 min: eluent A 47 mL / min to 23 mL / min, eluent B 23 mL / min to 47 mL / min; 10 to 12 min: eluent A 0 mL / min and eluent B 70 mL / min; Eluent C and eluent D have a constant flow rate of 5 mL / min each throughout the entire run time.

[00307] Microwave: Reactions employing microwave irradiation can be performed with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reaction times reported using microwave heating should be understood as fixed reaction times after reaching the indicated reaction temperature.

[00308] When the compounds according to the invention are purified by preparative HPLC using the methods described above in which the eluents contain additives, for example, trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention can be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention Petition 870260054097, dated 03 / 06 / 2026, p. 96 / 326 93 / 152 contain sufficient basic or acidic functionality. Such a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.

[00309] In the case of the synthesis intermediates and working examples of the invention described below, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and / or purification process. Unless specified in more detail, additions to names and structural formulas, such as hydrochloride, trifluoroacetate, sodium salt or x HCl, x CF3COOH, x Na+, should not be understood in a stoichiometric sense in the case of such salts, but are merely descriptive in relation to the salt-forming components present therein.

[00310] This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and / or purification processes described.

[00311] Enantiomer 1 is the enantiomer that eluted first from the column.

[00312] Enantiomer 2 is an enantiomer that eluted second down the column.

[00313] For example 3 (enantiomer 2), the absolute configuration was determined by single-crystal X-ray structure analysis as R. Consequently, all compounds annotated as enantiomer 2 must have an absolute configuration of R. The corresponding stereochemistry must survive all synthetic conditions due to its substitution pattern.

[00314] Diastereomeric mixture 1 defines a compound where its starting material is defined as Enantiomer 1 and reacts with a Petition 870260054097, dated 03 / 06 / 2026, page 97 / 326 94 / 152 building block containing at least one chiral center and where the configuration is not defined.

[00315] Diastereomeric mixture 2 defines a compound where its starting material is defined as Enantiomer 2 and reacts with a building block containing at least one chiral center and where the configuration is not defined.

[00316] Diastereoisomer 1 and Diastereoisomer 2 define the two compounds resulting from the chiral separation of the diastereomeric mixture 1 described above.

[00317] Diastereoisomer 3 and Diastereoisomer 4 define the two compounds resulting from the chiral separation of the diastereomeric mixture 2 described above.

[00318] Stereoisomer 1 defines a compound where its starting material is defined as Enantiomer 1 and reacts with a building block containing at least one chiral center and where the configuration is defined

[00319] Stereoisomer 2 defines a compound where its starting material is defined as Enantiomer 2 and reacts with a building block containing at least one chiral center and where the configuration is defined. Starting and intermediate compounds Intermediate 1A Example 1A tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (racemate)

[00320] A solution of 3-oxopiperidine-1-carboxylate of tert Petition 870260054097, dated 03 / 06 / 2026, p. 98 / 326 95 / 152 butyl [CAS No. 989-36-7] (300 g, 1.51 mol) in tetrahydrofuran (1.50 L) and methanol (300 mL) was added to benzyl hydrazine carboxylate [CAS No. 5331-43-1] (250 g, 1.51 mol) at 25 °C, then the mixture was stirred at 25 °C for 1 h. Then, NaBH4 (114 g, 3.01 mol) was added in portions to the mixture at 25 °C and stirred at 25 °C for 2 h. The reaction mixture was cooled to 10 °C and NH4Cl was added dropwise until pH ~6. The mixture was extracted with EtOAc (300 mL*2) and concentrated under vacuum. The residue was dissolved in MTBE (300 mL) and petroleum ether (300 mL) was added. The mixture was filtered and the precipitate was washed with petroleum ether (100 mL) yielding the title compound (400 g, 1.14 mol, 76.0% yield) as a white solid.

[00321] LC-MS: (Method 1) Rt = 0.832 min, MS (M-100+1 = 250.4). Example 2A tert-butyl acetic acid 3-hydrazinopiperidine-1-carboxylate (Racemate) x ch3cooh

[00322] To a solution of tert-butyl 3-{2-[(benzyloxy)carbonyl]hydrazino}piperidine-1-carboxylate (prepared analogously to Example 1A, 1.20 kg, 3.43 mol) in ethanol (11.0 L) was added acetic acid (415 g, 6.91 mol, 395 mL) and Pd / C (120 g, 20% purity) under H2 (15 psi). The mixture was stirred at 25 °C for 12 h. The mixture was filtered and the precipitate was washed with ethanol (11.0 L) to give a solution of the title compound in ethanol (945 g, acetic acid salt) as a black liquid; the filtrate was used for the next step without purification.

[00323] 1H-NMR (400 MHz, CDCb) 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) Petition 870260054097, dated 03 / 06 / 2026, p. 99 / 326 96 / 152

[00324] LC-MS: (Method 1) Rt = 0.263 min, MS (M-56+1 = 160.2) Example 3A 2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate ethyl o oF^XJ^'O / XCH3h3c^

[00325] A solution of ethyl 4,4-difluoro-3-oxobutanoate [CAS No. 352-24-9] (120 g, 722 mmol) and (diethoxymethoxy)ethane (240 ml, 1.4 mol) in acetic acid anhydride (200 ml, 2.2 mol) was stirred overnight at 140°C and evaporated to dryness, resulting in 155 g (quant.) of the title compound which was used in the next step without further purification.

[00326] Ή-NMR (600 MHz, CDCb) δ [ppm]: 1.306 (6.05), 1.318 (16.00), 1.330 (14.48), 1.341 (4.56), 1.428 (5.99), 1.436 (5.01), 1.440 (12.20), 1.448 (9.25), 1.451 (6.31), 1.460 (4.48), 2.095 (1.59), 2.225 (1.56), 4.247 (1.97), 4.260 (5.79), 4.271 (5.85), 4.277 (1.55),4.283 (2.00), 4.289 (4,40), 4,301 (4,37), 4,308 (2,03), 4,313 (1,64), 4,320 (5,74), 4,332 (5,78), 4,340 (1,60), 4,344 (2,01), 4,351 (4,21), 4,364 (4,20), 4,375 (1,37), 6,262 (1,79), 6,339 (1,35), 6,352 (3,56), 6,429 (2,63), 6,442 (1,72), 6,519 (1,28), 7,867 (5,48), 7,880 (7,31). Example 4A tert-butyl 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1carboxylate (Racemate) ch3

[00327] A mixture of tert-butyl acetic acid 3-hydrazinopiperidine-1-carboxylate (Example 2A, 945 g, 3.43 mol) in ethanol (20.0 L) Petition 870260054097, dated 03 / 06 / 2026, p. 100 / 326 97 / 152 was added ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate (prepared analogously to Example 3A, 840 g, 3.78 mol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated. The residue was poured into saturated aqueous NaHCO3 solution (10.0 L) and extracted with ethyl acetate (10.0 L*2). The combined organic layer was washed with brine (10.0 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with petroleum ether:ethyl acetate (50:1-25:1-10:1, Rf = 0.3) yielding 530 g (41.4% yield) of the title compound.

[00328] 1H-NMR (400 MHz, CDCh) δ [ppm]: 7.84 (s, 1H), 7.51 (t, J = 12.8 Hz, 1H), 4.47 - 4.41 (m, 1H), 4.30 - 4.10 (m, 4H), 3.19 - 3.13 (m, 1H), 2.69 (s, 1H), 2.15 - 2.10 (m, 2H), 1.83 - 1.78 (m, 1H), 1.60 - 1.55 (m, 1H), 1.40 (s, 9H), 1.32 - 1.29 (m, 3H)

[00329] LC-MS (Method 1) Rt = 0.992 min, MS (M-56+1 = 318.0). Example 5A Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazol-4-carboxylate (Racemate)

[00330] tert-butyl 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (prepared analogously to Example 4A, 593 g, 1.59 mol) was added to a solution of hydrogen chloride in dioxane (4 M, 2.50 L), the mixture was stirred at 25 °C for 12 h. The mixture was evaporated and the residue was dissolved in 1.00 L of water and extracted with 500 mL of MTBE. The aqueous phase was separated and the pH adjusted to 8-9 with NaHCO3. The aqueous phase was extracted with dichloromethane (1.00 L x 2), and the combined organic phases were washed with brine (1.00 L), dried over Na2SO4 and concentrated to yield 350 g (80.6% yield) of the title compound. Petition 870260054097, dated 03 / 06 / 2026, page 101 / 326 98 / 152

[00331] Ή-NMR (400 MHz, CDCb) δ [ppm]: 7.87 (s, 1H), 7.54 (t, J = 12.8 Hz, 1H), 4.55 - 4.54 (m, 1H), 4.34 - 4.28 (m, 2H), 3.25 - 3.03 (m, 3H), 2.71 - 2.65 (m, 1H), 2.19 - 1.86 (m, 4H), 1.63 - 1.60 (m, 1H), 1.35 (t, J = 7.2 Hz, 3H)

[00332] LC-MS: (Method 1) Rt = 0.644 min, MS (M +1) = 274.6

[00333] Analogous to Example 5A, ethyl 5-(difluoromethyl)-1-(piperidin-3yl)-1H-pyrazol-4-carboxylate (Racemate) was prepared using different protecting groups. The two enantiomers were separated by SFC [sample preparation: 20 g dissolved in 500 mL of methanol; injection volume: 15 mL; column: Daicel AZ SCF 20 µm, 400 x 50 mm; eluent: carbon dioxide / methanol / aqueous ammonia (1%) 80:19:1 to 60:39:1; flow rate: 400 mL / min; temperature: 40 °C; UV detection: 220 nm]. After separation, 8.1 g of enantiomer 1 (Example 6A), which eluted first, and 8.0 g of enantiomer 2 (Example 7A), which eluted later, were isolated. Example 6A Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazol-4-carboxylate (Enantiomer 1)

[00334] For separation conditions, see Example 5A.

[00335] SFC analytical: Rt = 0.980 min, ee = 100% [Chiralpak IC-3 column: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.2% diethylamine]: 90:10 flow rate: 3.0 mL / min; temperature: 25 °C; UV detection: 220 nm].

[00336] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.00 (s, 1H), 7.757.44 (m, 1H), 4.50-4.36 (m, 1H), 4.33-4.18 (m, 2H), 3.10-2.95 (m, 1H), 2.91-2.76 (m, 2H), 2.48-2.33 (m, 2H), 2.08-1.94 (m, 2H), 1.81-1.66 (m, 1H), 1.62-1.40 (m, 1H), 1.37-1.21 (m, 3H). Petition 870260054097, dated 03 / 06 / 2026, p. 102 / 326 99 / 152 Example 7A Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazol-4-carboxylate (Enantiomer 2)

[00337] For separation conditions, see Example 5A.

[00338] Analytical SFC: Rt = 1.227 min, ee = 97% [For Chiral Column IC-3: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.2% diethylamine]: 90:10 flow rate: 3.0 mL / min; temperature: 25°C; UV detection: 220 nm].

[00339] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01(s,1H), 7.757.43(m,1H), 4.50-4.37(m,1H), 4.27(q,2H), 3.09- 2.97(m,1H), 4.1. 2,942.81 (m, 2H), 2.47–2.34 (m, 2H), 2.06–1.92 (m, 2H), 1.79–1.66 (m, 1H), 1.60–1.41 (m, 1H), 1.29 (t, 3H). Example 8A 2-Bromo-4-chloro-1-[(4- methoxyphenyl)methoxy]benzene

[00340] 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 for approximately 19 hours at 70°C. 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 flash chromatography (silica gel, cyclohexane / ethyl acetate gradient) yielding 13.8 g Petition 870260054097, dated 03 / 06 / 2026, page 103 / 326 100 / 152 (86% yield) of the bond compound.

