Substituted pyrazolylpiperidine carboxylic acids

Abstract

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

Description

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

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

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

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

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

[0006] A promising approach to treat such diseases that is NO-independent and aims to affect the cGMP signaling pathway in the organism is one that is highly efficient and has few anticipated side effects.

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

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

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

[0010] The sGC activator Runcaciguat (Hahn et al., Drugs Future 43 (2018), 738, WO 2012 / 139888) is currently undergoing clinical development by BAYER (https: / / www.clinicaltrials.gov / NCT04507061). Our understanding of the redox balance of sGC in health and disease is limited. Therefore, the therapeutic potential of sGC activators is not fully understood. However, since oxidative stress can provide sGC activators of heme-free sGC enzymes, sGC activators may have broader therapeutic potential, but this potential remains to be further identified and confirmed in the future.

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

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

[0013] Therefore, one object of the present invention is to provide novel sGC activator compounds for the treatment and / or prevention of diseases in humans and animals, particularly cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD), cardiorenal and renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and various forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), and wound healing disorders such as diabetic foot ulcers (DFU). These compounds exhibit favorable pharmacokinetic behavior, possess good pharmacological activity characteristics, and beneficial physicochemical properties (e.g., solubility).

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

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

[0016]

[0017] in

[0018] R 1 Represents hydrogen or halogen,

[0019] R 2 Represents hydrogen or halogen,

[0020] R 3 Represents chlorine or trifluoromethyl

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

[0022] R 5 Groups representing the following formulas

[0023]

[0024] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0025] R 6 represent

[0026] C1-C6-alkyl groups optionally substituted with one or more substituents independently selected from the following: methyl, trifluoromethoxy, nitrile, amide;

[0027] C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0028] C3-C6-cycloalkyl,

[0029] C3-C6-cycloalkyl-methyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups,

[0030] C1-C6-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0031] C3-C6-cycloalkyl-carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0032] Oxycyclic butyl,

[0033] Spirocyclic [2.2]pentyl-2-methyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0034] R 7 Represents a C1-C4 alkyl carbonyl group optionally substituted with a C3-C6-cycloalkyl group.

[0035] R 8 Represents C2-C4-haloalkyl groups substituted with 1 to 6 fluorine substituents.

[0036] X1 represents nitrogen or carbon.

[0037] X2 represents nitrogen or carbon.

[0038] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific atom or group with a group selected from a specified group, provided that the normal valence state of the specified atom is not exceeded under normal conditions. Combinations of substituents and / or variables are permitted.

[0039] The term “one or more” as used herein, for example in the definition of substituents in compounds of general formula (I) of the present invention, means “1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more specifically 1, 2 or 3, or even more specifically 1 or 2”.

[0040] In the context of this invention, unless otherwise stated, substituents are defined as follows:

[0041] The term “halogen” or “halogenated” as in combination, such as in a haloalkyl group, refers to a fluorine, chlorine, bromine or iodine atom, especially a fluorine, chlorine or bromine atom, or even more specifically, a fluorine or chlorine atom.

[0042] The terms "C1-C4 alkyl", "C1-C5 alkyl", and "C1-C6 alkyl" refer to straight-chain or branched saturated monovalent hydrocarbon groups containing 1, 2, 3, or 4 carbon atoms, 1, 2, 3, 4, or 5 carbon atoms, and 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1 -Ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl, or isomers thereof. Specifically, the group has 1, 2, 3 or 4 carbon atoms (“C1-C4 alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, more specifically having 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0043] The terms “C1-C6-haloalkyl,” “C2-C6-haloalkyl,” “C1-C4-haloalkyl,” “C2-C4-haloalkyl,” “C1-C3-haloalkyl,” and “C1-C2-haloalkyl” represent straight-chain or branched saturated monovalent hydrocarbon groups, wherein “alkyl” is defined as above, and one or more hydrogen atoms are substituted by halogen atoms in the same or different ways. Specifically, the halogen atom is a fluorine atom. The C1-C6 haloalkyl groups are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl-1-yl, 1,1,1-trifluoropropyl-2-yl, 1,3-difluoropropyl-2-yl, 3-fluoropropyl-1-yl, 1,1,1-trifluorobutyl-2-yl, and 3,3,3-trifluoro-1-methyl-propyl-1-yl.

[0044] The terms "C1-C4-haloalkoxy" and "C1-C3-haloalkoxy" refer to straight-chain or branched saturated monovalent C1-C4-alkoxy or C1-C3-alkoxy (wherein the alkoxy group represents a straight-chain or branched saturated monovalent alkoxy group having 1 to 4 or 1 to 3 carbon atoms, such as and preferably methoxy, ethoxy, n-propoxy, isopropoxy), wherein one or more hydrogen atoms are substituted by halogen atoms in the same or different ways. In particular, the halogen atom is a fluorine atom. For example, the C1-C3 haloalkoxy group is fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or pentafluoroethoxy.

[0045] The term "(C1-C4)-alkylcarbonyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms connected to the remainder of the molecule via a carbonyl group [-C(=O)-]. The following may be mentioned by example and in preferred manner: acetyl, propionyl, n-butyryl, isobutyryl, tert-butyryl, n-valeryl, and neovaleryl.

[0046] The term "C3-C6 cycloalkyl" refers to a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms. For example, the C3-C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0047] The compounds described in this invention are compounds of formula (I) and their salts, solvates and solvates of their salts, as well as compounds of formula (I) and detailed herein as working examples, and their salts, solvates and solvates of their salts, to the extent that the compounds of formula (I) and detailed herein are not salts, solvates and solvates of their salts.

[0048] Depending on their structures, the compounds of the present invention can exist in different stereoisomeric forms, i.e., as configurational isomers, or, where appropriate, as conformational isomers (enantiomers and / or diastereomers, including rotational and rotation-resistant isomers). Therefore, the present invention comprises enantiomers and diastereomers, and mixtures thereof. Stereoisomerically homogeneous components can be separated from mixtures of enantiomers and / or diastereomers in a known manner; for this purpose, chromatography, particularly HPLC on achiral or chiral phases, is preferred.

[0049] This invention includes all possible tautomers of the compounds of this invention, as a single tautomer, or as any mixture of said tautomers in any proportion.

[0050] In this invention, the term "enantiomerically pure" should be understood as the presence of an enantiomer excess of greater than 95%, preferably greater than 97%, in terms of the absolute configuration of the chiral center. In this case, the enantiomer excess value (ee value) is calculated by evaluating the corresponding HPLC chromatogram on the chiral phase using the following formula:

[0051] ee = [E A (Area%)-E B [(Area%)] x 100% / [E] A (Area%) + E B (area%)]

[0052] (E A : More enantiomers, E B (fewer enantiomers)

[0053] This invention also covers all suitable isotopic variants of the compounds of this invention. Isotopic variants of the compounds of this invention are understood herein as compounds in which at least one atom is replaced by another atom of the same atomic number but with a different atomic mass than that commonly or predominantly found in nature. Examples of isotopes included in the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as... 2 H (deuterium) 3 H (tritium) 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 129 I and 131 I. Specific isotopic variants of the compounds of the present invention, particularly variants containing one or more radioactive isotopes, can be beneficial for, for example, studying the mechanism of action of the compounds or the distribution of active ingredients in vivo; they are also relatively easy to prepare and detect, especially using... 3 H or 14Compounds labeled with the carbon isotope are suitable for this purpose. Furthermore, the incorporation of an isotope (e.g., deuterium) can lead to specific therapeutic effects due to enhanced metabolic stability of the compound, such as prolonged in vivo half-life or reduced required active dose. Therefore, in certain circumstances, such modification of the compounds of the present invention can also constitute a preferred embodiment of the invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods further described below and the steps described in the examples, through appropriate isotopic modification of the corresponding reagents and / or starting compounds.

[0054] The preferred salts in this invention are physiologically acceptable salts of the compounds of this invention. However, this invention also includes salts that are not inherently suitable for pharmaceutical applications but can be used for purposes such as isolating or purifying the compounds of this invention.

[0055] Physiologically acceptable salts of the compounds of this invention include acid addition salts of inorganic acids, carboxylic acids, and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

[0056] Physiologically acceptable salts of the compounds of the present invention also include salts of conventional bases, such as and preferably alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as and preferably ethylamine, diethylamine, triethylamine, ethyl diisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, and choline.

[0057] This invention includes all possible salts of the compounds of this invention, as a single salt or any mixture of said salts in any proportion.

[0058] The invention described solvates This refers to the form of compounds of the present invention that form complexes in the solid or liquid state through coordination with solvent molecules. The compounds of the present invention may contain polar solvents, particularly water, methanol, or ethanol, as structural units of the compound's crystal lattice. A hydrate is a specific form of solvate coordinated with an aqueous phase. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, solvates or hydrates such as hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., are possible. The present invention includes all such hydrates or solvates.

[0059] Furthermore, the compounds described in this invention can exist as N-oxides, defined as compounds in which at least one nitrogen atom is oxidized in a known manner. This invention includes all such possible N-oxides.

[0060] Furthermore, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrug" includes compounds that may be biologically active or biologically inactive in themselves, but which are converted into the compounds of the present invention during their residence time in the body (e.g., through metabolism or hydrolysis).

[0061] In which R can be represented 5 In the formula for the group, the endpoint of the line marked with # does not represent a carbon atom or a CH2 group in each case, but is connected to R. 5 Part of the bond between the atoms.

[0062] The preferred formula (I) includes the compound and its salt, its solvate, and the solvate of its salt, wherein...

[0063] in

[0064] R 1 Represents hydrogen or halogen,

[0065] R 2 Represents hydrogen or halogen,

[0066] R 3 Represents chlorine or trifluoromethyl

[0067] R 4 Represents hydrogen or C1-C4-alkyl

[0068] R 5 Groups representing the following formulas

[0069]

[0070] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0071] R 6 represent

[0072] Optionally substituted with one or more substituents selected independently from the following: trifluoromethoxy, nitrile, amide;

[0073] C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0074] C3-C6-cycloalkyl,

[0075] C3-C6-cycloalkyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups

[0076] -methyl,

[0077] C1-C6-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0078] C3-C6-cycloalkyl-carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0079] Oxycyclic butyl,

[0080] Spirocyclic [2.2]pentyl-2-methyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0081] R 7 Represents a C1-C4 alkyl carbonyl group optionally substituted with a C3-C6-cycloalkyl group.

[0082] R 8 Represents C2-C4-haloalkyl groups substituted with 1 to 6 fluorine substituents.

[0083] X1 represents nitrogen or carbon.

[0084] X2 represents nitrogen or carbon.

[0085] The preferred formula (I) is a compound or a salt thereof, a solvate thereof, and a solvate thereof, wherein

[0086] R 1 Represents hydrogen and fluorine

[0087] R 2 Represents hydrogen and fluorine

[0088] R 3 Represents chlorine or trifluoromethyl

[0089] R 4 Represents hydrogen or methyl

[0090] R 5 Groups representing the following formulas

[0091]

[0092] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0093] R 6 represent

[0094] C1-C4-alkyl groups optionally substituted with one or more substituents independently selected from the following: methyl, trifluoromethoxy, nitrile;

[0095] C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0096] C3-C6-cycloalkyl groups optionally substituted with one or two fluorine substituents or trifluoromethyl groups

[0097] -methyl,

[0098] C1-C3-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0099] C3-C6-cycloalkyl-carbonyl,

[0100] R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group.

[0101] R 8 Represents a C2-C4-haloalkyl group optionally substituted with 1 to 3 fluorine substituents.

[0102] X1 represents nitrogen or carbon.

[0103] X2 represents nitrogen or carbon.

[0104] The preferred formula (I) is a compound or a salt thereof, a solvate thereof, and a solvate thereof, wherein

[0105] R 1 Represents hydrogen and fluorine

[0106] R 2 Represents hydrogen and fluorine

[0107] R 3 Represents chlorine or trifluoromethyl

[0108] R 4 Represents hydrogen or methyl

[0109] R 5 Groups representing the following formulas

[0110]

[0111] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0112] R 6 represent

[0113] C1-C4-alkyl groups optionally substituted with one or more substituents independently selected from the following: methyl, trifluoromethoxy, nitrile;

[0114] C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0115] C3-C6-cycloalkyl groups optionally substituted with one or two fluorine substituents or trifluoromethyl groups

[0116] -methyl,

[0117] C1-C3-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0118] C3-C6-cycloalkyl-carbonyl,

[0119] R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group.

[0120] R 8 Represents a C2-C4-haloalkyl group optionally substituted with 1 to 3 fluorine substituents.

[0121] X1 represents nitrogen or carbon.

[0122] X2 represents nitrogen or carbon.

[0123] The preferred formula (I) is a compound or a salt thereof, a solvate thereof, and a solvate thereof, wherein

[0124] R 1 Represents hydrogen

[0125] R 2 Represents hydrogen

[0126] R 3 Represents chlorine

[0127] R 4 Represents hydrogen

[0128] R 5 Groups representing the following formulas

[0129]

[0130] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0131] R 6 Represents C1-C4-alkyl groups optionally substituted with trifluoromethoxy or nitrile groups, C2-C3-haloalkyl groups substituted with 1 to 5 fluorine substituents, C3-C4-cycloalkyl-methyl groups optionally substituted with 1 to 2 fluorine substituents or trifluoromethyl groups, and C1-C3-alkylcarbonyl groups optionally substituted with 1 to 3 fluorine substituents.

[0132] Cyclopropyl-carbonyl,

[0133] R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group.

[0134] R 8 Represents C2-C4-haloalkyl groups substituted with 1 to 3 fluorine substituents.

[0135] X1 represents carbon.

[0136] X2 represents carbon.

[0137] The preferred formula (I) is a compound or a salt thereof, a solvate thereof, and a solvate thereof, wherein

[0138] R 1 Represents hydrogen

[0139] R 2 Represents hydrogen

[0140] R 3 Represents chlorine

[0141] R 4 Represents hydrogen

[0142] R 5 Groups representing the following formulas

[0143]

[0144] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0145] R 6 Represents C1-C4-alkyl groups substituted with trifluoromethoxy or nitrile groups, C2-C3-haloalkyl groups substituted with 1 to 5 fluorine substituents, C3-C4-cycloalkyl-methyl groups optionally substituted with 1 to 2 fluorine substituents or trifluoromethyl groups, and C1-C3-alkylcarbonyl groups optionally substituted with 1 to 3 fluorine substituents.

[0146] Cyclopropyl-carbonyl,

[0147] R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group.

[0148] X1 represents carbon.

[0149] X2 represents carbon.

[0150] The preferred formula (I) is a compound or a salt thereof, a solvate thereof, and a solvate thereof, wherein

[0151] R 1 Represents hydrogen

[0152] R 2 Represents hydrogen

[0153] R 3 Represents chloro or trifluoromethyl.

[0154] R 4 Represents hydrogen

[0155] R 5 Groups representing the following formulas

[0156]

[0157] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0158] R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group.

[0159] X1 represents carbon or nitrogen.

[0160] X2 represents carbon.

[0161] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0162] R 1 Represents hydrogen

[0163] R 2 Represents hydrogen

[0164] R 3 Represents chlorine

[0165] R 4 Represents hydrogen

[0166] R 5 Groups representing the following formulas

[0167]

[0168] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0169] R 6 Represents C1-C4-alkyl groups optionally substituted with trifluoromethoxy or nitrile groups, C2-C3-haloalkyl groups substituted with 1 to 5 fluorine substituents, C3-C4-cycloalkyl-methyl groups optionally substituted with 1 to 2 fluorine substituents or trifluoromethyl groups, and C1-C3-alkylcarbonyl groups optionally substituted with 1 to 3 fluorine substituents.

[0170] X1 represents carbon or nitrogen.

[0171] X2 represents carbon.

[0172] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0173] R 1 Represents hydrogen

[0174] R 2 Represents hydrogen

[0175] R 3 Represents chlorine

[0176] R 4 Represents hydrogen

[0177] R 5 Groups representing the following formulas

[0178]

[0179] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0180] R 6 Represents C1-C4-alkyl groups substituted with trifluoromethoxy or nitrile groups, C2-C3-haloalkyl groups substituted with 1 to 5 fluorine substituents, C3-C4-cycloalkyl-methyl groups optionally substituted with 1 to 2 fluorine substituents or trifluoromethyl groups, and C1-C3-alkylcarbonyl groups optionally substituted with 1 to 3 fluorine substituents.

[0181] X1 represents carbon or nitrogen.

[0182] X2 represents carbon.

[0183] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0184] R 1 Represents hydrogen

[0185] R 2 Represents hydrogen

[0186] R 3 Represents chlorine

[0187] R 4 Represents hydrogen

[0188] R 5 Groups representing the following formulas

[0189]

[0190] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0191] R 6 Represents a C1-C4-alkyl group substituted with a trifluoromethoxy or nitrile group, a trifluoroethyl group, a C3-C4-cycloalkyl-methyl group optionally substituted with one or two fluorine substituents or a trifluoromethyl group, or a C1-C3-alkylcarbonyl group optionally substituted with one or three fluorine substituents.

[0192] X1 represents carbon or nitrogen.

[0193] X2 represents carbon.

[0194] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0195] R 1 Represents hydrogen

[0196] R 2 Represents hydrogen

[0197] R 3 Represents chlorine

[0198] R 4 Represents hydrogen

[0199] R 5 Groups representing the following formulas

[0200]

[0201] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0202] R 6 Represents a C1-C4-alkyl group substituted with a trifluoromethoxy or nitrile group, a trifluoroethyl group, a C3-C4-cycloalkyl-methyl group optionally substituted with one or two fluorine substituents or a trifluoromethyl group, or a C1-C3-alkylcarbonyl group optionally substituted with one or three fluorine substituents.

[0203] X1 represents carbon or nitrogen.

[0204] X2 represents carbon.

[0205] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0206] R 1 Represents hydrogen

[0207] R 2 Represents hydrogen

[0208] R 3 Represents chlorine or trifluoromethyl

[0209] R 4 Represents hydrogen

[0210] R 5 Groups representing the following formulas

[0211]

[0212] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0213] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0214] X1 represents carbon or nitrogen.

[0215] X2 represents carbon.

[0216] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0217] R 1 Represents hydrogen

[0218] R 2 Represents hydrogen

[0219] R 3 Represents chlorine or trifluoromethyl

[0220] R 4 Represents hydrogen

[0221] R 5 Groups representing the following formulas

[0222]

[0223] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0224] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0225] X1 represents carbon or nitrogen.

[0226] X2 represents carbon.

[0227] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0228] R 1 Represents hydrogen

[0229] R 2 Represents hydrogen

[0230] R 3 Represents chlorine

[0231] R 4 Represents hydrogen

[0232] R 5 Groups representing the following formulas

[0233]

[0234] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0235] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0236] X1 represents carbon or nitrogen.

[0237] X2 represents carbon.

[0238] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0239] R 1 Represents hydrogen

[0240] R 2 Represents hydrogen

[0241] R 3 Represents chlorine

[0242] R 4 Represents hydrogen

[0243] R 5 Groups representing the following formulas

[0244]

[0245] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0246] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0247] X1 represents carbon or nitrogen.

[0248] X2 represents carbon.

[0249] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0250] R 1 Represents hydrogen

[0251] R 2 Represents hydrogen

[0252] R 3 Represents chlorine

[0253] R 4 Represents hydrogen

[0254] R 5 Groups representing the following formulas

[0255]

[0256] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0257] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0258] X1 represents carbon.

[0259] X2 represents carbon.

[0260] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0261] R 1 Represents hydrogen

[0262] R2 Represents hydrogen

[0263] R 3 Represents chlorine

[0264] R 4 Represents hydrogen

[0265] R 5 Groups representing the following formulas

[0266]

[0267] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0268] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0269] X1 represents carbon.

[0270] X2 represents carbon.

[0271] Preferably, the compounds are selected from the following: their salts, their solvates, and solvates of their salts.

[0272]

[0273]

[0274] Preferably, the compounds are selected from the following: their salts, their solvates, and solvates of their salts.

[0275]

[0276] The present invention further provides a method for preparing a compound of formula (I) or a salt thereof, a solvate thereof, or a solvate of a salt thereof, wherein...

[0277] In step [B], in the presence of a palladium source, a suitable ligand, and a base, the compound of formula (III) is reacted with the compound of formula (IV) to generate the compound of formula (II).

[0278]

[0279] Where R 1 R 2 and R 3 The definition is as above.

[0280]

[0281] Where R 4 R 5 And X1 and X2 are defined as above,

[0282] and

[0283] Where R 9 Represents hydrogen, methyl, or two Rs 9 4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane is formed via adjacent oxygen atoms.

[0284]

[0285] Where R 1 R 2 R 3 R 4 R 5 The definitions of X1 and X2 are as above.

[0286] and

[0287] In the second step [A]

[0288] The compound of formula (II) reacts with a base to produce the compound of formula (I).

[0289]

[0290] Where R 1 R 2 R 3 R 4 R 5 The definitions of X1 and X2 are as above.

[0291] Optionally, in step three [A]*, the compound of formula (I) is converted into a salt of the corresponding formula (Ia) in a suitable solvent in the presence of a suitable acid.

[0292]

[0293] Where R 1 R 2 R 3 R 4 R 5 The definitions of X1 and X2 are as above.

[0294] Reaction [A]* (salt formation)

[0295] The reaction [A]* is usually carried out in an inert solvent in the presence of an acid, preferably at atmospheric pressure in the temperature range of 0°C to 60°C.

[0296] Suitable acids for salt formation are typically sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, optionally added to water. Hydrogen chloride, hydrogen bromide, toluenesulfonic acid, methanesulfonic acid, or sulfuric acid are preferred.

[0297] Suitable inert solvents for salt formation include ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether, or other solvents such as acetone, ethyl acetate, ethanol, n-propanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylpropylene urea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of the above solvents may also be used. Diethyl ether, dioxane, tetrahydrofuran, or mixtures of these solvents are preferred.

[0298] Reaction [A] (Ester hydrolysis)

[0299] The hydrolysis of the ester group in the compounds of Formula II is carried out by conventional methods, by treating the ester with an acid or base in an inert solvent, wherein in the latter variation, the initially formed salt is converted into a free carboxylic acid by acid treatment. In the case of tert-butyl esters, ester hydrolysis is preferably carried out with an acid.