[00341] LC-MS (Method 3): Rt =2.48 min; MS (ESIneg): m / z = 324 [MH]

[00342] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 3.349 (10.98), 5.124 (16.00), 6.949 (0.87), 6.954), (6.98), (2.67) 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), 7.4.0, (7.4), (7.8), (3.6) 7.417 (3.04),7.421 (3.406 (3.89), 7.417 (3.402), 7.42 (7.406 (3.89), 7.417 (3.404), 7.42 (7.47),, 7.697 (6.701), (7.34). Example 9A 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5(difluoromethyl)-1H-pyrazole-4-ethyl carboxylate (Enantiomer 1) Cl t it. GH3

[00343] Under argon, a solution of 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared analogously to Example 8A, 10.0 g, 30.5 mmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared analogously to Example 6A, Enantiomer 1, 8.34 g, 30.5 mmol) in 1,4-dioxane (100 ml) was treated with cesium carbonate (29.8 g, 91.6 mmol), Pd2dba3 (2.80 g, 3.05 mmol) and rac-BINAP (3.80 g, 6.10 mmol) and the resulting mixture was stirred overnight at 100 °C. The reaction mixture was combined with a 500 mg test reaction, filtered over celite, rinsed with ethyl acetate, and evaporated. The residue was taken up in water 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 flash chromatography (silica gel, cyclohexane / ethyl acetate gradient) yielding 10.1 g (60% yield) of the title compound. Petition 870260054097, dated 03 / 06 / 2026, page 104 / 326 101 / 152

[00344] LC-MS (Method 4): Rt = 1.44 min; MS (ESIpos): m / z = 520 [M+ H]+ Example 10A Ethyl -[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4carboxylate (Enantiomer 1) Cl

[00345] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (Example 9A, Enantiomer 1, 10.1 g, 19.4 mmol) in dichloromethane (200 ml) was treated with trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was evaporated. The residue was taken up in ethyl acetate and washed once with water, once with a saturated solution of sodium bicarbonate, and finally once with a saturated solution of sodium chloride. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane / ethyl acetate gradient) yielding 7.17 g (83% purity, 77% yield) of the title compound.

[00346] LC-MS (Method 8): Rt = 1.26 min; MS (ESIpos): m / z = 400 [M+ H]+ Example 11A Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5(difluoromethyl)-1H-pyrazol-4-carboxylate (Enantiomer 1) Petition 870260054097, dated 03 / 06 / 2026, page 105 / 326 102 / 152

[00347] Under argon, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (Example 10A, Enantiomer 1, 7.17 g, 83% purity, 14.9 mmol) in dichloromethane (160 ml) was treated with triethylamine (5.2 ml, 37 mmol) and cooled to 0°C. Trifluoromethanesulfonic anhydride was added dropwise and the resulting mixture was stirred for 45 minutes at 0°C. The reaction mixture was diluted with dichloromethane (150 ml) and washed three times with water. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, cyclohexane / ethyl acetate gradient) yielding 7.89 g (quantity) of the title compound.

[00348] LC-MS (Method 4): Rt = 1.47 min; MS (ESIpos): m / z = 532 [M+ H]+Example 12A Ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5(difluoromethyl)-1H-pyrazol-4-carboxylate (Enantiomer 2) Cl

[00349] Under argon, a solution of ethyl 5-(difluoromethyl)-1-[piperidin-3yl]-1H-pyrazol-4-carboxylate (prepared analogously to Example 7A, Enantiomer 2, 43.6 g, 160 mmol) and 2-bromo-4-chloro-1-[(4 Petition 870260054097, dated 03 / 06 / 2026, page 106 / 326 103 / 152 methoxyphenyl)methoxy]benzene (prepared analogously to Example 8A, 52.3 g, 160 mmol) in 1,4-dioxane (680 ml) was treated with Pd2(dba)3 (14.6 g, 16.0 mmol), rac-BINAP (19.9 g, 31.9 mmol) and freshly ground cesium carbonate (156 g, 479 mmol) and stirred for 18 hours at 100°C. The reaction mixture was diluted with ethyl acetate and a 10% sodium chloride solution, filtered over Celite and rinsed with ethyl acetate. The aqueous phase of the filtrate was extracted with ethyl acetate. The combined organic layers were washed with a 10% sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel (dichloromethane / petroleum ether 4:1) resulting in 42 g (82% yield) of the title compound.

[00350] LC-MS (Method 3): Rt = 2.78 min; MS (ESIpos): m / z = 520 [M+ H]+

[00351] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.272 (3.65), 1.290 (7.68), 1.307 (3.76), 1.686 (0.44), 1.717 (0.54), 1.852 (0.73), 1.885 (0.50), 1.989 (0.47), 2.019 (0.56), 2.058 (0.99), 2.084 (0.61),2.587 (0.51), 2.616 (0.89), 2.642 (0.45), 3.030 (0.76), 3.057 (1.51),3.084 (0.83), 3.447 (0.72), 3,474 (0.69), 3,613 (0.74), 3,640 (0.67), 3,737 (16.00), 4,251 (1.13), 4,269 (3.48), 4,287 (3.45), 4,304 (1.12), 4,624 (0.40), 4,639 (0.48), 4,650 (0.76), 4,661 (0.51), 5,035 (6.45), 6,872 (3.47), 6,893 (5.67), 6,947 (0.98), 6,952 (0.85), 6,968 (1.72), 6,974 (1.67), 7,017 (2.84), 7,039 (1.57), 7.305 (3.66), 7.326 (3.43), 7.340 (0.56), 7.380 (0.41), 7.439 (0.93), 7.463 (0.64), 7.476 (0.48), 7.569 (1.65), 7.699 (0.76), 8.044 (3.66). Example 13A Ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4carboxylate (Enantiomer 2) Petition 870260054097, dated 03 / 06 / 2026, page 107 / 326 104 / 152 ci

[00352] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (prepared analogously to Example 12A, Enantiomer 2, 67.5 g, 130 mmol) in dichloromethane (1.0 L) was treated with trifluoroacetic acid (100 mL, 1.3 mol) and stirred overnight at room temperature. The reaction mixture was diluted with water (750 mL) and carefully treated with a 10% sodium carbonate solution (450 mL) until no more carbon dioxide was generated. The organic phase was dried over sodium sulfate and evaporated, resulting in 52 g (90% yield) of the title compound which was used in the next step without further purification.

[00353] LC-MS (Method 3): Rt = 2.42 min; MS (ESIpos): m / z = 400 [M+H]+ Example 14A Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5(difluoromethyl)-1H-pyrazol-4-carboxylate (Enantiomer 2)

[00354] A solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (Example 13A, Enantiomer 2 (52.0 g, 117 mmol) and triethylamine (49 ml, 350 mmol) in dichloromethane (330 ml) were cooled to -50°C. Acid Petition 870260054097, dated 03 / 06 / 2026, page 108 / 326 105 / 152 trifluoromethanesulfonic acid (28 mL, 160 mmol) was added dropwise and the resulting mixture was stirred for 1 hour at -50 °C. The reaction mixture was then diluted with dichloromethane (330 mL) and water (370 mL). The aqueous phase was extracted with dichloromethane (330 mL). The combined organic layers were washed with (370 mL), dried over sodium sulfate and evaporated. The resulting mixture was purified by flash chromatography (silica gel, dichloromethane / petroleum ether 6:4) resulting in 60 g (96% yield) of the title compound.

[00355] LC-MS (Method 3): Rt = 2.74 min; MS (ESIpos): m / z = 532 [M+ H]+

[00356] 1H-RMN (600 MHz, DMSO-d6) δ [ppm]: -0.021 (0.65), 1.082 (0.51), 1.270 (7.69), 1.282 (16.00), 1.294 (7.63), 1.772 (0.48), 1.780 (0.51) _)))), 7.391 (4.65), 7.406 (3.75), 7.431 (4.73), 7.435 (4.51), 7.492 (1.26), 7.579 (2.61), 7.666 (1.07), 8.026 (6.37). Example 15A 4-(4'-chloro-2'-{3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate tert-butyl (Enantiomer 2)

[00357] Under argon, a solution of ethyl 1-[1-{5-chloro-2[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (Example 14A, Enantiomer 2, 57.0 g, 107 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate [CAS No. 470478-90-1] (49.9 g, 129 mmol) in toluene (600 ml) and ethanol (600 ml) was treated with an aqueous solution of sodium carbonate (160 ml, 2.0 M, 320 mmol) and Tetrakis(triphenylphosphine)palladium(0) (6.19 g, 5.36 mmol). The resulting mixture was stirred for 4 hours at 100 °C. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with Petition 870260054097, dated 03 / 06 / 2026, p. 109 / 326 106 / 152 ethyl acetate and evaporated. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 9:1 to 8:2) yielding 62 g (89% yield) of the title compound.

[00358] LC-MS (Method 3): Rt = 3.15 min; MS (ESIpos): m / z = 644 [M+ H]+ Example 16A Ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3yl}-5-(difluoromethyl)-1H-pyrazol-4-carboxylate hydrochloride (Enantiomer 2)

[00359] A solution of tert-butyl 4-(4'-chloro-2'-{(3-[5-(difluoromethyl)-4(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylate (Example 15A, Enantiomer 2, 60.0 g, 93.1 mmol) in dichloromethane (250 mL) was treated with a solution of hydrogen chloride in dioxane (230 mL, 4.0 M, 930 mmol). The resulting mixture was stirred for 3 hours at room temperature and evaporated. The residue was co-evaporated twice with diethyl ether (250 mL x 2), stirred for 4 days in diisopropyl ether. The suspension was filtered, the solid was washed twice with diisopropyl ether, resulting in 57 g (quantity) of the compound title.

[00360] LC-MS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 544 [M+ H]+

[00361] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.029 (13.49), 1.044 (13.77), 1.262 (7.53), 1.280 (16.00), 1.297 (7.81), 1.496 (0.79), 1.506 (0.62), 1.527 (0.91), 1.559 (0.40), 1.716 (1.24), 1.749 (0.95), 1.888 (0.84), 1.897 (0.78), 1.918 (0.98), 1.926 (0.93), 1.966 (1.38), 1.995 (0.69), 2.580 (1.54), 2.606 (0.83), 2.992 (1.21), 3.018 (2.69), 3.044 Petition 870260054097, dated 03 / 06 / 2026, page 110 / 326 107 / 152 (2.33), 3.063 (1.24), 3.435 (5.96), 3.448 (7.25), 3.460 (5.00),3.570 (5.96), 3.448 (7.25), 3.460 (5.00), 3.570 (5.96), 3.448 (7.25),3.460 (5.00), 3.57,, 3.586 (0.87), 3.601 (1.12), 3.616 (0.85), 4.227 (5.38), 4.238 (6.62), 4.256 (9.26), 4.273 (7.97), 4.291 (2.70), 4.444 (0.41),4.455 (0.77), 4.470 (0.89), 4.481 (1.31), 4.491 (0.92), 4.507 (0.68),7.045 (6.02), 7.067 (6.86), 7.074 (5.10), 7.079 (5.42), 7.099 (2.25),7.104 (5.10), 7.079 (5.42), 7.099 (2.25), 7.104 (5.10), (5.10) (5.079), 7.099 (2.25), 7.104 (5.10) (5.10), 7.120 (3.55), 7.125 (3.10), 7.164 (6.27), 7,185 (3.37), 7,383 (1.62), 7,483 (6.90), 7,505 (6.40), 7,513 (3.75), 7,643 (1.34), 8,005, 9,399 (1.97). Example 17A -[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate de ethyla (Enantiomero 2)

[00362] A solution of ethyl hydrogen 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazol-4-carboxylate chloride (Example 16A, Enantiomer 2, 52.0 g, 84.3 mmol) in THF was treated with N,N-diisopropylethylamine (59 mL, 340 mmol) and 2-methylpropanal [CAS No. 78-84-2] (38 mL, 420 mmol) and stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (71.5 g, 337 mmol) was then added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was diluted with an aqueous solution of sodium bicarbonate (10%) and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a solution Petition 870260054097, dated 03 / 06 / 2026, page 111 / 326 108 / 152 aqueous sodium chloride, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate 8:2) yielding 47 g (93% yield) of the title compound.