[0300] Suitable inert solvents for these reactions are water or organic solvents commonly used for ester cracking. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, or 1,2-dimethoxyethane; or other solvents such as dichloromethane, acetone, methyl ethyl ketone, N,N-dimethylformamide, or dimethyl sulfoxide. Mixtures of these solvents can also be used. In the case of basic ester hydrolysis, a mixture of water with dioxane, tetrahydrofuran, methanol, ethanol, and / or dimethylformamide, or a mixture of tetrahydrofuran with methanol or ethanol, is preferred. In the case of reaction with trifluoroacetic acid, dichloromethane is preferred; in the case of reaction with hydrogen chloride, tetrahydrofuran, diethyl ether, dioxane, or water is preferred.

[0301] Suitable bases are commonly used inorganic bases. These particularly include alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide, or alkali metal or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, or calcium carbonate. Lithium hydroxide, sodium hydroxide, or potassium hydroxide are preferred.

[0302] Suitable acids for ester hydrolysis are typically sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. In the case of tert-butyl esters, hydrogen chloride or trifluoroacetic acid is preferred, and in the case of methyl esters, hydrochloric acid is preferred.

[0303] Ester hydrolysis is usually carried out in a temperature range of -20°C to +120°C, preferably in a range of 0°C to +80°C.

[0304] The compound of formula (II) is novel.

[0305]

[0306] Where R 1 R 2 R 3 R 4 R 5 The definitions of X1 and X2 are as above.

[0307] The compounds of formula (II) can be synthesized from the starting compounds of the corresponding formula (III) by the following method:

[0308] [B] In the presence of a suitable palladium catalyst, a base, and a suitable solvent, the compound of formula (III) is reacted with the compound of formula (IV) in the presence of a palladium source, a suitable ligand, and a base to generate the compound of formula (II).

[0309]

[0310] Where R 1 R 2 and R 3 The definition is as above.

[0311]

[0312] Where R 4 R 5 R 9 The definitions of X1 and X2 are as above.

[0313] Reaction [B] (Suzuki coupling)

[0314] The reaction [B] is generally carried out in an inert solvent in the presence of a suitable palladium catalyst and a suitable base, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0315] The inert solvent used in reaction step [B] is, for example, an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or tert-butanol; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; a hydrocarbon such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum; or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile, or water. Mixtures of the above solvents may also be used. A mixture of dimethylformamide / water and toluene / ethanol is preferred.

[0316] The base suitable for the reaction step is a commonly used inorganic base. This specifically includes alkali metal or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide; alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate; or alkali metal or alkaline earth metal carbonates, such as carbonates of lithium, sodium, potassium, calcium, or cesium; or alkali metal hydrogen phosphates, such as disodium hydrogen phosphate or dipotassium hydrogen phosphate. Preferred bases are sodium carbonate or potassium carbonate.

[0317] Examples of palladium catalysts suitable for the reaction step [“Suzuki coupling”] include: palladium on carbon, palladium(II) acetate, tetra-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II) chloride, bis-(acetonitrile)-palladium(II) chloride and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II)-dichloromethane complex [see Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].

[0318] The reaction steps are typically carried out in a temperature range of +20°C to +150°C, preferably in a range of +50°C to +100°C.

[0319] The compounds of formula (IV) are novel.

[0320]

[0321] Where R 4 R 5 R 9 The definitions of X1 and X2 are as above.

[0322] and

[0323] in

[0324] R 5 Groups representing the following formulas

[0325]

[0326] Where # represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0327] R 6 Represents a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from the following: methyl, trifluoromethoxy, nitrile, amide.

[0328] C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0329] C3-C6-cycloalkyl,

[0330] C3-C6-cycloalkyl-methyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups,

[0331] C1-C6-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0332] C3-C6-cycloalkyl-carbonyl groups optionally substituted with 1 to 3 fluorine substituents,

[0333] Oxycyclic butyl,

[0334] Spirocyclic [2.2]pentyl-2-methyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0335] R 7 Represents a C1-C4 alkyl carbonyl group optionally substituted with a C3-C6-cycloalkyl group.

[0336] R 8 Represents C2-C4-haloalkyl groups substituted with 1 to 6 fluorine substituents.

[0337] The compound of formula (IVb) is novel.

[0338]

[0339] Where R 4 R 6 R 9 The definitions of X1 and X2 are as above.

[0340] And its

[0341] [C] can be prepared by reacting a compound of formula (IVa) with a compound of formula (XV) in the presence of a reducing agent, a base, and a suitable solvent.

[0342]

[0343] Where R 4 R 9 The definitions of X1 and X2 are as above.

[0344] R 6a -CHO(XV)

[0345] in

[0346] R 6a Represents C1- which is optionally substituted by one or more substituents independently selected from the following.

[0347] C5-alkyl groups: methyl, trifluoromethoxy, nitrile, amide.

[0348] C2-C5-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0349] C3-C6-cycloalkyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups,

[0350] Spirocyclic [2.2]but-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]butyl)methyl,

[0351] Or alternative

[0352] [D] is prepared by reacting a compound of formula (IVa) with a compound of formula (XVI) in the presence of a base and a suitable solvent.

[0353]

[0354] Where R 4 R 9 The definitions of X1 and X2 are as above.

[0355] R 6 -X(XVI)

[0356] Where R 6 Defined as above, and X is Br, OTs, OTf.

[0357] Or alternative

[0358] [F] First, the compound of formula (IVa) is reacted with the compound of formula (XVII) in the presence of a base and a suitable solvent to produce the compound of formula (IVc).

[0359]

[0360] Where R 4 R 9 The definitions of X1 and X2 are as above.

[0361]

[0362] in

[0363] R 10 Represents C1- which is optionally substituted by one or more substituents independently selected from the following.

[0364] C5-alkyl groups: methyl, trifluoromethoxy, nitrile, amide.

[0365] C2-C5-haloalkyl groups substituted with 1 to 5 fluorine substituents

[0366] C3-C6-cycloalkyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups,

[0367] Spirocyclic [2.2]but-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]butyl)methyl,

[0368]

[0369] Where R 4 R 9 R 10 And X1 and X2 are defined as above and

[0370] [E] Further, by reacting the compound of formula (IVc) in the presence of a reducing agent and a suitable solvent, a compound of formula (IVd) is generated.

[0371]

[0372] Where R 4 R 9 R 10 The definitions of X1 and X2 are as above.

[0373]

[0374] Where R 4 R 9 R 10 And X1 and X2 are defined as above,

[0375] The compound of formula (IVc) will also be used in the above reaction [B] (Suzuki coupling).

[0376] Reaction [C] (reductive amination)

[0377] The reaction in step [C] is usually carried out in an inert solvent in the presence of a reducing agent, or, if appropriate, in the presence of a base and / or a dehydrating agent, preferably at atmospheric pressure in a temperature range of 0°C to 60°C.

[0378] The reducing agents suitable for reductive amination are alkali metal borohydrides commonly used for this purpose, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; sodium triacetoxyborohydride is preferred.

[0379] Adding acids, especially acetic acid, and / or dehydrating agents, such as molecular sieves, trimethyl orthoformate, or triethyl orthoformate, to these reactions may be advantageous.

[0380] The bases are, for example, organic bases, such as trialkylamines like triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, or diisopropylethylamine or pyridine. Bases such as N,N-diisopropylethylamine and triethylamine, in particular, may be advantageous in these reactions.

[0381] Solvents suitable for these reactions include, in particular, alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of these solvents; tetrahydrofuran is preferred.

[0382] The reaction is generally carried out in a temperature range of 0℃ to +60℃.

[0383] The aldehyde in formula (XV) is commercially available or can be synthesized from known raw materials using known processes.

[0384] The raw materials for formula (IVa) are commercially available, known, or obtainable through known processes.

[0385] [D] (alkylation) reaction

[0386] Reaction [D] is typically carried out in the temperature range of 0°C to +120°C, preferably +20°C to +80°C, and, if suitable, in a microwave. The reaction can be carried out at atmospheric pressure, high pressure, or reduced pressure (e.g., 0.5-5 bar).

[0387] Suitable inert solvents for alkylation are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene, or chlorobenzene; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions; or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of these solvents may also be used. Dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran are preferred.

[0388] Suitable bases for alkylation are conventional inorganic or organic bases. These preferably include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; alkali metal or alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, or cesium carbonate; alkali metal iodides, such as sodium iodide or potassium iodide, if suitable; alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, or sodium tert-butoxide or potassium tert-butoxide; alkali metal hydrides, such as sodium hydride or potassium hydride; and amides, such as sodium amide or bis(trimethylsilyl) amide. Lithium amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane Potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine are preferred.

[0389] The alkylating agent of formula (XVI) is known, commercially available, or obtainable by known methods.

[0390] The raw materials for formula (IVa) are commercially available, known, or obtained through known processes.

[0391] Reaction [E] (reduction)

[0392] The reaction [E] is typically carried out in an inert solvent, preferably in a temperature range of 0°C to +65°C, more preferably in a range of 0°C to +40°C, and, if suitable, in a microwave. The reaction can be carried out under atmospheric pressure, high pressure, or reduced pressure (e.g., 0.5-5 bar).

[0393] Suitable inert solvents for reduction are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene, or chlorobenzene; ethers such as diethyl ether, dioxane, or tetrahydrofuran; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions. Mixtures of these solvents may also be used. Tetrahydrofuran is preferred.

[0394] Suitable reducing agents for amide reduction in the process steps are, for example, lithium aluminum hydride or borane tetrahydrofuran complexes. Borane tetrahydrofuran complexes are preferred.

[0395] The raw materials for formula (IVc) are commercially available, known, or obtainable through known processes or reactions [F].

[0396] Reaction [F] (Amide formation)

[0397] The reaction [F] is typically carried out in an inert solvent, in the presence of a condensing agent, preferably at a temperature of -20°C to +100°C, and more preferably at a temperature of 0°C to +60°C. The reaction can be carried out at atmospheric pressure, high pressure, or reduced pressure (e.g., 0.5-5 bar). Typically, the reaction is carried out at atmospheric pressure.

[0398] Inert solvents used for amide formation are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions; halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene, or chlorobenzene; or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylpropylene urea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of these solvents may also be used. Dichloromethane, tetrahydrofuran, dimethylformamide, or mixtures of these solvents are preferred.

[0399] Suitable condensing agents for amide formation include, for example, carbodiimides such as N,N'-diethyl-, N,N'-dipropyl-, N,N'-diisopropyl, N,N'-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N'-carbonyldiimidazole (CDI), and 1,2-oxazonium compounds such as 2-ethyl-5-phenyl-1,2-oxazonium 3-sulfate or 2-tert-butyl-5-methyl Benzoxazonium perchlorate, amide compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or potassium isobutyl chlorate, propanephosphonic anhydride (T3P), 1-chloro-N,N,2-trimethylpropen-1-ene-1-amine, diethyl cyanophosphate, bis-(2-oxo-3-oxazolyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)hexafluorophosphate phosphorium, benzotriazol-1-yloxytris(pyrrolidinyl)hexafluorophosphate phosphorium (PyBOP), O -(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylureonium tetrafluoroborate (TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate (HATU) Or O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TCTU), if suitable, in combination with other auxiliaries such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and also as an alkali metal carbonate, such as sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, or an organic base such as a trialkylamine, such as triethylamine, N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine. Preferred combinations are TBTU with N-methylmorpholine, 1-chloro-N,N,2-trimethylprop-1-en-1-amine, or HATU with N,N-diisopropylethylamine.

[0400] Alternatively, the carboxylic acid can be initially converted to the corresponding carboxyl chloride, and then reacted directly or in a separate reaction with an amine to give the compound of the present invention. The formation of carboxyl chloride from the carboxylic acid is carried out by methods known to those skilled in the art, for example by treatment with thionyl chloride, thionyl chloride, or oxalyl chloride in the presence of a suitable base, such as pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.

[0401] The raw materials for formula (IVc) are commercially available, known, or obtainable through known processes or reactions [F].

[0402] The acylating agent of formula (XVII) is commercially available, known, or obtainable by known processes.

[0403] The compound of formula (IVf) is novel.

[0404]

[0405] Where R 4 R 9 X1 and X2 are as defined above.

[0406] Where R 7a Indicates C1-C2-alkyl, cyclopropyl

[0407] They can be obtained in the following ways:

[0408] [G] React the compound of formula (IVe) with the compound of formula (XVIII) in the presence of a base and a suitable solvent.

[0409]

[0410] Where R 4 R 9 X1 and X2 are as defined above.

[0411]

[0412] Where R 7a It represents C1-C2-alkyl or cyclopropyl.

[0413] [G] (acylation) reaction

[0414] Reaction [G] is typically carried out in an inert solvent, in the presence of a base and a dehydrating agent, preferably in a temperature range of 0°C to +100°C, more preferably 0°C to +40°C, and, if suitable, in a microwave. The reaction can be carried out at atmospheric pressure, high pressure, or reduced pressure (e.g., 0.5-5 bar).

[0415] Suitable inert solvents for acylation are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene, or chlorobenzene; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions; or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N,N′-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of these solvents may also be used. Dimethylformamide or dichloromethane is preferred.

[0416] Suitable bases for alkylation are conventional inorganic or organic bases. These preferably include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; alkali metal or alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, or cesium carbonate; alkali metal iodides, such as sodium iodide or potassium iodide, if suitable; alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, or sodium tert-butoxide or potassium tert-butoxide; alkali metal hydrides, such as sodium hydride or potassium hydride; and amides, such as sodium amide or bis(trimethylsilyl) amide. Lithium amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane Pyridine, triethylamine, or N,N-diisopropylethylamine are preferred.

[0417] Compounds of formula (IVe) are known, commercially available, or obtainable by known processes.

[0418]

[0419] Where R 4 R 9 X1 and X2 are as defined above.

[0420] Compounds of formula (XVIII) are known, commercially available, or obtainable by known processes.

[0421]

[0422] Where R 7a As defined above.

[0423] Compounds of formula (IVi) are novel.

[0424]

[0425] Where R 4 R 8 R 9 And X1 and X2 are as defined above, and can be obtained in the following ways

[0426] [I] First, the compound of formula (IVg) is reacted with an acid in a suitable solvent to obtain a compound having formula (IVh).

[0427]

[0428] Where R4 R 9 And X1 and X2 as defined above

[0429]

[0430] Where R 4 R 9 X1 and X2 are as defined above.

[0431] as well as

[0432] [H] Next, the compound of formula (IVh) is reacted with the compound of formula (XVIII) in the presence of a base and a suitable solvent to obtain a compound having formula (IVi).

[0433]

[0434] Where R 4 R 9 X1 and X2 are as defined above.

[0435] XR 8 (XIX)

[0436] Where X is I, OTf

[0437] And R 8 As defined above

[0438]

[0439] Where R 4 R 8 R 9 X1 and X2 are as defined above.

[0440] [H] (alkylation) reaction

[0441] The reaction [H] is typically carried out in the temperature range of 0°C to +120°C, preferably +20°C to +80°C, and, if suitable, in a microwave. The reaction can be carried out under atmospheric pressure, high pressure, or reduced pressure (e.g., 0.5-5 bar).

[0442] Suitable inert solvents for alkylation are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene, or chlorobenzene; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions; or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of these solvents may also be used. Dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran are preferred.

[0443] Suitable bases for alkylation are conventional inorganic or organic bases. These preferably include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; alkali metal or alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, or cesium carbonate; alkali metal iodides, such as sodium iodide or potassium iodide, if suitable; alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, or sodium tert-butoxide or potassium tert-butoxide; alkali metal hydrides, such as sodium hydride or potassium hydride; and amides, such as sodium amide or bis(trimethylsilyl) amide. Lithium amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane Potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine are preferred.

[0444] Reaction [I] (Deprotection)

[0445] The reaction [I] is generally carried out in an inert solvent in the presence of a suitable acid, preferably in a temperature range of 0°C to 60°C at atmospheric pressure.

[0446] The acid is, for example, an organic or inorganic acid, such as sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or a mixture thereof, optionally added to water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0447] Solvents suitable for these reactions include alcohols such as methanol, ethanol, n-propanol or isopropanol, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of such solvents; tetrahydrofuran is preferred.

[0448] The reaction is usually carried out in a temperature range of 0°C to +60°C.

[0449] The alkylating agent of formula (XVI) is known, commercially available, or obtainable by known methods.

[0450] The raw materials of formula (IVa) are commercially available, known, or obtainable through known processes.

[0451] The compounds of formula (IVg) are known, commercially available, or obtainable from known raw materials by known processes.

[0452] The compounds of formula (XIX) are known, commercially available, or obtainable from known raw materials by known processes.

[0453] The compound of formula (III) is novel.

[0454]

[0455] Where R 1 R 2 and R 3 As defined above, and can be prepared in the following ways:

[0456] [J] By reacting the compound of formula (V) with trifluoromethanesulfonic anhydride in the presence of a base and an inert solvent,

[0457]

[0458] Where R 1 R 2 and R 3 As defined above.

[0459] Reaction [J] (Trifluoromethanesulfonation)

[0460] The reaction [J] is usually carried out in an inert solvent, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0461] The base is, for example, an organic base such as an alkali metal amine or pyridine, or an inorganic base such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or an alkali metal carbonate such as cesium carbonate, sodium carbonate or potassium carbonate, or an alkoxide such as potassium tert-butoxide or sodium tert-butoxide, or a pyridine such as pyridine or 2,6-dimethylpyridine, or a basic amine such as triethylamine or N,N-diisopropylethylamine; preferably triethylamine.

[0462] The inert solvent is, for example, an ether 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 a mixture of solvents; preferably dichloromethane.

[0463] The compound of formula (V) is novel.

[0464]

[0465] Where R 1 R 2 and R 3 As defined above.

[0466] The compound of formula (V) can be prepared as follows:

[0467] [K] By reacting the compound of formula (VI) with an acid optionally in an inert solvent,

[0468]

[0469] Where R 1 R 2 and R 3 As defined above.

[0470] Reaction [K] (Acidic Deprotection)

[0471] The reaction [K] is usually carried out in an inert solvent or in the absence of a solvent, preferably at atmospheric pressure in the range of 0°C to solvent reflux.

[0472] Inert solvents include, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethoxyethane, N-methylpyrrolidone, dimethylacetamide, acetonitrile, acetone or pyridine, or mixtures of solvents; preferably dichloromethane or dioxane.

[0473] Suitable acids for acidic deprotection are typically sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0474] The compound of formula (VI) is novel.

[0475]

[0476] Where R 1 R 2 and R 3 As defined above.

[0477] The compound of formula (VI) can be prepared as follows:

[0478] [L] By reacting the compound of formula (VII) with the compound of formula (VIII) in the presence of a palladium source, a suitable ligand, and a base,

[0479]

[0480] Where R 1 and R 2 As defined above,

[0481]

[0482] Where R 3 As defined above.

[0483] The reaction [L] (Buchwald-Hartwig coupling)

[0484] The reaction [L] is typically carried out in an inert solvent in the presence of a palladium source, a suitable ligand and a base, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0485] Palladium sources and suitable ligands are, for example, palladium on carbon, palladium(II) acetate, tris(dibenzylacetone)palladium(O), tetra-(triphenylphosphine)-palladium(O), bis-(triphenylphosphine)-palladium(II), bis-(acetonitrile)-palladium(II), [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complexes, optionally in combination with other phosphine ligands, such as 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), (2- Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate (XPhos-Pd-G3, CAS-No: 1445085-55-1), (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos, CAS-No: CAS-No: 564483-18-7), bis(2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium (Xantphos: CAS-No: 161265-03-8) [see, for example, Hassan J. et al.] 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-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (SPhos, CAS-No: 657408-07) -6), 2-dicyclohexylphosphine-2′,6′-diisopropoxybiphenyl (RuPhos, CAS-No: 787618-22-8), 2-(di-tert-butylphosphine)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos) and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (tert-ButylXPhos). Alternatively, a suitable precatalyst such as chloro-[2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl))-phenyl]palladium(II) (BrettPhos precatalyst) [see, for example, SLBuchwald et al., Chem. Sci. 2013, 4, 916] may be used, optionally in combination with other phosphine ligands, such as 2-(dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos).

[0486] Preferably, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), tris(dibenzylideneacetone)palladium (0), or in combination with 4,5-bis(diphenylphosphine)-9,9-dimethylxanthocyanidin (Xantphos) or dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos) are used.

[0487] The base is, for example, a suitable inorganic or organic base, such as alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonates, or sodium bicarbonate or potassium bicarbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, barium hydroxide or potassium hydroxide; alkali metal or alkaline earth metal phosphates such as potassium phosphate; alkali metal alkoxides such as sodium tert-butyrate or potassium tert-butyrate and sodium methoxide, alkali metal phenolates such as sodium phenoxide, potassium acetate, amides such as sodium amide, lithium-, sodium- or potassium-bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Cesium carbonate, sodium carbonate, potassium carbonate or sodium bicarbonate are preferred.

[0488] The inert solvent is, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, di-n-butyl ether, cyclopentylmethyl ether, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as tert-butanol or pentanol, or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene or acetonitrile or mixtures of said solvents; preferably tert-butanol, 1,4-dioxane and toluene.

[0489] The compounds of formula (VIII) are known, or can be synthesized by known methods from the corresponding commercially available starting compounds.

[0490] The compound of formula (VII) is novel.

[0491]

[0492] Where R 1 and R 2 As defined above.

[0493] The compound of formula (VII) can be prepared as follows:

[0494] [M] By reacting the compound of formula (IX) with an acid in an inert solvent,

[0495]

[0496] Where R 1 and R 2 As defined above.

[0497] Reaction [M] (debocylation)

[0498] The reaction [M] is usually carried out in an inert solvent in the presence of a suitable acid, preferably at atmospheric pressure in a temperature range of 0°C to 60°C.

[0499] The acid is an organic or inorganic acid, such as sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or a mixture thereof, optionally added to water. Hydrogen chloride or trifluoroacetic acid is preferred.

[0500] The inert solvent is an alcohol such as methanol, ethanol or isopropanol; an ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane, dichloromethane; a polar aprotic solvent such as acetonitrile or N,N-dimethylformamide (DMF) or a mixture of such solvents; 1,4-dioxane is preferred.

[0501] The compounds of formula (IX) are novel.

[0502]

[0503] Where R 1 and R 2 As defined above.

[0504] The compound of formula (IX) can be prepared as follows:

[0505] [N] By reacting a compound of formula (X) with a compound of formula (XI) in a solvent,

[0506]

[0507] Where R 1 and R 2 As defined above,

[0508]

[0509] Reaction [N] (Pyrazole formation)

[0510] The reaction [L] is usually carried out in a solvent at room temperature to reflux temperature.