[00363] LC-MS (Method 9): Rt = 3.42 min; MS (ESIpos): m / z = 600 [M+ H]+ Example 18A 1-(2-Methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]piperazine

[00364] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl]piperazine (350 mg, 1.21 mmol) was placed in 7.4 mL of THF and N,N-diisopropylethylamine (320 µL, 1.8 mmol). Then, 2-methylpropanal (440 µL, 4.9 mmol) was added and the mixture was stirred for 10 min. Next, sodium triacetoxyborohydride (772 mg, 3.64 mmol) was added and the mixture was stirred at 55°C for 4 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated. 342 mg of the target compound were obtained (79% of theory, 97% purity).

[00365] LC-MS (Method 3): Rt = 1.23 min; MS (ESIpos): m / z = 345 [M+ H]+

[00366] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.058 (0.55), 0.927 Petition 870260054097, dated 03 / 06 / 2026, page 112 / 326 109 / 152 (4.09), 0.938 (4.13), 1.316 (16.00), 2.121 (0.98), 2.133 (0.89), 2.492 (0.99), 2.508 (0.99), 2.559 (2.25), 2.599 (2.62), 3.241 (1.07), 3.249 (1.38), 3.257 (0.98), 6.935 (1.05), 6.949 (1.07), 7.552 (1.15), 7.56 (1.949 (1.07). EXPERIMENTAL SECTION - EXAMPLE OF COMPOUNDS Example 1 1-[1-{4-Chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylic acid hydrochloride (Enantiomer 1) Cl CH3 x HCl

[00367] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (prepared analogously to Example 11A, Enantiomer 1, 80.0 mg, 147 pmol) and 1-(2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18A 62.8 mg, 97% purity, 177 pmol) were placed under argon in toluene / ethanol (820 / 820 pL). A 2 M sodium carbonate solution (220 pL, 2.0 M, 440 pmol) and tetrakis(triphenylphosphine) palladium(0) (8.52 mg, 7.37 pmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate and 1 M hydrochloric acid was added. The aqueous phase was extracted three times with ethyl acetate. The organic phase was dried with sodium sulfate, filtered, and evaporated. The crude mixture was dissolved with THF / ethanol (2.0 / 0.2 mL), 1 M lithium hydroxide solution (1.5 mL, 1.5 mmol) was added, and the mixture was Petition 870260054097, dated 03 / 06 / 2026, page 113 / 326 110 / 152 stirred at room temperature overnight. A 1 M lithium hydroxide solution (740 μL, 740 μmol) was added again. After approximately 6 h, the reaction mixture was evaporated at 50 °C. The residue was dissolved in acetonitrile / water / 0.25 mL trifluoroacetic acid and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with the addition of 0.1% trifluoroacetic acid). The crude product was purified by thick-layer chromatography (dichloromethane / methanol / formic acid: 10 / 1 / 0.1). The silica gel mixture was stirred with 1 M dichloromethane / hydrochloric acid in dioxane (10 / 1) in ethanol, filtered, and carefully evaporated at 30 °C and lyophilized. 34 mg of the target compound were obtained (36% of theory, 95% purity).

[00368] LC-MS (Method 6): Rt = 1.23 min; MS (ESIpos): m / z = 572 [M-HCl+ H]+

[00369] 1H-RMN (600 MHz, DMSO-d6) δ [ppm]: 1,004 (15,87), 1,015 (16,00), 1,500 (0,51), 1,521 (0,57), 1,728 (0,73), 1,750 (0,61), 1,897 (0,57), 1,917 (0,62), 1,975 (0,79), 2,122 (0,42), 2,133 (0,84),2,144 (1,02), 2,156 (0,79), 2,571 (0,47), 2,587 (0,91), 2,610 (0,52),3,004 (0,47), 2,587 (0,91), 2,610 (0,52), 3,004 (0,47), 2,587 (0,91),2,610 (0,52),, 3,022 (2,01), 3,026 (2,20), 3,038 (3,72), 3,048 (2,50),3,065 (0,75), 3,154 (2,66), 3,161 (2,75), 3,169 (2,36), 3,177 (1,88), 3,22), (0,169), 3,177 (1,88), 3,22 (0,169),, 3,237 (0,70), 3,589 (1,41), 3,602 (1,80), 3,825 (1,02), 3,841 (0,78), 3,866 (1,05), 3,882 (0,75),4,223 (2,57), 4,445 (0,882) (0,75), 4,223 (2,57), 4,445 (0,88), 4,75 (0,75), 4,223 (2,57), 4,445 (0,882) (0,75), 4,23 (2,57), 4,445 (0,882) (0,75,, 4.481 (0.57), 7.045 (0.55), 7.055 (3.63), 7.070 (3.72), 7.084 (2.72), 7.087 (3.09), 7.110 (1.47), 7.113 (71.11), (2.47),,7.163 (3.67), 7.177 (2.19), 7.215 (0.46), 7.428 (0.83), 7.495 (4.24),7.510 (4.02), 7.515 (2.097), 7.7.602 (0.7.602). 9.484 (0.54). Example 2 Petition 870260054097, dated 03 / 06 / 2026, p. 114 / 326 111 / 152 Acid 1-[1-{4-Chloro-4'-[4-(2-methylpropyl)piperazine-1-yl][1,1'-biphenyl]-2 il}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylic (2)Enantiomer Method A

[00370] A solution of ethyl 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate (prepared analogously to Example 17A, Enantiomer 2, 50.8 g, 84.6 mmol) in a 9:1 THF / methanol mixture (1.0 L) was treated with an aqueous solution of lithium hydroxide (850 mL, 1.0 M, 850 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated, diluted with dichloromethane (1.5 L), and adjusted to pH = 2 with an aqueous solution of hydrogen chloride (2N). The resulting suspension was stirred for 45 minutes at room temperature. The solid was filtered, washed with water, and dried under vacuum, resulting in 43 g (90% yield) of the title compound.

[00371] LC-MS (Method 7): Rt = 1.27 min; MS (ESIpos): m / z = 572 [M+ H]+

[00372] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.002 (15.68), 1.013 (16.00), 1.080 (0.57), 1.092 (1.18), 1.103 (0.63), 1.498 (0.74), 1.519 (0.83), 1.719 (1.03), 1.741 (0.88), 1.902 (0.78), 1.908 (0.74), 1.922 (0.88), 1.928 (0.83), 1.943 (0.45), 1.978 (1.13), 1.994 (0.74), 2.102 (0.71), 2.112 (0.85), 2.123 (0.70), 2.571 (1.40), 2.591 (0.77), 2.882 (1,10), 3,018 (1,27), 3,035 (3,01), 3,053 (2,14), 3,239 (2,40), 3,254 (2,32), 3,368 (1,13), 3,379 (1,40), 3,391 (1,33), 3,403 (0,92), 3,493 Petition 870260054097, dated 03 / 06 / 2026, page 115 / 326 112 / 152 (0.76), 4.463 (0.65), 4.482 (1.12), 4.500 (0.62), 7.033 (4.22), 7.08 (1.12), 4.500 (0.62), 7.033 (4.22), 7.08 (1.12), 4.500 (0.62), 7.033 (4.22), 7.08 (1.12), 4.500 (0.62), 7.074 (3.47), 7.077 (4.04), 7.100 (1.85), 7.103 (1.52), 7.113 (2.53), 7.117 (2.34), 7.162 (4.18), 7.175 (2.71), 7.439 (1.03), 7.481 (4.8) (2.71), 7.439 (1.03), 7.481 (4.8) (2.71), 7.439 (1.03), 7.18 (7.175), 7.495 (4.57), 7.526 (2.04), 7.613 (0.91), 7.952 (5.28). Method B

[00373] 1-{1-[4-Chloro-4'-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (prepared analogously to Example 3, Enantiomer 2, 31.2 mg, 51.3 pmol) was dissolved in 17 mL of dichloromethane and 1 mL of methanol. The solution was stirred once with 1.5 mL of saturated aqueous sodium bicarbonate solution. The phases were separated. 5 mL of dichloromethane and 3 mL of methanol were added to the organic phase. The organic phase was then dried over sodium sulfate, filtered, evaporated, and purified by preparative HPLC (RP18 column, acetonitrile / water gradient, neutral without acid addition). The product fractions were combined and lyophilized. 22 mg of the target compound were obtained (74% of the theoretical amount).

[00374] LC-MS (Method 3): Rt = 1.73 min; MS (ESIpos): m / z = 572 [M+ H]+

[00375] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.887 (15.60), 0.898 (16.00), 1.493 (0.64), 1.514 (0.70), 1.695 (0.89), 1.718 (0.74), 1.799 (.48), 1.811 (.88), 1.822 (1.12), 1.833 (.92), 1.844 (.48), 1.890 (.68), 1.910 (.74), 1.977 (.93), 1.995 (.62), 2.118 (3.91), 2.130 (3.66), 2.516 (5.14), 3.017 (1.09), 3.035 (2.76), 3.053 (1.94), 3.181 (5.03), 3.185 (5.02), 3.267 (1.53), 4.473 (0.55), 4.491 (0.96), 4.509 (0.54), 6.963 (3.96), 6.977 (4.06), 7.048 (3.13), 7.051 (3.31), 7.081 (1.60), 7.084 (1.26), 7.095 (2.21), 7.098 (1.89), 7.152 (3.52), 7.16 (2.21), 7.098 (1.89), 7,152 (3,52), 7,16 (2,21), 7,098 (1,89), 7,152 (3,52), 7,16 (2,21),, 7,434 (4,45), 7,448 (4,50), Petition 870260054097, dated 03 / 06 / 2026, page 116 / 326 113 / 152 7,533 (1.51), 7,621 (0.67), 7,930 (4.14). Example 3 1-{1-[4-Chloro-4'-(4-isobutylpiperazin-1-yl)[biphenyl]-2yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazol-4-carboxylic acid hydrochloride (Enantiomer 2) Cl CH3x HCl Method A

[00376] A suspension of 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)1H-pyrazol-4-carboxylic acid (prepared analogously to Example 2, Enantiomer 2, 43.5 g, 76.0 mmol) in diethyl ether (870 ml) was treated with a solution of hydrogen chloride in diethyl ether (84 ml, 1.0 M, 84 mmol). The resulting mixture was stirred overnight at room temperature and evaporated, resulting in 46.1 g (quantity) of the title compound.

[00377] LC-MS (Method 3): Rt = 1.72 min; MS (ESIpos): m / z = 572 [M+ H]+

[00378] 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.026 (15.64), 1.037 (16.00), 1.497 (0.56), 1.519 (0.61), 1.722 (0.78), 1.743 (0.65), 1.903 (0.59) (0.45), 2.557 (0.64), 2.577 (1.02), 2.594 (0.55), 2.992 (1.81), 3.002 (2.77), 3.012 (1.87), 3.018 (1.15), 3.036 (2.40), 3.054 (1.60), 3.133 (1.12), 3.148 (1.19), 3.168 (0.53), 3.237 (0.88), 3.250 (0.76), 3.338 (0.81), 3.360 (1.42), 3.379 (0.88), 3.580 (1.61), 3.791 (0.89), 3.819 (1.25), 3.844 (0.81), 4,463 (0.89), 4,474 (0.97), 4,481 (1.26), 4,488 Petition 870260054097, dated 03 / 06 / 2026, page 117 / 326 114 / 152 (0.99), 4.499 (0.88), 7.051 (3.56), 7.065 (3.77), 7.077 (2.72), 7.080 (3.14), 7.103 (1.42), 7.106 (1.13), 7.116 (2.00), 7.120 (1.84), 7.165 (3.40), 7.178 (2.22), 7.443 (0.84), 7.489 (4.04), 7.504 (3.79), 7.84 (1.66), 7.618 (0.72), 7.954 (4.33), 10.519 (0.49). Method B

[00379] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3yl]-5-(difluoromethyl)-1H-pyrazol-4-carboxylate ethyl (prepared analogously to Example 14A, Enantiomer 2, 80.0 mg, 150 pmol) and 1-(2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (Example 18A 64.1 mg, 97% purity, 180 pmol) were dissolved under argon in toluene / ethanol (0.83 / 0.83 ml). Tetrakis(triphenylphosphine) palladium(0) (8.69 mg, 7.52 pmol) and 2 M sodium carbonate solution (226 pL, 452 pmol) were added and the mixture was stirred at 100 °C overnight. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was acidified with 1 M hydrochloric acid. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and evaporated.The crude product was dissolved in THF / ethanol (3.9 / 0.39 ml), 1 M aqueous lithium hydroxide solution (1.5 ml, 1.5 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was evaporated, the residue was dissolved in acetonitrile / TFA / water and purified using preparative HPLC (RP18 column, acetonitrile / water gradient with the addition of 0.1% TFA). The product fractions were combined and evaporated. The residue was mixed with 0.1 M hydrochloric acid in dioxane, carefully evaporated at 30°C (twice), and then lyophilized. 53 mg of the target compound were obtained (55% of theory, 95% purity).

[00380] LC-MS (Method 4): Rt = 0.91 min; MS (ESIpos): m / z = 572 [M-HCl+ H]+ Petition 870260054097, dated 03 / 06 / 2026, page 118 / 326 115 / 152

[00381] Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.004(15.46), 1.020(16.00), 1.491(0.44), 1.522(0.50), 1.722(0.68), 1.753(0.55), 1.890 (0.47), 1.920 (0.55), 1.967 (0.84), 2.129 (0.76), 2.146 (0.96),2.163 (0.76), 2.582 (0.91), 2.613 (0.48), 2.999 (0.86), 3.010 (1.71),3.025 (3.88), 3.041 (2.30), 3.131 (0.88), 3.161 (1.25), 3.177 (2.08),3.213 (1.75), 3.242 (1.16), 3.467 (1.06), 3.496 (0.84), 3.503 (0.60),3.519 (0.54), 3.525 (0.50), 3.549 (0.75), 3.555 (0.84), 3.572 (1.57),3.582 (1.48), 3.589 (1.38), 3.601 (2.78), 3.608 (1.89), 3.633 (0.44),3.640 (0.41), 3.811 (0.94), 3.847 (1.32), 3.878 (0.71), 4.329 (0.49),4.439 (0.46), 4.466 (0.73), 4.477 (0.52), 4.839 (0.49), 7.047 (3.30), 7.07 (3.52) 3.839 (0.49),, 7.082 (2.61), 7.087 (3.29), 7.104 (1.46), 7.109 (0.86), 7.124 (2.34), 7.129 (2.03), 7.160 (3.99), 7.181 (1.96), 7.388 (0.88), 7.49) (7.181., 7.512 (3.81), 7.519 (2.20), 7.650 (0.72), 7.959 (3.78), 9.708 (0.41). [a]D20= -73.05°, c = 0.465 g / 100 cm3, trichloromethane.

[00382] Example 3 Enantiomer 2 has an absolute R configuration as shown in example 4 below.

[00383] 1-{3(R)-1-[4-Chloro-4'-(4-isobutylpiperazin1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazol-4-carboxylic acid hydrochloride Example 4 1-{3(R)-1-[4-Chloro-4'-(4-isobutylpiperazin-1yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazol-4-carboxylic acid hydrochloride hemihydrate Cl F ^NH0 Cl- L^CH3 x 0.5 H2O CH3

[00384] Hydrochloride of 100 mg 1-{1-[4-Chloro-4'-( ... 116 / 152 isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1Hpyrazol-4-carboxylic acid (Enantiomer 2) (example 3) were dissolved at 60 °C in 3.5 mL of 2-propanol, wherein the 2-propanol was added in 100 µL portions at 60 °C until a clear solution was obtained. The vessel was then sealed with a septum and placed in a slow-cooling sand bath from 60 °C to room temperature over the weekend – small amounts of solids were detected. Next, a cannula was fitted to the septum to allow the solvent to evaporate slowly. After 4 weeks, the crystals were collected and inspected under a microscope. Single-crystal X-ray structure analysis:

[00385] Crystal structure determination was performed using a Bruker diffractometer (QS-no.: 02506) equipped with an Apex II-CCD area detector, a ^S microsource with CuKa radiation, mirrors as a monochromator, and a low-temperature Cryostream device (T = 110 k). Fullsphere data collection, omega and phi scans. Software used: Apex II v2014.11.0 data collection and reduction (Bruker AXS, 2014), SADABS absorption correction / scaling. Crystal structure solution was obtained using direct methods implemented in SHELXTL Version 6.14 (Bruker AXS, 2003) and visualized using the XP program. Missing atoms were subsequently located from Fourier difference synthesis and added to the atom list. Least squares refinement in F2 using all measured intensities was performed using the SHELXTL Version 6.14 program (Bruker AXS, 2003). All non-hydrogen atoms were refined, including anisotropic shift parameters. Chirality Check* correct structure inverted structure Flack Parameter (standard deviation) 0.094 (0.009) 0.906 (0.009) Petition 870260054097, dated 03 / 06 / 2026, page 120 / 326 117 / 152 wR2 value (with Flack parameter) 0.2357 0.2522 Chirality R(C22) S(C22) * HD Flack, Acta Cryst., 1983, A39, 876-881 HD Flack, G. Bernardinelli, J. Appl. Crystal., 2000, 33, 11431148 S. Parsons, HD Flack, T. Wagner, Acta Cryst., 2013, B69, 249-259. Table 1. Crystal data and structure refinement for example 4 of identification code 4. Empirical Formula Weight of the Formula Temperature Wavelength System Crystal Group Space Unit Cell Dimensions b = 9.8693(5) A c = 54.159(3) A Volume 4568.5(5) A 3 Z 3 Density (calculated) Absorption Coefficient F(000) 1950 Crystal Size Theta Range for Data Collection Index Ranges Collected Reflections Independent Reflections Completeness for theta = 63.664° C60 H76 Cl4 F4 N10 O5 1235.10 110 K 1.54178 A Trigonal P3221 a = 9.8693(5) A α = 90°. β = 90°. γ = 120°. 1.347 Mg / m 3 2.341 mm -1 0.14 x 0.10 x 0.06 mm 3 4.899 at 63.664°. -11 < h < 10, -10 < k < 11, -62 < l < 61 27868 4640 [R(int) = 0.0378] 95.9% Petition 870260054097, dated 03 / 06 / 2026, page 121 / 326 118 / 152 Correction of maximum and minimum absorption transmission. Complete refinement method in F2. Data / constraints / parameters Goodness of fit in F2 Final R-indices [I>2sigma(I)] R-indices (all data) Absolute structure parameter Extinction coefficient Semi-empirical equivalents of 0.87 and 0.74 Matrix least squares 4640 / 11 / 593 1,047 R1 = 0.0848, wR2 = 0.2336 R1 = 0.0864, ​​wR2 = 0.2357 0.094(9) n / a Greater difference between peak and hole. 0.601 and -0.650 and -3 Table 2. Connection lengths [Â] and angles [°] for example 4. Cl(2)- C(3) Cl(2')- C(3') F(1)- C(30) F(2)- C(30) F(1')- C(30') F(2')- C(30') O(1)- C(29) O(2)- C(29) O(2)-H(2A) O(1')- C(29') O(2')- C(29') O(2')-H(2B) N(1)- C(10) N(1)-C(16) N(1)-C(13) N(2)-C(14) N(2)-C(15) N(2)-C(17) 1.767(13) 1.772(13) 1.341(7) 1.339(7) 1.339(7) 1.38(2) 1.22(2) 1.30(2) 0.8400 1.17(2) 1.36(2) 0.8400 1.416(9) 1.434(12) 1.470(10) 1.497(9) 1.498(9) 1.512(8) Petition 870260054097, dated 03 / 06 / 2026, p. 122 / 326 119 / 152 N(2)-H(2C) 1.0000 N(3)-C(25) 1.46(2) N(3)-C(21) 1.46(5) N(3)-C(1) 1.47(3) N(4)-C(26) 1.30(3) N(4)-N(5) 1.32(3) N(4)-C(22) 1.47(2) N(5)-C(28) 1.37(2) N(3')-C(1') 1.38(3) N(3')-C(21') 1.44(IV) N(3')-C(25') 1.46(2) N(4')-N(5') 1.38(3) N(4')-C(26') 1.42(3) N(4')-C(22') 1.46(2) N(5')-C(28') 1.32(2) C(1)- C(6) 1.35(3) C(1)- C(2) 1.42(IV) C(2)- C(3) 1.37(3) C(2)-H(2D) 0.9500 C(3)- C(4) 1.33(2) C(4)- C(5) 1.390(19) C(4)-H(4A) 0.9500 C(5)- C(6) 1.41(2) C(5)-H(5A) 0.9500 C(6)- C(7) 1.506(17) C(7)- C(8) 1.36(2) C(7)- C(12) 1.382(19) C(7)- C(6') 1.58(2) C(8)- C(9) 1.378(13) C(8)-H(8A) 0.9500 Petition 870260054097, dated 03 / 06 / 2026, p. 123 / 326 120 / 152 C(9)- C(10) 1,390(15) C(9)-H(9A) 0,9500 C(10)- C(11) 1,390(16) C(11)- C(12) 1,391(11) C(11)-H(11A) 0,9500 C(12)-H(12A) 0,9500 C(13)- C(14) 1,524(10) C(13)-H(13A) 0,9900 C(13)-H(13B) 0,9900 C(14)-H(14A) 0,9900 C(14)-H(14B) 0,9900 C(15)- C(16) 1,519(10) C(15)-H(15A) 0,9900 C(15)-H(15B) 0,9900 C(16)-H(16A) 0,9900 C(16)-H(16B) 0,9900 C(17)- C(18) 1,499(10) C(17)-H(17A) 0,9900 C(17)-H(17B) 0,9900 C(18)- C(20) 1,509(11) C(18)- C(19) 1,538(10) C(18)-H(18A) 1,0000 C(19)-H(19A) 0,9800 C(19)-H(19B) 0,9800 C(19)-H(19C) 0,9800 C(20)-H(20A) 0,9800 C(20)-H(20B) 0,9800 C(20)-H(20C) 0,9800 C(21)- C(22) 1,541(7) C(21)-H(21A) 0,9900 Petição 870260054097, de 03 / 06 / 2026, pág. 124 / 326 121 / 152 C(21)-H(21B) C(22)- C(23) C(22)-H(22A) C(23)- C(24) C(23)-H(23A) C(23)-H(23B) C(24)- C(25) C(24)-H(24A) C(24)-H(24B) C(25)-H(25A) C(25)-H(25B) C(26)- C(27) C(26)- C(30) C(27)- C(28) C(27)- C(29) C(28)-H(28A) C(30)-H(30A) C(1')- C(2') C(1')- C(6') C(2')-C(3') C(2')-H(2E) C(3')-C(4') C(4')-C(5') C(4')-H(4B) C(5')-C(6') C(5')-H(5B) C(21')-C(22') C(21')-H(21C) C(21')-H(21D) C(22')-C(23') 0,9900 1,56(2) 1,0000 1,52(3) 0,9900 0,9900 1,52(2) 0,9900 0,9900 0,9900 0,9900 1,42(2) 1,500(7) 1,34(3) 1,50(3) 0,9500 1,0000 1,39(3) 1,42(2) 1,39(3) 0,9500 1,36(2) 1,392(19) 0,9500 1,40(2) 0,9500 1,59(2) 0,9900 0,9900 1,52(2) Petição 870260054097, de 03 / 06 / 2026, pág. 125 / 326 122 / 152 C(22')-H(22B) 1,0000 C(23')-C(24') 1,52(2) C(23')-H(23C) 0,9900 C(23')-H(23D) 0,9900 C(24')-C(25') 1,55(2) C(24')-H(24C) 0,9900 C(24')-H(24D) 0,9900 C(25')-H(25C) 0,9900 C(25')-H(25D) 0,9900 C(26')-C(27') 1,35(3) C(26')-C(30') 1,46(3) C(27')-C(28') 1,41(2) C(27')- C(29') 1,50(3) C(28')-H(28B) 0,9500 C(30')-H(30B) 1,0000 O(1W)-H(1W) 0,9010 O(1W)-H(1 W)# 1 0,9010 C(29)-O(2)-H(2A) 109,5 C(29')-O(2')-H(2B) 109,5 C(10)-N(1)-C(16) 117,9(8) C(10)-N(1)-C(13) 113,5(6) C(16)-N(1)-C(13) 109,6(5) C(14)-N(2)-C(15) 109,2(5) C(14)-N(2)-C(17) 108,8(5) C(15)-N(2)-C(17) 113,0(5) C(14)-N(2)-H(2C) 108,6 C(15)-N(2)-H(2C) 108,6 C(17)-N(2)-H(2C) 108,6 C(25)-N(3)-C(21) 107(2) C(25)-N(3)-C(1) 116,5(18) Petição 870260054097, de 03 / 06 / 2026, pág. 126 / 326 123 / 152 C(21)-N(3)-C(1) 112,2(18) C(26)-N(4)-N(5) 113(2) C(26)-N(4)-C(22) 127(2) N(5)-N(4)-C(22) 120(2) N(4)-N(5)-C(28) 104(2) C(1')-N(3')-C(21') 112,1(19) C(1')-N(3')-C(25') 117,2(19) C(21')-N(3')-C(25') 119,2(19) N(5')-N(4')-C(26') 109(2) N(5')-N(4')-C(22') 118,1(15) C(26')-N(4')-C(22') 128(2) C(28')-N(5')-N(4') 106,9(15) C(6)-C(1)-C(2) 119(2) C(6)-C(1)-N(3) 120,5(18) C(2)-C(1)-N(3) 120(2) C(3)-C(2)-C(1) 118,4(19) C(3)-C(2)-H(2D) 120,8 C(1)-C(2)-H(2D) 120,8 C(4)-C(3)-C(2) 123,8(15) C(4)-C(3)-Cl(2) 120,9(12) C(2)-C(3)-Cl(2) 115,1(14) C(3)-C(4)-C(5) 117,5(14) C(3)-C(4)-H(4A) 121,3 C(5)-C(4)-H(4A) 121,3 C(4)-C(5)- C(6) 121,0(15) C(4)-C(5)-H(5A) 119,5 C(6)-C(5)-H(5A) 119,5 C(1)-C(6)- C(5) 119,5(15) C(1)-C(6)- C(7) 112,0(17) C(5)-C(6)- C(7) 128,4(16) Petição 870260054097, de 03 / 06 / 2026, pág. 127 / 326 124 / 152 0(8)-0(7)- 0(12) 115.2(8) 0(8)-0(7)- 0(6) 109.3(13) 0(12)-0(7)- 0(6) 135.5(15) 0(8)-0(7)- 0(6') 13.6(13) 0(12)-0(7)- 0(6') 108.4(14) 0(7)-0(8)- 0(9) 124.1(12) 0(7)-0(8)-H(8A) 118.0 0(9)-0(8)-H(8A) 118.0(0(8)-0(8)-0(9) 120.2(13) 0(8)-0(9)-H(9A) 119.9 0(10)-0(9)-H(9A) 119.9 0(9)-0(10)-0(11) 117.3(8) 0(9)-0(10)-N(1) 121.7(10) 0(11)-0(10)-N(1) 120.9(9) 0(10)-0(11)-0(12) 120.2(11) 0(10)-0(11)-H(11A) 119.9 0(12)-0(11)-H(11)-0(19)-0(19) 0(11) 123.0(13) 0(7)-0(12)-H(12A) 118.5 0(11)-0(12)-H(12A) 118.5 N(1)-0(13)- 0(14) 110.8(6) N(1)-0(13.5)-H(13.5) 0(14)-0(13)-H(13A) 109.5 N(1)-0(13)-H(13B) 109.5 0(14)-0(13)-H(13B) 109.5 H(13A)-0(13)-H(13B) 108.1(2)-0(13)-N(13B) 110.7(6) N(2)-0(14)-H(14A) 109.5 0(13)-0(14)-H(14A) 109.5 N(2)-0(14)-H(14B) 109.5 Petition 870260054097, of 03 / 06 / 2026, p. 128 / 326 125 / 152 C(13)-C(14)-H(14B) 109,5 H(14A)-C(14)-H(14B) 108,1 N(2)-C(15)- C(16) 110,4(6) N(2)-C(15)-H(15A) 109,6 C(16)-C(15)-H(15A) 109,6 N(2)-C(15)-H(15B) 109,6 C(16)-C(15)-H(15B) 109,6 H(15A)-C(15)-H(15B) 108,1 N(1)-C(16)- C(15) 112,1(7) N(1)-C(16)-H(16A) 109,2 C(15)-C(16)-H(16A) 109,2 N(1)-C(16)-H(16B) 109,2 C(15)-C(16)-H(16B) 109,2 H(16A)-C(16)-H(16B) 107,9 C(18)-C(17)- N(2) 115,7(5) C(18)-C(17)-H(17A) 108,4 N(2)-C(17)-H(17A) 108,4 C(18)-C(17)-H(17B) 108,4 N(2)-C(17)-H(17B) 108,4 H(17A)-C(17)-H(17B) 107,4 C(17)-C(18)- C(20) 114,1(6) C(17)-C(18)- C(19) 108,2(6) C(20)-C(18)- C(19) 110,6(6) C(17)-C(18)-H(18A) 107,9 C(20)-C(18)-H(18A) 107,9 C(19)-C(18)-H(18A) 107,9 C(18)-C(19)-H(19A) 109,5 C(18)-C(19)-H(19B) 109,5 H(19A)-C(19)-H(19B) 109,5 C(18)-C(19)-H(19C) 109,5 Petição 870260054097, de 03 / 06 / 2026, pág. 129 / 326 126 / 152 H(19A)-C(19)-H(19C) 109,5 H(19B)-C(19)-H(19C) 109,5 C(18)-C(20)-H(20A) 109,5 C(18)-C(20)-H(20B) 109,5 H(20A)-C(20)-H(20B) 109,5 C(18)-C(20)-H(20C) 109,5 H(20A)-C(20)-H(20C) 109,5 H(20B)-C(20)-H(20C) 109,5 N(3)-C(21)- C(22) 106(3) N(3)-C(21)-H(21A) 110,4 C(22)-C(21)-H(21A) 110,4 N(3)-C(21)-H(21B) 110,4 C(22)-C(21)-H(21B) 110,4 H(21A)-C(21)-H(21B) 108,6 N(4)-C(22)- C(21) 110(2) N(4)-C(22)- C(23) 106,8(16) C(21)-C(22)- C(23) 105(2) N(4)-C(22)-H(22A) 111,7 C(21)-C(22)-H(22A) 111,7 C(23)-C(22)-H(22A) 111,7 C(24)-C(23)- C(22) 108,9(13) C(24)-C(23)-H(23A) 109,9 C(22)-C(23)-H(23A) 109,9 C(24)-C(23)-H(23B) 109,9 C(22)-C(23)-H(23B) 109,9 H(23A)-C(23)-H(23B) 108,3 C(23)-C(24)- C(25) 112,6(13) C(23)-C(24)-H(24A) 109,1 C(25)-C(24)-H(24A) 109,1 C(23)-C(24)-H(24B) 109,1 Petição 870260054097, de 03 / 06 / 2026, pág. 130 / 326 127 / 152 C(25)-C(24)-H(24B) 109,1 H(24A)-C(24)-H(24B) 107,8 N(3)-C(25)- C(24) 107,3(15) N(3)-C(25)-H(25A) 110,3 C(24)-C(25)-H(25A) 110,3 N(3)-C(25)-H(25B) 110,3 C(24)-C(25)-H(25B) 110,3 H(25A)-C(25)-H(25B) 108,5 N(4)-C(26)- C(27) 107,8(18) N(4)-C(26)-C(30) 124(2) C(27)-C(26)-C(30) 127,8(16) C(28)-C(27)-C(26) 102,7(18) C(28)-C(27)-C(29) 133(2) C(26)-C(27)- C(29) 124,0(19) C(27)-C(28)- N(5) 112,9(19) C(27)-C(28)-H(28A) 123,6 N(5)-C(28)-H(28A) 123,6 O(1)-C(29)- O(2) 123(2) O(1)-C(29)- C(27) 125,0(19) O(2)-C(29)- C(27) 112(2) F(2)-C(30)- F(1) 104,4(13) F(2)-C(30)- C(26) 112,1(18) F(1)-C(30)- C(26) 110,6(17) F(2)-C(30)-H(30A) 109,9 F(1)-C(30)-H(30A) 109,9 C(26)-C(30)-H(30A) 109,9 N(3')-C(1')-C(2') 119,2(17) N(3')-C(1')-C(6') 120,3(18) C(2')-C(1')-C(6') 120(2) C(1')-C(2')-C(3') 118,4(18) Petição 870260054097, de 03 / 06 / 2026, pág. 131 / 326 128 / 152 C(1')-C(2')-H(2E) 120,8 C(3')-C(2')-H(2E) 120,8 C(4')-C(3')-C(2') 125,1(15) C(4')-C(3')-Cl(2') 118,0(12) C(2')-C(3')-Cl(2') 116,8(12) C(3')-C(4')-C(5') 114,4(13) C(3')-C(4')-H(4B) 122,8 C(5')-C(4')-H(4B) 122,8 C(4')-C(5')-C(6') 125,3(14) C(4')-C(5')-H(5B) 117,3 C(6')-C(5')-H(5B) 117,3 C(5')-C(6')-C(1') 116,2(16) C(5')-C(6')-C(7) 109,8(15) C(1')-C(6')-C(7) 131,7(15) N(3')-C(21')-C(22') 109(2) N(3')-C(21')-H(21C) 109,9 C(22')-C(21')-H(21C) 109,9 N(3')-C(21')-H(21D) 109,9 C(22')-C(21')-H(21D) 109,9 H(21C)-C(21')-H(21D) 108,3 N(4')-C(22')-C(23') 108,7(16) N(4')-C(22')-C(21') 111,0(16) C(23')-C(22')-C(21') 117,6(19) N(4')-C(22')-H(22B) 106,3 C(23')-C(22')-H(22B) 106,3 C(21')-C(22')-H(22B) 106,3 C(22')-C(23')-C(24') 107,4(15) C(22')-C(23')-H(23C) 110,2 C(24')-C(23')-H(23C) 110,2 C(22')-C(23')-H(23D) 110,2 Petição 870260054097, de 03 / 06 / 2026, pág. 132 / 326 129 / 152 C(24')-C(23')-H(23D) 110,2 H(23C)-C(23')-H(23D) 108,5 C(23')-C(24')-C(25') 114,0(14) C(23')-C(24')-H(24C) 108,8 C(25')-C(24')-H(24C) 108,8 C(23')-C(24')-H(24D) 108,8 C(25')-C(24')-H(24D) 108,8 H(24C)-C(24')-H(24D) 107,7 N(3')-C(25')-C(24') 106,9(15) N(3')-C(25')-H(25C) 110,3 C(24')-C(25')-H(25C) 110,3 N(3')-C(25')-H(25D) 110,3 C(24')-C(25')-H(25D) 110,3 H(25C)-C(25')-H(25D) 108,6 C(27')-C(26')-N(4') 105,4(19) C(27')-C(26')-C(30') 134,7(19) N(4')-C(26')-C(30') 120(3) C(26')-C(27')-C(28') 108,0(15) C(26')-C(27')-C(29') 128,4(19) C(28')-C(27')-C(29') 123,1(17) N(5')-C(28')-C(27') 110,3(16) N(5')-C(28')-H(28B) 124,8 C(27')-C(28')-H(28B) 124,8 O(1')-C(29')- O(2') 126,1(19) O(1')-C(29')- C(27') 124,4(16) O(2')-C(29')- C(27') 109,4(19) F(1')-C(30')- F(2') 107,3(18) F(1')-C(30')- C(26') 111,2(19) F(2')-C(30')- C(26') 112,0(17) F(1')-C(30')-H(30B) 108,7 Petição 870260054097, de 03 / 06 / 2026, pág. 133 / 326 130 / 152 F(2')-C(30')-H(30B) 108,7 C(26')-C(30')-H(30B) 108.7 H(1W)-O(1W)-H(1 W)# 1 107.2