[0511] Suitable solvents include alcohols such as methanol, ethanol, or isopropanol; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane, dichloromethane; polar aprotic solvents such as acetonitrile or N,N-dimethylformamide (DMF) or mixtures of these solvents; ethanol is preferred.

[0512] The compounds of formula (XI) are known or can be synthesized from the corresponding starting compounds by known methods.

[0513] The compound of formula (X) is novel.

[0514]

[0515] Where R 1 and R 2 As defined above.

[0516] Compounds of formula (X) can be prepared as follows:

[0517] [O] By reacting the compound of formula (XII) with palladium on carbon in the presence of hydrogen in a suitable solvent,

[0518]

[0519] Where R 1 and R 2 As defined above.

[0520] The reaction [O](Z deprotection)

[0521] The reaction [O] is typically carried out in a suitable solvent in the presence of palladium on carbon at room temperature to reflux temperature, preferably at 1 bar.

[0522] 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; and polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), NMP, acetic acid or water or mixtures of such solvents; preferably ethanol / acetic acid.

[0523] The compound of formula (XII) is novel.

[0524]

[0525] Where R 1 and R 2 As defined above.

[0526] Compounds of formula (XII) can be prepared as follows:

[0527] [P] By reacting a compound of formula (XIII) with a compound of formula (XIV) in the presence of a reducing agent and a suitable solvent,

[0528]

[0529] Where R 1 and R 2 As defined above

[0530]

[0531] The compounds of formula (XIV) are known and commercially available, or can be synthesized from the corresponding starting compounds by known methods.

[0532] The compounds of formula (XIII) are known and commercially available, or can be synthesized from the corresponding starting compounds by known methods.

[0533] The preparation of the starting compound and the compound of formula (I) can be described by the following synthetic schemes 1 to 4.

[0534] Option 1

[0535]

[0536] Option 2

[0537]

[0538] Option 3

[0539]

[0540] Option 4

[0541]

[0542]

[0543]

[0544] The compounds of this invention have important pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0545] The compounds of this invention are potent activators of soluble guanylate cyclase. These compounds induce vasodilation, inhibit platelet aggregation, lower blood pressure, and increase coronary and renal blood flow. These effects are mediated by direct, heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP.

[0546] Furthermore, the compounds of the present invention have favorable pharmacokinetic properties, particularly in terms of their bioavailability and / or duration of action after intravenous or oral administration.

[0547] Compared to compounds disclosed in the prior art (WO 2012 / 058132, e.g., Example 174), the compounds of the present invention exhibit superior pharmacokinetic (PK) properties (see Experimental Section, Tables 3-4). The examples shown in the present invention exhibit lower plasma clearance (CL) in rats compared to the prior art compounds disclosed as Example 174 in WO 2012 / 058132. 血浆 and the resulting higher exposure levels (AUC) 标准 The half-life and mean residence time (MRT) of most of the embodiments were within a comparable range after intravenous (iv) administration. However, Example 20 showed a longer half-life and mean residence time (MRT). Following oral (po) administration in rats (see Experimental Section, Table 4), most of the embodiments (except Example 19) did indeed show equivalent to higher exposures (AUC) compared to the prior art compound disclosed as Example 174 in WO 2012 / 058132. 标准 ).

[0548] The compounds of this invention possess an unpredictable and useful pharmacological activity spectrum and favorable pharmacokinetic behavior, particularly with adequate blood exposure above the minimum effective concentration within a given dosing interval after oral administration. This characteristic results in an increased peak-to-trough ratio (the quotient of the maximum and minimum concentrations) within a given dosing interval, which has the advantage of allowing the compound to be administered at less frequency and significantly lower doses to achieve its effect. They are compounds that activate soluble guanylate cyclase.

[0549] In the context of this invention, the term "treatment" or "treating" includes the suppression, delay, obstruction, relief, mitigation, limitation, weakening, prevention, resistance, or cure of a disease, symptom, obstacle, injury, or health problem, or the development, course, or progression of these conditions and / or symptoms of these conditions. The term "therapy" is hereby understood to be synonymous with the term "treatment."

[0550] In the context of this invention, “prevention,” “prophylaxis,” and “preclusion” are used as synonyms, referring to avoiding or reducing the risk of the development or progression of infection, illness, ailment, disorder, injury, or health problem, or the symptoms of these conditions.

[0551] Treatment or prevention of disease, ailment, disability, injury, or health problem may be partial or complete.

[0552] Furthermore, the compounds of the present invention have other superior properties, particularly in terms of their lung-selective effect (compared to systemic effects), lung retention time, and / or duration of effect after intrapulmonary administration.

[0553] The compounds of the present invention are particularly suitable for the treatment and / or prevention of vascular and cardiac diseases, heart and kidney diseases, cardiopulmonary and pulmonary diseases, thromboembolic diseases, fibrotic diseases and / or wound healing disorders.

[0554] The compounds of the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF), hypertension (HTN), peripheral artery disease (PAD, PAOD); cardiorenal and kidney diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD); cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH) and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrotic diseases; systemic sclerosis (SSc), sickle cell disease (SCD), and wound healing disorders such as diabetic foot ulcers (DFU).

[0555] Therefore, the compounds of the present invention can be used in medicaments for the treatment and / or prevention of the following diseases, such as cardiovascular, cardiopulmonary, and cardiorenal diseases, including hypertension (hypertension), heart failure, coronary artery disease, stable and unstable angina, pulmonary arterial hypertension (PAH) and secondary pulmonary arterial hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal hypertension, renovascular hypertension and refractory hypertension, peripheral and cardiovascular diseases, arrhythmias, atrial and ventricular arrhythmias and conduction disorders, such as grade I-III atrioventricular block, supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachycardia, torsades de pointes, atrial and ventricular premature contractions, atrioventricular junctional premature contractions, sick sinus syndrome, syncope, atrioventricular nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), and so on. This medication is used to treat and / or prevent diseases such as autoimmune heart disease (pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy), Boxer cardiomyopathy, aneurysm, shock such as cardiogenic shock, septic shock, and anaphylactic shock. It is also used in medications for the treatment and / or prevention of diseases such as thromboembolic diseases and local ischemia such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient ischemic attack, preeclampsia, inflammatory cardiovascular diseases, coronary and peripheral artery spasm, edema such as pulmonary edema, cerebral edema, renal edema, or edema caused by heart failure, impaired peripheral perfusion, reperfusion injury, arterial and venous thrombosis, microalbuminuria, heart failure, endothelial dysfunction, microvascular and large vessel injury (vasculitis), and to prevent restenosis following procedures such as thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation, and bypass surgery.

[0556] In the context of this invention, the term “pulmonary hypertension” includes two subtypes: primary and secondary, as defined below according to their respective etiologies in the Dana Point classification [see D. Montana and G. Simonneau, in the following articles: AJPeacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206; M. Hoeper et al., J. Am. Coll. Cardiol. 2009, 54(1), S85-S96]. These specifically include Group 1 pulmonary hypertension (PAH), which includes idiopathic and familial forms (IPAH and FPAH, respectively). In addition, pulmonary hypertension also includes persistent pulmonary hypertension in newborns and associated pulmonary hypertension (APAH) associated with the following conditions: collagenous disorders, congenital systemic pulmonary shunts, portal hypertension, HIV infection, intake of certain medications and agents (e.g., appetite suppressants), diseases with a significant venous / capillary component such as pulmonary venous occlusion and pulmonary capillary hemangioma, or other conditions such as thyroid disease, glycogen storage disease, Gaucher disease, hereditary teleangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. Group 2 of the Dana Point classification includes patients with pulmonary hypertension due to left ventricular disease (e.g., ventricular, atrial, or valvular disease). Group 3 includes forms of pulmonary hypertension associated with lung diseases (e.g., chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary fibrosis (IPF)) and / or hypoxemia (e.g., sleep apnea syndrome, alveolar hypoventilation, chronic high altitude sickness, hereditary malformations)). Group 4 includes patients with pulmonary hypertension who have chronic thrombotic and / or embolic diseases, such as proximal and distal pulmonary thromboembolic occlusion (CTEPH) or non-thrombotic embolism (e.g., due to tumors, parasites, foreign bodies, etc.). Group 5 summarizes less common forms of pulmonary hypertension, such as those present in patients with sarcoidosis, histiocytosis X, or lymphangioma.

[0557] In the context of this invention, the term "heart failure" includes acute heart failure and chronic heart failure, as well as more specific or related types of diseases such as acute decompensated heart failure, right heart failure, left heart failure, biventricular heart failure, diastolic heart failure and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with moderate ejection fraction (HFmEF), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease and cardiomyopathy, valvular heart defects, heart failure associated with valvular heart defects, mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, tricuspid stenosis, tricuspid regurgitation, pulmonary stenosis, pulmonary regurgitation, mixed valvular heart defects, myocarditis (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, and cardiac storage diseases.

[0558] In addition, the compounds of the present invention can also be used to treat and / or prevent arteriosclerosis, lipid metabolism disorders, hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, mixed hyperlipidemia, hypercholesterolemia, abeta-lipoproteinemia, sitosterolemia, xanthomas, Tangier disease, obesity, and metabolic syndrome.

[0559] Furthermore, the compounds of the present invention can be used to treat and / or prevent primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, hearing impairment, tinnitus, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcers, gangrene, CREST syndrome, lupus erythematosus, onychomycosis, and rheumatism.

[0560] Furthermore, the compounds of this invention can be used to treat sickle cell disease (SCD), sickle cell anemia, and other symptoms of diseases associated with sickle cell disease (e.g., end-organ damage affecting the lungs, brain, kidneys, or heart), as well as vascular occlusive events or pain crises such as malaria, thalassemia, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemia, or rhabdomyopathies, achalasia, and hemolytic angiopathy. Moreover, since similar pathophysiological mechanisms are effective in transfusing blood to patients with indications for transfusion (e.g., by increasing free hemoglobin concentration through storage), these compounds can be used in patients receiving transfusions. Finally, in the future, the combination of sGC activators with synthetic hemoglobin-like oxygen carriers may alleviate the side effects caused by reduced NO availability that have been identified to date [Weiskopf, Anesthesia & Analgesia, 110:3; 659-661, 2010], thereby allowing for further clinical applications.

[0561] The compounds of the present invention can also be used to prevent ischemic injury and / or reperfusion-related injury to organs or tissues, and can also be used as additives to perfusion and preservation solutions of organs, organ parts, tissues or tissue parts derived from humans or animals, particularly in the fields of surgical intervention or transplant medicine.

[0562] Furthermore, the compounds of this invention are suitable for the treatment and / or prevention of kidney diseases, particularly renal insufficiency and renal failure. In the context of this invention, renal insufficiency and renal failure include acute and chronic symptoms (chronic kidney disease; CKD), as well as underlying or related kidney diseases such as renal hypoperfusion, dialysis-related hypotension, obstructive urinary tract disease, glomerulonephropathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, kidney diseases such as primary and congenital kidney diseases, nephritis, immune-mediated kidney diseases such as kidney transplant rejection and immune complex-induced kidney diseases, toxic substance-induced kidney diseases, and contrast agent-induced kidney diseases. Diabetic and non-diabetic nephropathy, diabetic nephropathy (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, characterized by features such as abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme (e.g., gamma-glutamyl synthase) activity, altered urine osmolality or volume, increased microalbuminuria or macroalbuminuria, glomerular and arteriolar damage, renal tubular dilatation, hyperphosphatemia, and / or the need for dialysis. This invention also covers the use of the compounds of this invention in the treatment and / or prevention of the sequelae of renal insufficiency, such as hypertension, pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hypercalcemia, hyponatremia), and bone and carbohydrate metabolism disorders.