[00386] Symmetry transformations used to generate equivalent atoms: #1 y- 1,x +1,-z+1 Table 3. Angles of twist [°] for example 4 C(26)-N(4)-N(5)-C(28) C(22)-N(4)-N(5)-C(28) C(26')-N(4')-N(5')-C(28') C(22')-N(4')-N(5')-C(28') C(25)-N(3)-C(1)-C(6) C(21)-N(3)-C(1)-C(6) C(25)-N(3)-C(1)-C(2) C(21)-N(3)-C(1)-C(2) C(6)-C(1)-C(2)-C(3) N(3)-C(1)-C(2)-C(3) C(1)-C(2)-C(3)-C(4) C(1)-C(2)-C(3)-Cl(2) C(2)-C(3)-C(4)-C(5) Cl(2)-C(3)-C(4)-C(5) C(3)-C(4)-C(5)-C(6) C(2)-C(1)-C(6)-C(5) N(3)-C(1)-C(6)-C(5) C(2)-C(1)-C(6)-C(7) N(3)-C(1)-C(6)-C(7) C(4)-C(5)-C(6)-C(1) C(4)-C(5)-C(6)-C(7) C(1)-C(6)-C(7)-C(8) C(5)-C(6)-C(7)-C(8) C(1)-C(6)-C(7)-C(12) 4(2) -173,4(17) 0(2) -157.8(16) 148.8(17) -87(3) -25(3) 99(3) 9(3) -177,2(18) -7(3) 178.6(14) 5(3) 178.8(12) -4(2) -8(3) 178.0(16) 169.6(16) -5(2) 6(2) -171.3(14) 148.5(14) -34.4(18) -33.3(19) Petition 870260054097, dated 03 / 06 / 2026, p. 134 / 326 131 / 152 C(5)-C(6)-C(7)-C(12) 143,8(15) C(12)-C(7)-C(8)-C(9) 2,5(13) C(6)-C(7)-C(8)-C(9) -178,9(9) C(6')-C(7)-C(8)-C(9) 178,8(11) C(7)-C(8)-C(9)-C(10) -1,1(13) C(8)-C(9)-C(10)-C(11) -1,0(11) C(8)-C(9)-C(10)-N(1) -179,4(7) C(16)-N(1)-C(10)-C(9) -176,9(7) C(13)-N(1)-C(10)-C(9) -46,9(9) C(16)-N(1)-C(10)-C(11) 4,8(10) C(13)-N(1)-C(10)-C(11) 134,9(8) C(9)-C(10)-C(11)-C(12) 1,5(12) N(1)-C(10)-C(11)-C(12) 179,9(7) C(8)-C(7)-C(12)-C(11) -1,9(13) C(6)-C(7)-C(12)-C(11) 179,9(11) C(6')-C(7)-C(12)-C(11) -179,2(10) C(10)-C(11)-C(12)-C(7) 0,0(14) C(10)-N(1)-C(13)-C(14) 167,0(7) C(16)-N(1)-C(13)-C(14) -58,8(8) C(15)-N(2)-C(14)-C(13) -55,6(7) C(17)-N(2)-C(14)-C(13) -179,3(6) N(1)-C(13)-C(14)-N(2) 57,9(8) C(14)-N(2)-C(15)-C(16) 55,1(8) C(17)-N(2)-C(15)-C(16) 176,4(6) C(10)-N(1)-C(16)-C(15) -168,9(6) C(13)-N(1)-C(16)-C(15) 59,3(7) N(2)-C(15)-C(16)-N(1) -58,4(8) C(14)-N(2)-C(17)-C(18) 178,4(6) C(15)-N(2)-C(17)-C(18) 56,9(8) N(2)-C(17)-C(18)-C(20) 58,0(8) Petition 870260054097, dated 03 / 06 / 2026, p. 135 / 326 132 / 152 N(2)-C(17)-C(18)-C(19) -178.5(6) C(25)-N(3)-C(21)-C(22) -75(3) C(1)-N(3)-C(21)-C(22) 156(2) C(26)-N(4)-C(22)-C(21) 131(3) N(5)-N(4)-C(22)-C(21) -52(3) C(26)-N(4)-C(22)-C(23) -116(2) N(5)-N(4)-C(22)-C(23) 61(2) N(3)-C(21)-C(22)-N(4) -177(2) N(3)-C(21)-C(22)-C(23) 68(3) N(4)-C(22)-C(23)-C(24) -173.8(14) C(21)-C(22)-C(23)-C(24) -57(2) C(22)-C(23)-C(24)-C(25) 53.5(18) C(21)-N(3)-C(25)-C(24) 67(2) C(1)-N(3)-C(25)-C(24) -166.6(17) C(23)-C(24)-C(25)-N(3) -56.8(19) N(5)-N(4)-C(26)-C(27) -3(2) C(22)-N(4)-C(26)-C(27) 174.2(19) N(5)-N(4)-C(26)-C(30) 179.8(15) C(22)-N(4)-C(26)-C(30) -3(3) N(4)-C(26)-C(27)-C(28) 1(2) C(30)-C(26)-C(27)-C(28) 177.7(15) N(4)-C(26)-C(27)-C(29) -175.0(16) C(30)-C(26)-C(27)-C(29) 2(3) C(26)-C(27)-C(28)-N(5) 2(2) C(29)-C(27)-C(28)-N(5) 176.9(18) N(4)-N(5)-C(28)-C(27) -3.6(19) C(28)-C(27)-C(29)- O(1) 146.4(19) C(26)-C(27)-C(29)- O(1) -39(3) C(28)-C(27)-C(29)- O(2) -31(3) C(26)-C(27)-C(29)- O(2) 143(2) Petition 870260054097, dated 03 / 06 / 2026, page 136 / 326 133 / 152 N(4)-C(26)-C(30)- F(2) 53(2) C(27)-C(26)-C(30)- F(2) -124(2) N(4)-C(26)-C(30)- F(1) -63(2) C(27)-C(26)-C(30)- F(1) 120(2) C(21')-N(3')-C(1')- C(2') 112(2) C(25')-N(3')-C(1')- C(2') -31(3) C(21')-N(3')-C(1')-C(6') -71(2) C(25')-N(3')-C(1')-C(6') 146,4(17) N(3')-C(1')-C(2')-C(3') 180,0(19) C(6')-C(1')-C(2')-C(3') 3(3) C(1')-C(2')-C(3')-C(4') 2(3) C(1')-C(2')-C(3')-Cl(2') 179,1(15) C(2')-C(3')-C(4')-C(5') -4(3) Cl(2')-C(3')-C(4')-C(5') 179,0(12) C(3')-C(4')-C(5')-C(6') 1(2) C(4')-C(5')-C(6')-C(1') 4(3) C(4')-C(5')-C(6')-C(7) 168,4(15) N(3')-C(1')-C(6')-C(5') 177,6(19) C(2')-C(1')-C(6')-C(5') -5(3) N(3')-C(1')-C(6')-C(7) 17(3) C(2')-C(1')-C(6')-C(7) -166,3(19) C(8)-C(7)-C(6')-C(5') -39,2(19) C(12)-C(7)-C(6')-C(5') 137,2(12) C(8)-C(7)-C(6')-C(1') 122,5(19) C(12)-C(7)-C(6')-C(1') -61(2) C(1')-N(3')-C(21')-C(22') 168,4(18) C(25')-N(3')-C(21')-C(22') -49(3) N(5')-N(4')-C(22')-C(23') 65(2) C(26')-N(4')-C(22')-C(23') -88(3) N(5')-N(4')-C(22')-C(21') -66(3) Petition 870260054097, dated 03 / 06 / 2026, page 137 / 326 134 / 152 C(26')-N(4')-C(22')-C(21') N(3')-C(21')-C(22')-N(4') N(3')-C(21')-C(22')-C(23') N(4')-C(22')-C(23')-C(24') C(21')-C(22')-C(23')-C(24') C(22')-C(23')-C(24')-C(25') C(1')-N(3')-C(25')-C(24') -161.9 C(21')-N(3')-C(25')-C(24') C(23')-C(24')-C(25')-N(3') N(5')-N(4')-C(26')-C(27') C(22')-N(4')-C(26')-C(27') N(5')-N(4')-C(26')-C(30') C(22')-N(4')-C(26')-C(30') N(4')-C(26')-C(27')-C(28') C(30')-C(26')-C(27')-C(28') N(4')-C(26')-C(27')-C(29') C(30')-C(26')-C(27')-C(29') N(4')-N(5')-C(28')-C(27') C(26')-C(27')-C(28')-N(5') C(29')-C(27')-C(28')-N(5') C(26')-C(27')-C(29')- O(1') C(28')-C(27')-C(29')- O(1') C(26')-C(27')-C(29')- O(2') C(28')-C(27')-C(29')- O(2') C(27')-C(26')-C(30')- F(1') N(4')-C(26')-C(30')- F(1') C(27')-C(26')-C(30')- F(2') N(4')-C(26')-C(30')- F(2') 141(2) 169,0(19) 43(3) -173.4(15) -46(2) 55(2) (18) 58(2) -59(2) -1(2) 154(2) -176.3(16) -21(3) 1.2(19) 175.6(19) -171.1(16) 3(3) 1(2) -1(2) 171.6(15) 162.9(18) -8(3) -21(2) 167.6(16) 132(2) -54(2) -108(2) 66(2)

[00387] Symmetry transformations used to generate equivalent atoms: #1 y- 1,x +1,-z+1 Petition 870260054097, dated 03 / 06 / 2026, page 138 / 326 135 / 152 Table 4. Hydrogen bonds for example 4 [A and °], D4H d(DH) d(H..A) <DHA d(D..A) A Ο2ώ-Η2Αώ 0.840 2.268 171.52 3.102 Cll [x+l,y-4,z| O2'b-H2Bb 0.840 2.219 158 79 3.018 Cl 1 [x+l, yl,z | N2-H2C 1,000 2,158 162.74 3,128 Cll [yK-z+l | 01W-HIW 0 901 2.448 164.20 3.324 Cll Figure 1: Orthop-Plot (50%) with labeling scheme (without disorder), Example 4 Figure 2: Independent molecules in the asymmetric unit (with disorder), Example 4 Figure 3: C22 configuration, Example 4 Comparative Example 174 (WQ2012 / 058132) 1-{1-[4-Chloro-4'-(4-cyclopropylmethylpiperazin-1-yl)[biphenyl]-2yl]pyridin-3-yl}-5-(trifluoromethyl)-1H-pyrazol-4-carboxylic acid

[00388] The compound was synthesized according to the procedures disclosed in WO 2012 / 058132 (experimental part, pages 58 to 84). B. Evaluation of pharmacological efficacy and pharmacokinetic profile

[00389] The following abbreviations are used: ATP adenosine triphosphate Brij35 polyoxyethylene (23) lauryl ether Bovine serum albumin (BSA): Petition 870260054097, dated 03 / 06 / 2026, p. 139 / 326 136 / 152 TDT dithiothreitol triethanolamine tea Biological investigations

[00390] The examples of test experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

[00391] The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.

[00392] The examples were tested in selected biological assays one or more times. When tested more than once, the data are reported as mean values ​​or as median values, where • the mean value, also called the arithmetic mean value, represents the sum of the values ​​obtained divided by the number of times tested, and • the median value represents the middle number of the group of values ​​when sorted in ascending or descending order. If the number of values ​​in the data set is odd, the median will be the middle value. If the number of values ​​in the data set is even, the median is the arithmetic mean of the two middle values.

[00393] The examples have been synthesized one or more times. When synthesized more than once, the biological assay data represent average values ​​calculated using datasets obtained from testing one or more synthetic batches.

[00394] The in vitro activity of the compounds of the present invention can be demonstrated in the following assays.

[00395] The pharmacological action of the compounds of the invention can be demonstrated in the following tests: B-1. Effect on a recombinant guanylate cyclase reporter cell line Petition 870260054097, dated 03 / 06 / 2026, page 140 / 326 137 / 152

[00396] The cellular activity of the compounds according to the invention was determined using a recombinant guanylate cyclase reporter cell line, as described in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

[00397] Representative MEC (MEC = minimum effective concentration) and EC50 (half the maximum effective concentration) values ​​for the compounds of the invention are shown in the table below (in some cases as average values ​​from individual determinations): Table 2: Example MEC [nM] EC50 [nM] 1 2.3 9.2 2 1.0 8.6 3 0.6 2.7 B-2. Vasorelaxant effect in vitro

[00398] Rabbits were euthanized under deep anesthesia and exsanguinated. The aorta was removed, freed from adherent tissue, and divided into 1.5 mm wide rings, which were individually placed under pretension in 5 mL organ baths with carbogen-sprayed Krebs-Henseleit solution at 37°C with the following composition (each in mM): sodium chloride: 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2; sodium bicarbonate: 25; glucose: 10. To generate a contraction, phenylephrine was added to the bath cumulatively in increasing concentration. After several control cycles, the substance under study was added in increasing dosage at each subsequent run, and the magnitude of the contraction was compared with the magnitude of the contraction achieved in the last previous run. This was used to calculate the concentration needed to reduce the magnitude of the control value. Petition 870260054097, dated 03 / 06 / 2026, page 141 / 326 138 / 152 in 50% (IC50 value). The standard administration volume was 5 μL; the DMSO content in the bath solution corresponds to 0.1%. B-3. ​​Blood pressure measurement in anesthetized rats

[00399] Male Wistar rats weighing 300-350 g were anesthetized with thiopental (100 mg / kg i.p.). After tracheotomy, a catheter was introduced into the femoral artery to measure blood pressure. The substances to be tested were administered as solutions, orally by gavage or intravenously via the femoral vein (Stash et al. Br. J. Pharmacol. 2002; 135: 344-355). B-4. Radiotelemetry measurement of blood pressure in conscious and spontaneously hypertensive rats

[00400] A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, was employed to measure blood pressure in conscious rats described below.

[00401] The system consists of 3 main components:

[00402] implantable transmitters (Physiotel® telemetry transmitter)

[00403] receivers (Physiotel® receiver) that were connected via a multiplexer (DSI Data Exchange Matrix 2.0) to a

[00404] data acquisition computer.

[00405] The telemetry system allows continuous recording of blood pressure, heart rate and body movement of conscious animals in their usual habitat. Animal material

[00406] The studies were conducted on spontaneously hypertensive adult female rats (SHR Okamoto) weighing > 200 g. SHR / NCrl from the Kyoto Okamoto School of Medicine, 1963, were a crossbreed of male Wistar Kyoto rats with very high blood pressure and female rats with slightly elevated blood pressure, and were delivered in F13 to the National Institutes of Petition 870260054097, dated 03 / 06 / 2026, page 142 / 326 139 / 152 US healthcare.

[00407] After the transmitter was implanted, the experimental animals were housed individually in Makrolon type 3 cages. They had free access to standard feed and water.

[00408] The day / night rhythm in the experimental laboratory was altered by the room lighting at 6 am and 7 pm. Transmitter deployment

[00409] The HD S 10 telemetry transmitters used were surgically implanted under aseptic conditions in experimental animals at least 14 days prior to first experimental use. Animals instrumented in this manner can be used repeatedly after wound healing and implant settling.

[00410] For implantation, fasted animals were anesthetized with isoflurane (Rimadyl analgesia) and shaved and disinfected over a large area of ​​their abdomens. After opening the abdominal cavity along the linea alba, the fluid-filled measuring catheter was inserted into the descending aorta cranially above the bifurcation and secured with tissue glue (VetBonD™, 3M). The transmitter casing was secured intraperitoneally to the abdominal wall muscle and the wound was closed layer by layer.

[00411] An antibiotic (Ursocycline 10% pro inj., Serumwerk, sc) was administered postoperatively for infection prophylaxis. Substances and solutions

[00412] Unless otherwise indicated, the substances to be studied were administered orally by gavage to a group of animals in each case (n = 6). According to an administration volume of 2 mL / kg body weight, the test substances were dissolved in suitable solvent mixtures or suspended. Petition 870260054097, dated 03 / 06 / 2026, page 143 / 326 140 / 152 in ti lose at 0.5%.

[00413] A group of animals treated with solvent was used as a control. Experimental procedure

[00414] The telemetry measurement unit present was configured for 24 animals. Each experiment was recorded under an experiment number (van, month, day).

[00415] Each of the instrumented rats living in the system was given a separate receiver antenna (RPC-1 Receiver, DSI).

[00416] The implanted transmitters can be activated externally by means of a built-in magnetic switch. They were switched to transmission in the period preceding the experiment. The emitted signals can be detected online by a data acquisition system (Physio Tel HD, DSI) and processed accordingly. The data were stored in each case in a file created for this purpose and numbered with the experiment number.

[00417] In the standard procedure, the following was measured over 10-second periods in each case: Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), activity (TEMP).

[00418] The acquisition of measurements was repeated under computer control at 5-minute intervals. The source data obtained as absolute values ​​were corrected in the chart with the currently measured barometric pressure (Ambient Pressure Reference Monitor; APR-1) and stored as individual data. Further technical details were provided in the extensive documentation from the manufacturer (DSI).

[00419] Unless otherwise indicated, the test substances were Petition 870260054097, dated 03 / 06 / 2026, page 144 / 326 141 / 152 administered at 9:00 AM on the day of the experiment. After administration, the parameters described above were measured over 24 hours. Evaluation

[00420] After the experiment ended, the individual data acquired were classified using analysis software (Ponemah V 6.x). The blank value was assumed here to be the time 2 hours before administration and therefore the selected dataset covers the period from 7:00 am on the day of the experiment to 9:00 am the following day.

[00421] The data were smoothed over a predefined period by determining the average (30-minute average) and transferred as an Excel file to a storage medium. The measured values, pre-sorted and compressed in this way, were transferred to Excel templates and tabulated. For each day of the experiment, the data obtained were stored in a dedicated file with the experiment number. The results and test protocols were stored in paper files sorted by numbers. Literature:

[00422] Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Bjorn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured With Radio-Telemetry. Physiology and Behavior 55(4): 783-787, 1994. B-5. Determination of pharmacokinetic parameters after intravenous and oral administration.

[00423] The pharmacokinetic parameters of the compounds according to Petition 870260054097, dated 03 / 06 / 2026, p. 145 / 326 142 / 152 with the invention were determined in male Wistar rats and / or female beagles and / or cynomolgus monkeys and / or male CD-1 mice. Intravenous administration in mice and rats was performed using a specific plasma / DMSO formulation, and in dogs and monkeys using a water / PEG400 / ethanol formulation. In all species, oral administration of the dissolved substance was performed by gavage, based on the water / PEG400 / ethanol formulation.

[00424] An internal standard (which may also be a chemically unrelated substance) was added to samples of the compounds of the invention, calibration samples and qualifiers, followed by protein precipitation using excess acetonitrile. The addition of a buffer solution compatible with LC conditions and subsequent vortexing was followed by centrifugation at 1000 g. The supernatant was analyzed by LC-MS / MS using C18 reversed-phase columns and variable mobile phase mixtures. The substances were quantified by means of the peak heights or areas of ion chromatograms extracted from specific selected ion monitoring experiments.

[00425] The determined plasma concentration / time graphs were used to calculate pharmacokinetic parameters such as AUC, Cmax, t1 / 2 (terminal half-life), F (bioavailability), MRT (mean residence time) and CL (clearance), using a validated pharmacokinetic calculation program.

[00426] Since the quantification of the substance was performed in plasma, it was necessary to determine the blood / plasma distribution of the substance in order to adjust the pharmacokinetic parameters accordingly. To this end, a defined quantity of the substance was incubated in K3 EDTA whole blood of the species in question in Petition 870260054097, dated 03 / 06 / 2026, page 146 / 326 143 / 152 oscillating roller mixer for 20 min. After centrifugation at 1000 g, the plasma concentration was measured (by LC-MS / MS; see above) and determined by calculating the ratio of the blood concentration to the plasma concentration.

[00427] Table 3 shows data for representative compounds of the present invention after intravenous administration in rats: Table 3: Example AUCnorm [kg-h / L] CLplasma [L / h / kg] t1 / 2 [h] MRT [h] 1 1.77 0.56 1.64 2.24 2 7.08 0.14 3.13 3.44 174 (WO2012 / 058132) 0.77 1.30 2.33 2.78

[00428] Table 4 shows data for representative compounds of the present invention after oral administration in rats: Table 4: Example AUCnorm [kg-h / L] t1 / 2 [h] MRT [h] F [%] 1 0.57 3.24 6.28 31.4 2 3.77 3.96 6.23 53.3 174 (WO2012 / 058132) 0.63 3.60 8.40 81.8

[00429] Table 5 shows data for representative compounds of the present invention after intravenous administration in dogs: Table 5: Example AUCnorm [kg-h / L] CLplasma [L / h / kg] t1 / 2 [h] MRT [h] 2 81.7 0.01 17.7 25.6 174 (WO2012 / 058132) 5.00 0.20 10.8 7.23

[00430] Table 6 shows data for representative compounds of the present invention after oral (po) administration in dogs: Table 6: Petition 870260054097, dated 03 / 06 / 2026, page 147 / 326 144 / 152 Example AUCnorm [kg-h / L] t1 / 2 [h] MRT [h] F [%] 2 67.7 14.0 21.3 82.8 174 (WO2012 / 058132) 2.08 7.05 6.10 41.6

[00431] The compounds according to the present invention exhibit superior pharmacokinetic (PK) properties compared to compounds disclosed in the prior art (WO 2012 / 058132) (see experimental section, tables 3 to 6). For example, Example 2 of the present invention shows a lower plasma clearance (CLplasma) (up to 10 times) and therefore a much higher exposure compared to the prior art compound disclosed as Example 174 in WO 2012 / 058132 in rats as well as in dogs. Example 2 also shows a long half-life and a mean residence time (MRT) in all species tested after postoperative (oral) administration. Due to the significantly lower plasma clearance of Example 2 and the resulting very high exposure (AUCnorm, exposure, area under the normalized curve) with good bioavailability after postoperative administrationIn all species tested, we observed a clear superiority of pharmacokinetic (PK) properties versus example 174 disclosed in WO 2012 / 058132. B-6. Metabolic study

[00432] To determine the metabolic profile of the compounds of the invention, they were incubated with recombinant human cytochrome P450 (CYP) enzymes, liver microsomes or fresh primary hepatocytes from various animal species (e.g., rats, dogs) and also from human origin, in order to obtain and compare information on a very substantially complete phase I and phase II liver metabolism and on the enzymes involved in the metabolism.

[00433] The compounds of the invention were incubated at a concentration of about 0.1-10 μM. For this purpose, the following were prepared Petition 870260054097, dated 03 / 06 / 2026, page 148 / 326 145 / 152 Stock solutions of the compounds of the invention were prepared with a concentration of 0.01–1 mM in acetonitrile and then pipetted at a 1:100 dilution into the incubation mixture. Liver microsomes and recombinant enzymes were incubated at 37 °C in 50 mM potassium phosphate buffer pH 7.4 with and without an NADPH generating system consisting of 1 mM NADP+, 10 mM glucose-6-phosphate, and 1 glucose-6-phosphate dehydrogenase unit. Primary hepatocytes were incubated in suspension in Williams E medium, also at 37 °C. After an incubation time of 0–4 h, the incubation mixtures were stopped with acetonitrile (final concentration of approximately 30%) and the protein was centrifuged at approximately 15,000 x g. The samples thus preserved were analyzed directly or stored at -20 °C until analysis.