[0563] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of urinary system diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), urinary incontinence (e.g., mixed, urge, stress, or overflow urinary incontinence (MUI, UUI, SUI, OUI)), pelvic pain, interstitial cystitis (IC), as well as erectile dysfunction and female sexual dysfunction.

[0564] The compounds of the present invention are also suitable for the treatment and / or prevention of asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), α-1 antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (e.g., emphysema caused by cigarette smoke) and cystic fibrosis (CF).

[0565] The compounds described in this invention are also active compounds for the prevention and treatment of central nervous system diseases characterized by NO / cGMP system disorders. They are particularly suitable for improving perception, attention, learning, or memory following cognitive impairment, such as those associated with conditions / diseases / syndromes including: mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia, post-traumatic brain injury, general attention deficit, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontal lobe degenerative dementia including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, corticobasal degenerative dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating diseases, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia, or Korsakoff psychosis. They are also applicable to the treatment and / or prevention of central nervous system disorders, such as states of anxiety, tension and depression, central nervous system-related sexual dysfunction and sleep disorders, as well as pathological disorders for controlling the intake of food, stimulants and addictive substances.

[0566] Furthermore, the compounds of the present invention are also suitable for regulating cerebral blood flow, and are therefore effective agents for controlling migraines. The compounds of the present invention are also suitable for preventing and controlling sequelae of cerebral infarction (stroke), such as stroke, cerebral ischemia, and traumatic brain injury. The compounds of the present invention can also be used to control pain states.

[0567] Furthermore, the compounds of the present invention have anti-inflammatory effects and can therefore be used as anti-inflammatory drugs for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory kidney disease, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases, and inflammatory eye diseases.

[0568] Furthermore, the compounds of the present invention are also suitable for treating and / or preventing fibrotic diseases of visceral organs such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatological fibrosis and ocular fibrosis. In the context of this invention, the term "fibrotic disease" specifically includes diseases such as liver fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, endocardial myocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic diseases, scleroderma, systemic sclerosis, morphine, keloids, hypertrophic scars, nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue diseases (e.g., sarcoidosis). The compounds of the present invention can also be used to promote wound healing, including the healing of finger ulcers and diabetic foot ulcers, to control postoperative scarring, such as scars caused by glaucoma surgery, and for cosmetic purposes on aging and keratinized skin.

[0569] Based on their active properties, the compounds of the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and cardiopulmonary diseases, such as primary and secondary pulmonary hypertension, heart failure, angina pectoris and hypertension, and also for the treatment and / or prevention of thromboembolic diseases, local ischemia, vascular diseases, impaired microcirculation, renal insufficiency, fibrotic diseases and arteriosclerosis.

[0570] The present invention also provides the use of the compounds of the present invention for the treatment and / or prevention of diseases, particularly the aforementioned diseases.

[0571] The present invention also provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing diseases, particularly the aforementioned diseases.

[0572] The present invention also provides a medicament comprising at least one compound of the present invention for treating and / or preventing diseases, particularly the aforementioned diseases.

[0573] The present invention also provides the use of the compounds of the present invention in methods for treating and / or preventing diseases, particularly the aforementioned diseases.

[0574] The present invention also provides a method for treating and / or preventing diseases, particularly the aforementioned diseases, using an effective amount of at least one compound of the present invention.

[0575] Therefore, the compounds of the present invention are suitable for use as medicines for treating and / or preventing diseases in humans and animals.

[0576] The present invention further provides the use of the compounds of the present invention for the treatment and / or prevention of diseases, particularly cardiovascular diseases, preferably thrombotic diseases or thromboembolic diseases and / or thrombotic complications or thromboembolic complications, such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral artery occlusive disease, and / or diabetes, and / or genitourinary diseases, especially those associated with these diseases.

[0577] For the purposes of this invention, "thrombotic disease or thromboembolic disease" includes diseases preferably occurring within arterial vessels and treatable with the compounds of this invention, particularly diseases causing peripheral arterial occlusion and diseases occurring within the coronary arteries of the heart, such as acute coronary syndrome (ACS), ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis following coronary interventions (such as angioplasty, stenting, or aortic coronary artery bypass grafting), and thrombotic or thromboembolic diseases in cerebrovascular vessels, such as transient ischemic attack (TIA), ischemic stroke including cardiogenic stroke such as stroke caused by atrial fibrillation, non-cardiogenic stroke such as lacunar stroke, stroke caused by disease of large or small arteries, or stroke due to uncertain factors, cryptogenic stroke, embolic stroke, embolic stroke of unknown origin, or thrombotic and / or thromboembolic origin events leading to stroke or TIA.

[0578] Furthermore, the compounds of the present invention are particularly suitable for treating and / or preventing diseases in which pro-inflammatory components play an important role, including vasculitis such as Kawasaki disease, aortitis, and thromboangiitis obliterans (Bergler's disease), as well as inflammatory diseases such as myocarditis.

[0579] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of urogenital diseases such as overactive bladder, interstitial cystitis, and bladder pain syndrome.

[0580] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of diabetes, including its end-organ manifestations such as diabetic retinopathy and diabetic nephropathy.

[0581] Furthermore, the compounds of the present invention are particularly suitable for the treatment and / or prevention of neurological diseases such as neuropathic pain, neurodegenerative diseases, and dementias such as vascular dementia or Alzheimer's disease and Parkinson's disease.

[0582] Furthermore, the compounds of the present invention are particularly suitable for the treatment and / or prevention of lung diseases such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD).

[0583] The present invention further provides the use of the compounds of the present invention for treating and / or preventing diseases, especially the aforementioned diseases.

[0584] The present invention further provides the use of the compounds of the present invention in the preparation of medicaments for treating and / or preventing diseases, especially the aforementioned diseases.

[0585] The present invention further provides a method for treating and / or preventing diseases, particularly the aforementioned diseases, using a therapeutically effective amount of the compound of the present invention.

[0586] The present invention further provides the compounds of the present invention for use in methods of treating and / or preventing diseases, especially the aforementioned diseases, wherein the method uses a therapeutically effective amount of the compounds of the present invention.

[0587] This invention specifically provides compounds of the invention for use in methods of treating and / or preventing thrombotic or thromboembolic diseases, particularly atherosclerotic thrombotic diseases, wherein the method uses a therapeutically effective amount of the compounds of the invention.

[0588] The present invention further provides a medicament comprising the compounds of the present invention and one or more other active compounds.

[0589] Furthermore, the compounds of the present invention can also be used to prevent in vitro clotting, for example, to protect organs to be transplanted from organ damage caused by blood clot formation and to protect organ recipients from thromboembolism from transplanted organs, to preserve blood and plasma products, to clean / pretreat catheters and other medical assistive devices and instruments, to coat synthetic surfaces of medical assistive devices and instruments used in vivo or in vitro, or to biological samples that may contain factor XIa or plasma kallikrein.

[0590] The present invention further provides a method for preventing blood clotting in vitro, particularly in banked blood or biological samples that may contain factor XIa or plasma kallikrein or both of these enzymes, characterized by the addition of an effective amount of the compound of the present invention for anticoagulation.

[0591] The compounds of the present invention can act systemically and / or locally. Therefore, they can be administered in suitable ways, such as via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival, or auditory canal routes, or as implants or stents.

[0592] For these routes of administration, the compounds of the present invention can be administered in a suitable form.

[0593] For oral administration, the compounds of the present invention can be formulated into dosage forms known in the art for rapid and / or improved delivery of the compounds of the present invention, such as tablets (uncoated or coated tablets, e.g., enteric or controlled-release coatings with delayed dissolution or non-dissolution), orally disintegrating tablets, films / capsules, films / lyophilized forms, capsules (such as hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. The compounds of the present invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved forms.

[0594] Parenteral administration can be performed without absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or including absorption steps (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable forms of administration for parenteral administration are especially preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized forms, or sterile powders.

[0595] Suitable for extraocular (topical) administration are administration forms operated according to existing technology that release the active compound rapidly and / or in an improved or controlled manner, and contain the active compound in crystalline and / or amorphous and / or dissolved forms, such as eye drops, sprays, and lotions (e.g., solutions, suspensions, vesicle / colloid systems, emulsions, aerosols), powders for eye drops, sprays, and lotions (e.g., ground active compounds, mixtures, lyophilized substances, precipitated active compounds), semi-solid ocular preparations (e.g., hydrogels, in situ hydrogels, creams, and ointments), and ocular introductions (solid and semi-solid preparations, such as bioadhesives, films / capsules, tablets, and contact lenses).

[0596] Intraocular drug delivery includes, for example, intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar, and subconjunctival administration. Suitable forms of administration for intraocular drug delivery are those operating according to existing technology that rapidly and / or in a modified or controlled manner release the active compound and contain the active compound in crystalline and / or amorphous and / or dissolved forms, such as injectable formulations and concentrates of injectable formulations (e.g., solutions, suspensions, vesicle / colloid systems, emulsions), powders of injectable formulations (e.g., ground active compounds, mixtures, lyophilized substances, precipitated active compounds), injectable formulation gels (semi-solid formulations, such as hydrogels, in-situ hydrogels), and implants (solid formulations, such as biodegradable and non-biodegradable implants, implantation pumps).

[0597] Oral administration is preferred.

[0598] Examples of other routes of administration include inhaled drug forms [especially powder inhalers and sprays], nasal drops, nasal solutions, and nasal sprays; tablets / films / capsules / sacs for administration via the tongue, sublingually, or orally; suppositories; eye drops, eye ointments, eye washes, eye inserts, ear drops, ear sprays, ear powders, ear washes, and ear plugs; vaginal capsules, aqueous suspensions (washes, shaken mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapy systems (e.g., patches), lotions, pastes, foams, powders, implants, or stents.

[0599] The compounds of the present invention can be incorporated into the described dosage form. This can be achieved by mixing with pharmaceutically suitable excipients in a manner known per se. Pharmaceutically suitable excipients include, in particular,

[0600] • Fillers and carriers (e.g., cellulose, microcrystalline cellulose) ), lactose, mannitol, starch, calcium phosphate (e.g.) )),

[0601] • Ointment base (e.g., petroleum glue, paraffin, triglycerides, wax, lanolin, lanolin alcohol, hydrophilic ointment, polyethylene glycol),

[0602] • Suppository base (e.g., polyethylene glycol, cocoa butter, stearin),

[0603] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0604] Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g.) ), sorbitol fatty acid esters (e.g. ), polyoxyethylene sorbitan fatty acid esters (e.g.) ), polyoxyethylene fatty acid glycerides (e.g. ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamer (e.g.) ),

[0605] • Buffers, acids, and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, thiamin, triethanolamine),

[0606] • Isotonic agents (e.g., glucose, sodium chloride),

[0607] • Adsorbent (e.g., highly dispersed silica),

[0608] • Tackifiers, gelling agents, thickeners and / or adhesives (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g.) (); alginate, gelatin),

[0609] • Disintegrants (e.g., modified starch, sodium carboxymethyl cellulose, sodium glycolate starch (e.g.) ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g.) )),

[0610] • Flow conditioners, lubricants, flow aids, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g.) )),

[0611] • Coating materials (e.g., sugar, shellac) and film-forming agents for rapidly dissolving or in a modified manner dissolving films or diffusion films (e.g., polyvinylpyrrolidone). Polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate, etc. ),

[0612] • Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[0613] • Synthetic polymers (e.g., polylactic acid, polyglycolic acid, polyacrylate, polymethacrylate) ), polyvinylpyrrolidone (e.g.) Polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers),

[0614] Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerin, triacetyl triacetate, triacetyl citrate, dibutyl phthalate),

[0615] • Penetration enhancer

[0616] • Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[0617] • Preservatives (such as parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0618] • Colorants (e.g., inorganic pigments, such as iron oxide and titanium dioxide),

[0619] • Flavoring agents, sweeteners, flavor and / or odor masking agents.