[00434] The analysis was performed by high-performance liquid chromatography with ultraviolet and mass spectrometry detection (HPLC-UV-MS / MS). For this purpose, the supernatants of the incubation samples were chromatographed with suitable C18 reversed-phase columns and variable mobile phase mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid. The UV chromatograms, together with mass spectrometry data, served for identification, structural elucidation and quantitative estimation of the metabolites, and for quantitative metabolic reduction of the compound of the invention in the incubation mixtures. B-7. Caco-2 permeability test

[00435] The permeability of a test substance was determined with the aid of the Caco-2 cell line, an established in vitro model for predicting permeability at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991). Correlation between oral absorption of drugs in humans and apparent drug permeability coefficients in human intestinal epithelial cells Petition 870260054097, dated 03 / 06 / 2026, page 149 / 326 146 / 152 (Caco-2), Biochem, Biophys. 175 (3), 880-885). Caco-2 cells (ACCNo. 169, DSMZ, Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany) were seeded in 24-well plates with an insert and cultured for 14–16 days. For permeability studies, the test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES). To determine the apical-to-basolateral permeability (PapPA-B) of the test substance, the solution comprising the test substance was applied to the apical side of the Caco-2 cell monolayer and transport buffer to the basolateral side. To determine the basolateral-apical permeability (PapPB-A) of the test substance, the solution comprising the test substance was applied to the basolateral side of the Caco-2 cell monolayer and transport buffer to the apical side.At the beginning of the experiment, samples were taken from their respective donor compartments to ensure mass balance. After a two-hour incubation period at 37 °C, samples were taken from both compartments. The samples were analyzed by LC-MS / MS and apparent permeability coefficients (Papp) were calculated. For each cell monolayer, the permeability of Lucifer Yellow was determined to ensure cell layer integrity. In each test run, the permeability of atenolol (low permeability marker) and sulfasalazine (active excretion marker) was also determined as a quality control. B-8. Determination of the solubility of substances in pH 6.5 buffer

[00436] 2-4 mg of the test compound were dissolved in DMSO to achieve a concentration of 50 g / L (solution A, 515 pg / L). To 10 pL of this solution, 960 pL of PBS pH 6.5 buffer were added; the mixture was stirred for 24 h at room temperature in a 96-liter plate. Petition 870260054097, dated 03 / 06 / 2026, page 150 / 326 147 / 152 wells. An aliquot was centrifuged at 42,000 rpm for 30 minutes. The supernatant was diluted with ACN / water (8:2) 1:10 and 1:1000 resp. These diluted samples were analyzed by LC-MSMS.

[00437] Calibration: 10 pL of solution A were diluted with 823 pL of DMSO (final concentration: 600 pg / mL), which was subsequently diluted with ACN / water 8:2 by a factor of 100 (solution B).

[00438] The calibration curve was obtained from solution B by further diluting it with ACN / water 8:2 with target concentrations of 1.2-12 - 60- 600 ng / mL and injecting these four solutions for MS measurement.

[00439] MS method optimization:

[00440] Solution B was used for optimization of the MS method.

[00441] PBS-Puffer: 6.18 g of sodium chloride and 3.96 g of sodium dihydrogen phosphate were dissolved in 1 L of water, the pH was adjusted to 6.5 with 1 N sodium hydroxide.

[00442] LC-MSMS Optimization:

[00443] The following configurations were used for optimization

[00444] AB Sciex TRIPLE QUAD 4500, Agilent 1260 Infinity (G1312B), degasser (G4225A), column oven (G1316 C or G1316A), CTC Analytics PAL HTS-xt or HTC-xt injection system.

[00445] Eluent A: 0.5 mL of formic acid (50% ig) / L water, Eluent B: 0.5 mL of formic acid (50% ig) / L of acetonitrile Time [min] Flow [pL / min] %B 0.00 200 70 0.08 200 70 0.09 25 70 0.60 25 70 0.65 200 70 1.10 200 70

[00446] Autosampler: no advance automatic injection setting Petition 870260054097, dated 03 / 06 / 2026, p. 151 / 326 148 / 152 Column: Stainless steel capillary; Oven temperature: 22°C; Flow rate: Gradient flow; Injected volume: 2 pL

[00447] Quattro Micro MS water, Agilent 1100 (G1312A), degasser (G1322A), column furnace (G1316A), CTC Analytics PAL HTS injection system, eluents as above time [min] flow [pL / min] % B 0.00 250 70 1.50 250 70

[00448] Automatic sampler: with injection configuration Automatic advance column: stainless steel capillary furnace temperature: 22°C flow rate: gradient flow injected volume: 5 pL MS Method: Flow Injection Analysis (FIA) for optimization ("MSOPTI"); Ionization mode: ABSciex-MS: ESI- pos / neg, Waters-MS: ESI- pos HPLC method for MSMS quantification: Eluent A, B as above ABSciex-MS time [min] % A% B 0 9010 0.5 595 0.84 595 0.85 9010 1.22 9010

[00449] Autosampler: no advance automatic injection setting Petition 870260054097, dated 03 / 06 / 2026, page 152 / 326 149 / 152 column: Waters OASIS HLB, 2.1 x 20 mm, 25 μ Column temperature: 30 °C Flow rate: 2.5 ml Injected volume: 2 μL Divider (before MS) Waters-MS 1:20 Time [min] 0 % A % B 90 10 0.5 5 95 0.84 5 95 0.85 90 10 1.5 90 10

[00450] Automatic sampler ahead Column: Automatic: with injection configuration Waters OASS HLB, 2.1 x 20 mm, 25 μL Column temperature: 30°C Flow rate: 2.5 ml Injected volume: 5 μL Divider (before MS) MS Method: 1:20 Multiple Reaction Monitoring (MRM) B-9. Determination of the solubility of the solid

[00451] For each solvent, an Eppendorf plastic bottle was loaded with 0.5–1 mg of the test compound (exact weight), 2–3 glass beads (3 mm diameter), and 1.0 mL of the respective solvent. The bottle was closed and shaken at room temperature for 24 h (1400 rpm; Thermomixer, Eppendorf). Then, 230 μL of each solution / suspension were transferred to one or more centrifuge bottles (Beckman Coulter) and centrifuged at 42000 rpm for 30 min (Beckman Coulter Optima L90). At least 100 μL of the supernatant were removed and subsequently diluted with DMSO in Petition 870260054097, dated 03 / 06 / 2026, page 153 / 326 150 / 152 two dilution concentrations: 1:5 and 1:50 (the latter obtained in the 1:5 dilution step by the subsequent addition of DMSO). This liquid handling was done manually or with the aid of a pipetting robot (Lissy, Zinsser Analytic).

[00452] For quantification by HPLC, calibration solutions of the test compound in DMSO were prepared. Starting from an initial concentration of 600 pg / mL, three calibration solutions were prepared: 100 pg / mL, 20 pg / mL and 2.5 pg / mL (manually or via Lissy).

[00453] Both calibration solutions and the supernatant were analyzed by HPLC / UV detection at an appropriate wavelength. Solubility was determined using the linear calibration curve. HPLC Systems: Hewlett Packard / Agilent HPLC systems, G1311A+G1316A+G1315B, as well as G1312A+G1316A+G1315A injector system: CTC-Analytik HTCPAL or with an Agilent UPLCA system (G7117C, G7116B, G7167B and G7120) oven temperature: 30 °C, detection: 210 and / or 254 nm, injected volume: 20 pL eluent A: 0.1% TFA in water, eluent B: 0.1% TFA in acetonitrile column: ZORBAXExtend-C18, 3.0 x 50 mm, 3.5 pm Gradient: Time [min] A [%] B [%] Flow rate: [mL / min] 0.0 98 2 1.5 0.2 98 2 1.5 3.3 10 90 1.5 4.0 10 90 1.5 Petition 870260054097, dated 03 / 06 / 2026, page 154 / 326 151 / 152 4.1 98 2 2.5 4.7 98 2 2.5 5.0 98 2 1.5 C. Practical examples of pharmaceutical compositions

[00454] The compounds of the invention can be converted into pharmaceutical preparations as follows: Tablet: Composition:

[00455] 100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

[00456] Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. Production:

[00457] The mixture of the compound of the invention, lactose and starch, is granulated with a 5% (w / w) solution of PVP in water. The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is compressed using a conventional tablet press (see tablet shape above). The reference value used for pressing is a pressing force of 15 kN.

[00458] Suspension for oral administration: Composition:

[00459] 1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

[00460] 10 mL of oral suspension corresponds to a single dose of 100 mg of the compound of the invention. Petition 870260054097, dated 03 / 06 / 2026, p. 155 / 326 152 / 152 Production:

[00461] Rhodigel is suspended in ethanol; the compound of the invention is added to the suspension. Water is added while stirring. The mixture is stirred for about 6 h until the swelling of Rhodigel is complete.

[00462] Solution for oral administration: Composition:

[00463] 500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution corresponds to a single dose of 100 mg of the compound of the invention. Production:

[00464] The compound of the invention is suspended in a mixture of polyethylene glycol and polysorbate with stirring. The stirring process continues until the compound according to the invention is completely dissolved. Solution IV:

[00465] The compound according to the invention is dissolved at a concentration below the saturation solubility in a physiologically tolerated solvent (e.g., isotonic saline solution, 5% glucose solution and / or 30% PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection containers. Petition 870260054097, dated 03 / 06 / 2026, page 156 / 326< / vii>

Claims

1 / 5 CLAIMS 1. Compound, characterized in that it has Formula (I), OH (I) in which: R1 represents hydrogen or halogen, R2 represents hydrogen or halogen, R3 represents chlorine or trifluoromethyl, R4 represents hydrogen or C1-C4-alkyl, R5 represents C1-C6-alkyl, X1 represents nitrogen or carbon, X2 represents nitrogen or carbon, or salts thereof.

2. Compound according to claim 1, characterized in that: R1 represents hydrogen, fluorine, R2 represents hydrogen, fluorine, R3 represents chlorine or trifluoromethyl, R4 represents hydrogen or methyl, R5 represents isobutyl, X1 represents carbon, X2 represents carbon, or salts thereof.

3. Compound, according to claim 1 or 2, Petition 870260054097, dated 03 / 06 / 2026, page 157 / 326 2 / 5 characterized in that it has the formula Cl L^,CH3 ch3 or salts thereof.

4. Compound, according to any one of claims 1 to 3, characterized in that it has the formula yCHs ch3 or salts thereof.

5. Compound, according to any one of claims 1 to 4, characterized in that it has the formula O l___ch3 6. Compound, according to any one of claims 1 to 5, characterized in that it presents the formula Petition 870260054097, dated 03 / 06 / 2026, page 158 / 326 3 / 5 Cl ch3 Cl x 0.5 H2O 7. Process for preparing a compound of Formula (I), or salts thereof, as defined in claim 1, characterized in that: in a first step [D], the compounds of Formula (VIII), (VIII), in which R1, R2 and R3 are as defined in claim 1, are reacted with compounds of Formula (VII), (VII), in which R4, R5, and X1 and X2 are as defined in claim 1, and R9 represents hydrogen, methyl or both R9 form, through the adjacent oxygen atoms, a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, in the presence of a palladium source, a suitable ligand. Petition 870260054097, dated 03 / 06 / 2026, p. 159 / 326 4 / 5 and a base to provide compounds of Formula (II), (II), wherein R1, R2, R3, R4, R5 and Xi and X2 are as defined in claim 1; in a second step [A], react a compound of Formula (II), (II), with a base in a suitable solvent to provide a compound of Formula (I), (I), Petition 870260054097, dated 03 / 06 / 2026, page.160 / 326 5 / 5 in which R1, R2, R3, R4, R5 and Xi and X2 are as defined in claim 1; optionally, the compounds of Formula (I) are transferred in a third step [A]* into the corresponding salts of Formula (Ia), (Ia) in the presence of a suitable acid in a suitable solvent.

8. A medicament, characterized in that it comprises a compound, as defined in claim 1, in combination with an inert, non-toxic, pharmaceutically suitable excipient. Petition 870260054097, dated 03 / 06 / 2026, p. 161 / 326

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