[0620] The present invention also relates to a pharmaceutical composition comprising at least one compound of the present invention, typically together with one or more pharmaceutically suitable excipients, and to their use according to the present invention.

[0621] One embodiment of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) of the present invention, preferably together with at least one inert, non-toxic, pharmaceutically suitable excipient, and use of such pharmaceutical composition for the above-mentioned purpose.

[0622] According to another aspect, the present invention covers pharmaceutical compositions, particularly medicines, which comprise at least one compound of the general formula (I) of the present invention and at least one or more other active ingredients, particularly for the treatment and / or prevention of cardiovascular diseases, preferably thrombotic or thromboembolic diseases and diabetes, as well as genitourinary and ophthalmic diseases.

[0623] The term "combination" in this invention is used as is known to those skilled in the art, and the combination can be a fixed combination, a non-fixed combination, or a kit-of-part component.

[0624] The term "fixed combination" in this invention, as known to those skilled in the art, is defined as a combination in which, for example, a first active ingredient such as one or more compounds of general formula (I) of this invention, and other active ingredients are present together in a unit dose or a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and other active ingredients are present in a mixture such as a formulation for simultaneous administration. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and other active ingredients are present in a single unit rather than in a mixture.

[0625] The non-fixed combination or "kit component" of the present invention is as known to those skilled in the art and is defined as a combination in which a first active ingredient and other active ingredients are present in more than one unit. An example of a non-fixed combination or kit component is a combination in which the first active ingredient and other active ingredients are present separately. The components of a non-fixed combination or kit component may be administered individually, sequentially, simultaneously, concurrently, or in a time-sequential manner.

[0626] The compounds of the present invention can be used alone or, if desired, in combination with other active ingredients. The present invention further provides medicaments comprising at least one compound of the present invention and one or more other active ingredients, particularly medicaments for treating and / or preventing the aforementioned diseases. Preferred examples of suitable combinations of active ingredients include:

[0627] • Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0628] • Compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP), such as phosphodiesterase (PDE) 1, 2, 5 and / or 9 inhibitors, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, mirodenafil, lodenafil or PF-00489791;

[0629] • Compounds that inhibit the breakdown of cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 3 and 4 inhibitors, especially cilostazol, milrinone, roflumilast, apremilast, or crisaborole.

[0630] • Active ingredients that lower blood pressure, such as and preferably calcium channel blockers, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, neutral endopeptidase (NEP) inhibitors, angiopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, p-kinase inhibitors, and diuretics;

[0631] • Antiarrhythmic drugs, such as and preferably sodium channel blockers, beta-blockers, potassium channel blockers, calcium channel blockers, If-channel blockers, digitalis, parasympathetic blockers, sympathomimetic drugs and other antiarrhythmic drugs such as adenosine, adenosine receptor agonists and vernakalant;

[0632] • Positive cardiotonic agents, such as cardiac glycosides (Dogoxin), β-adrenergic and dopaminergic agonists, such as isoproterenol, epinephrine, noradrenaline, dopamine or dobutamine;

[0633] • Vasopressin receptor antagonists, such as and preferably the compounds described in WO2010 / 105770, WO2011 / 104322 and WO 2016 / 071212;

[0634] • Active ingredients that alter lipid metabolism, such as, and preferably, thyroid receptor agonists, cholesterol synthesis inhibitors, such as, and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, lipase inhibitors, polymerized bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein(a) antagonists.

[0635] • Bronchodilators, such as and preferably β-adrenergic receptor agonists, such as and preferably salbutamol, isoproterenol, orsinol, terbutaline, formoterol or salmeterol; or anticholinergic drugs, such as and preferably ipratropium bromide;

[0636] • Anti-inflammatory agents, such as and preferably glucocorticoids, such as and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolone, budesonide or fluticasone; and nonsteroidal anti-inflammatory drugs (NSAIDs), such as and preferably acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5-aminosalicylic acid derivatives, leukotriene antagonists, TNF-α inhibitors and chemokine receptor antagonists, such as CCR1, 2 and / or 5 inhibitors;

[0637] • Medications that regulate the immune system, such as immunoglobulins;

[0638] • Drugs that inhibit signal transduction cascades, such as, and preferably, kinase inhibitors, such as, and preferably, tyrosine kinase and / or serine / threonine kinase inhibitors;

[0639] • Drugs that inhibit the degradation and modification of the extracellular matrix, such as and preferably matrix metalloproteinase (MMP) inhibitors, such as and preferably inhibitors of chymotrypsin, matrix lysin, collagenase, gelatinase and proteoglycanase (preferably MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13), as well as inhibitors of metalloelastase (MMP-12) and neutrophil elastase (HNE), such as cevelexat or DX-890;

[0640] • Drugs that block the binding of serotonin to its receptors, such as, and preferably, 5-HT2b receptor antagonists;

[0641] • Organic nitrates and NO donors, such as and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0642] • A NO-independent but heme-dependent stimulant for soluble guanylate cyclase, such as and preferably the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO2012 / 028647 and WO 2012 / 059549;

[0643] • A NO-independent but heme-dependent activator of soluble guanylate cyclase, such as and preferably the compounds described in WO01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510;

[0644] • Drugs that stimulate the synthesis of cyclic guanosine monophosphate, such as soluble guanylate cyclase modulators, such as and preferably riociguat, cinaciguat, vericiguat, or runcaciguat;

[0645] • Prostacyclin analogues, such as and preferably iloprost, belaprost, treprost, or eprostol;

[0646] • Drugs that inhibit soluble epoxide hydrolase (sEH), such as and preferably N,N'-dicyclohexylurea, 12-(3-adamantane-1-ylureido)-dodecanoic acid or 1-adamantane-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea;

[0647] • Drugs that interact with glucose metabolism, such as and preferably insulin, biguanide, thiazolidinedione, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-2 inhibitors, such as empagliflozin, dapagliflozin, canagliflozin, soragliflozin;

[0648] • Natriuretic peptides, such as and preferably atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, Nesiritid), natriuretic peptide type C (CNP), or urodilatin;

[0649] • Activators of cardiac myosin, such as and preferably omecamtiv mecarbil (CK-1827452);

[0650] • Calcium sensitizers, such as, and preferably, levosimendan;

[0651] • Drugs that affect cardiac energy metabolism, such as and preferably etomoxi, dichloroacetate, ranolazine or trimetazine, complete or partial adenosine A1 receptor agonists, such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate.

[0652] • Medications that affect heart rate, such as, and preferably, ivabradine;

[0653] • Cyclooxygenase inhibitors, such as bromfenac and nepafenamide;

[0654] • Inhibitors of the kallikrein-kinin system, such as saliband and icarapotetide;

[0655] • Inhibitors of the sphingosine 1-phosphate signaling pathway, such as sonepcizumab;

[0656] • Complement C5a receptor inhibitors, such as eculizumab;

[0657] • Plasminogen activators (thrombolytics / fibrinolytics) and compounds that promote thrombolysis / fibrinolysis, such as inhibitors of plasminogen activator inhibitors (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitors (TAFI inhibitors), such as tissue plasminogen activator (t-PA, e.g. Streptokinase, reteplase, and urokinase, or plasminogen regulators that lead to increased plasmin formation;

[0658] • Anticoagulants, such as heparin (UFH), low molecular weight heparin (LMW), such as tinzaparin, sertoparin, parheparin, nadroparin, adeparin, enoxaparin, low molecular weight heparin, dalteparin, danateparin, smoparin (AVE5026), adorimiparin (M118) and EP-42675 / ORG42675;

[0659] • Direct thrombin inhibitors (DTIs), such as Pradaxa (dabigatran), ategatran (AZD-0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanoside (BIBT-986 and prodrug BIBT-1011) and hirudin;

[0660] • Direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban (DU-176b), betraxaban (PRT-54021), R-1663, darixaban (YM-150), omexaban (FXV-673 / RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanojugrandiol (BIBT-986, prodrug: BIBT-1011), epoxetine, and fondaparinux.

[0661] • Inhibitors of coagulation factors XI and XIa, such as FXI ASO-LICA, fesomersen, BAY121-3790, MAA868, BMS986177, EP-7041, and AB-022;

[0662] • Substances that inhibit platelet aggregation (platelet aggregation inhibitors, serum cell aggregation inhibitors), such as acetylsalicylic acid (e.g., aspirin), P2Y12 antagonists, such as ticlopidine (ticlad), clopidogrel (pulidone), prasugrel, ticagrelor, canagrelor and enoxaparin, as well as PAR-1 antagonists, such as vorapazol and PAR-4 antagonists;

[0663] • Platelet adhesion inhibitors, such as GPVI and / or GPIb antagonists, such as Revacept or caplacizumab;

[0664] • Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists), such as abciximab, epitubatide, tirofiban, lamifiban, legafiban, and frafafiban;

[0665] • Recombinant human activated protein C, such as thrombectomycin (Xigris) or recombinant thrombomodulin.

[0666] Antithrombotic agents are preferably understood as compounds derived from platelet aggregation inhibitors, anticoagulants, or fibrinolytic substances.

[0667] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a platelet aggregation inhibitor, such as and preferably aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, or dipyridamole.

[0668] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thrombin inhibitor, such as and preferably tamegatran, dabigatran, melagatan, bivalirudin, or ketamine.

[0669] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a GPIIb / IIIa antagonist, such as, and preferably, tirofiban or abciximab.

[0670] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with factor Xa inhibitors, such as and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, betraxaban, omexaban, fildexaban, razaxan, letaxaban, eribaxaban, fondaparinux sodium, epoxetine, PMD-3112, darixaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

[0671] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an inhibitor of factor XI or factor XIa, such as and preferably FXI ASO-LICA, fexomethenol, BAY 121-3790, MAA868, BMS986177, EP-7041 or AB-022.

[0672] In a preferred embodiment of the invention, the compound of the invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0673] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vitamin K antagonist, such as, and preferably, coumarin.

[0674] Antihypertensive agents are preferably understood to be compounds selected from calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, p-kinase inhibitors, and diuretics.

[0675] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcium antagonist, such as and preferably nifedipine, amlodipine, verapamil, or diltiazem.

[0676] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an α-1-receptor blocker, such as, and preferably, prazosin.

[0677] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a β-receptor blocker, such as and preferably propranolol, atenolol, timolol, indolol, alpraolol, metenprol, pentbuprol, blavolol, metenprol, nadolol, metindotin, carazalol, sotalol, metoprolol, betalol, celylolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adalolol, landilolol, nebivolol, epamnolol, or buxinolol.

[0678] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an angiotensin II antagonist, such as and preferably losartan, candesartan, valsartan, telmisartan or embusartan, or in combination with a dual angiotensin II antagonist / neprilysin inhibitor, such as and preferably LCZ696 (valsartan / sacubitril).

[0679] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril, or trandopril.

[0680] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an endothelin antagonist, such as and preferably bosentan, darushentan, ambesentan or sitashentan.

[0681] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a renin inhibitor, such as and preferably aliskiren, SPP-600 or SPP-800.

[0682] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a mineralocorticoid receptor antagonist, such as and preferably spironolactone, AZD9977, fenelitonee or eplerenone.

[0683] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with the following substances: loop diuretics, such as furosemide, torasemide, bumetanide, and pyrrolizidine; potassium-sparing diuretics, such as amiloride and triamterene; aldosterone antagonists, such as spironolactone, canilenate potassium, and eplerenone; and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, sipamide, and indapamide.

[0684] Lipid metabolism regulators are preferably understood to be compounds selected from the following: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymerized bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0685] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CETP inhibitor, such as and preferably dacetrapip, acetrapip, tochepus (CP-529 414), JJT-705 or the CETP vaccine (Avant).

[0686] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thyroid receptor agonist, such as and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or acitirox (CGS26214).

[0687] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a statin HMG-CoA reductase inhibitor, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0688] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

[0689] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACAT inhibitor, such as and preferably avamidib, methyllinoleamide, partemidib, irubib, or SMP-797.

[0690] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an MTP inhibitor, such as and preferably impetatae, BMS-201038, R-103757 or JTT-130.

[0691] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-γ agonist, such as and preferably pioglitazone or rosiglitazone.

[0692] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a PPAR-δ agonist, such as and preferably GW 501516 or BAY 68-5042.

[0693] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tequila, or pambroside.

[0694] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipase inhibitor, a preferred example being orlistat.

[0695] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a polymeric bile acid adsorbent, such as and preferably cholestyramine, colestipol, colesolvam, colestigule, or colestilan.

[0696] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a bile acid reabsorption inhibitor, such as and preferably an ASBT (=IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0697] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipoprotein (a) antagonist, such as and preferably gemcarbene calcium (CI-1027) or niacin.

[0698] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a lipoprotein (a) antagonist, such as and preferably gemcarbene calcium (CI-1027) or niacin.

[0699] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an sGC modulator, such as and preferably riociguat, cinaciguat, or veliciguat.

[0700] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with drugs that affect glucose metabolism, such as and preferably insulin, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors empagliflozin, dapagliflozin, canagliflozin, and soragliflozin.

[0701] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a TGFβ antagonist, such as, and preferably, pirfenidone or fresolimumab.

[0702] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CCR2 antagonist, such as and preferably CCX-140.

[0703] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a TNFα antagonist, such as, and preferably, adalimumab.

[0704] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a galactolectin-3 inhibitor, such as and preferably GCS-100.

[0705] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an Nrf-2 inhibitor, such as, and preferably, bardoxazoline.

[0706] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a BMP-7 agonist, such as and preferably THR-184.

[0707] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a NOX1 / 4 inhibitor, such as and preferably GKT-137831.

[0708] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug that affects vitamin D metabolism, such as and preferably calcitriol, alfacalcidol, ducalcidol, mascalcalcidol, paricalcitol, cholecalciferol, or paracalcitol.

[0709] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a cell growth inhibitor, such as, and preferably, cyclophosphamide.

[0710] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an immunosuppressant, such as, and preferably, cyclosporine.

[0711] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a phosphate binder, such as and preferably colestilan, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[0712] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a proximal renal tubular phosphate cotransporter, such as and preferably nicotinic acid or nicotinamide.

[0713] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a calcimimetic agent for the treatment of hyperparathyroidism.

[0714] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug for treating iron deficiency, such as, and preferably, an iron product.

[0715] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a drug for treating hyperuricemia, such as, and preferably, allopurinol or raburicase.

[0716] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a glycoprotein hormone for treating anemia, such as and preferably erythropoietin, dapoxetine, molistat, roxadustat, vadadustat, or dedustat.

[0717] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a biological agent for immunotherapy, such as and preferably abatacept, rituximab, eculizumab or belimumab.

[0718] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a vasopressin antagonist (vaptanes) for the treatment of heart failure, such as and preferably tolvaptan, conivatan, lisiputan, mozavaptan, shadavaptan, pecavaptan, or relcovaptan.

[0719] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a Jak inhibitor, such as and preferably ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, retasinib, paricitinib (SB1518) or TG101348.

[0720] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a prostacyclin analogue for treating microthrombosis.

[0721] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an alkaline therapy drug, such as, and preferably, sodium bicarbonate.

[0722] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an mTOR inhibitor, such as and preferably everolimus or rapamycin.

[0723] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an NHE3 inhibitor, such as and preferably AZD1722 or ternapanol.

[0724] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an eNOS modulator, such as, and preferably, sapropterin.

[0725] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CTGF inhibitor, such as and preferably FG-3019.

[0726] The present invention further provides a medicament comprising at least one compound of the present invention, typically with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and provides use of the medicament for the aforementioned purposes.

[0727] The compounds of the present invention can act systemically and / or locally. Therefore, they can be administered in suitable ways, such as via oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, dermal, transdermal, conjunctival, or ocular routes, or as implants or scaffolds.

[0728] The compounds of the present invention can be administered in a manner suitable for these routes of administration.

[0729] Suitable forms of administration for oral administration are those that function according to the prior art, which rapidly and / or in an improved manner release the compound of the invention, and contain the compound of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example having an anti-gastric juice or slow-dissolving or insoluble coating that controls the release of the compound of the invention), tablets or films / capsules that rapidly disintegrate in the oral cavity, films / lyophilized forms or capsules (e.g., hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions.

[0730] Parenteral administration can bypass absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or include absorption steps (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable forms of administration for parenteral administration include injectable and infusion formulations in the form of solutions, suspensions, emulsions, lyophilized forms, or sterile powders.

[0731] For other routes of administration, suitable examples are inhalable drug forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films / capsules or capsules for tongue, sublingual or oral administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, transdermal therapy systems (e.g., patches), emulsions, creams, foams, powders, implants or stents.

[0732] Oral or parenteral administration is preferred, especially oral and intravenous administration.

[0733] The compounds of the present invention can be converted into the above-described dosage forms. This can be accomplished in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polysorbate oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxide), and flavoring and / or taste-enhancing agents.

[0734] Generally, it has been found that, in the case of parenteral administration, a dosage of about 0.001 to 1 mg / kg body weight, preferably about 0.01 to 0.5 mg / kg body weight, is advantageous for obtaining effective results. In the case of oral administration, the dosage is about 0.01-100 mg / kg body weight, preferably about 0.01-20 mg / kg body weight, and most preferably 0.1-10 mg / kg body weight.

[0735] However, deviations from the prescribed dosage may be necessary in appropriate circumstances, particularly based on body weight, route of administration, individual response to the active compound, the nature of the formulation, and the time or interval of administration. For example, in some cases, less than the minimum dosage mentioned above may be sufficient, while in others, the mentioned upper limit must be exceeded. In cases involving large doses, it is recommended to divide these medications into several individual doses throughout the day.

[0736] The total amount of active ingredient to be administered typically ranges from about 0.001 mg / kg body weight to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg body weight to about 50 mg / kg body weight per day, and more preferably from about 0.01 mg / kg body weight to about 20 mg / kg body weight per day. Clinically useful dosing schedules range from once or three times daily to once every four weeks. Furthermore, "drug holidays," i.e., periods during which patients do not take the medication, may be beneficial for the overall balance between pharmacological effects and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more or less daily. For injectable administration, including intravenous, intramuscular, subcutaneous, and parenteral administration, as well as administration using infusion techniques, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. For rectal administration, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. For vaginal administration, the average daily dose is preferably from 0.01 to 200 mg / kg body weight. The preferred average daily topical administration regimen is 0.1 to 200 mg, administered 1 to 4 times daily. The preferred transdermal concentration is the concentration required to maintain a daily dose of 0.01 to 200 mg / kg. The preferred average daily inhalation administration regimen is 0.01 to 100 mg / kg of total body weight.

[0737] Of course, the specific initial and continuous dosing regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending physician, the activity of the specific compound used, the patient's age and general condition, the timing of administration, the route of administration, the drug excretion rate, and the combination of drugs. The desired treatment modality and dosage of the compounds of the present invention, or their pharmaceutically acceptable salts or esters, or combinations thereof, can be determined by those skilled in the art through conventional treatment trials.

[0738] However, it may be necessary to deviate from the prescribed amount, depending on body weight, route of administration, individual response to the active substance, type of formulation, and the time or interval of administration. Therefore, in some cases, using less than the minimum amount mentioned above may be sufficient, while in others, the prescribed upper limit must be exceeded. When administering larger doses, it is recommended to divide these medications into several separate doses throughout the day.

[0739] According to another embodiment, the compound of formula (I) of the present invention is administered orally once, twice, or three times daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once or twice daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once daily. For oral administration, a rapid-release or modified-release formulation may be used.

[0740] Unless otherwise stated, all percentages in the following tests and examples are weight percentages; parts are parts by weight. Solvent ratios, dilution ratios, and concentration data for liquid / liquid solutions are based on volume in each case. “w / v” means “weight / volume”. For example, “10% w / v” means that 100 ml of solution or suspension contains 10 g of substance.

[0741] Experimental Section

[0742] Experimental Section - General Principles

[0743] NMR peak shapes are described according to their appearance in the spectrum, without taking into account possible higher-order effects.

[0744] The selected compound 1 H-NMR data with 1 The peaks are listed in the form of a H-NMR peak list. For each signal peak, the δ value is given in ppm, followed by the signal intensity in parentheses. δ value-signal intensity pairs for different peaks are separated by commas. Therefore, a peak list is described in a general form: δ1 (intensity 1), δ2 (intensity 2), ..., δ i (strength i ), ..., δ n (strength n ).

[0745] In a printed NMR spectrum, the intensity of a sharp signal is related to the signal height (in cm). When compared to other signals, this data can be correlated with the actual ratio of signal intensity. In the case of a wide signal, more than one peak or signal center and its relative intensity are shown compared to the strongest signal displayed in the spectrum. 1 The H-NMR peak list is similar to the classic one. 1 H-NMR readings, therefore, typically contain all the peaks listed in the classical NMR interpretation. Furthermore, similar to classical...1 The H-NMR spectrum and peak list can display the solvent signal, the signal originating from the enantiomers of the title compound (which is also the subject of this invention), and / or impurity peaks. The peaks of the enantiomers and / or impurities typically show lower intensity compared to the peaks of the title compound (e.g., purity >90%). These enantiomers and / or impurities may be typical of a particular manufacturing method, and therefore their peaks may help identify the reproducibility of the manufacturing method of this invention based on the "byproduct fingerprint." Experts who calculate the title compound peaks using known methods (MestReC, ACD simulation, or expected values ​​evaluated empirically) can separate the title compound peaks as needed, optionally using additional intensity filters. Such operation is similar to classical... 1 Peak-picking in H-NMR interpretation. A detailed description of NMR data recorded in peak list form can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see Research Disclosure Database Number 605005, 2014, August 1, 2014, or http: / / www.researchdisclosure.com / searching-disclosures). During peak-picking, as described in Research Disclosure Database Number 605005, the parameter "minimum height" can be adjusted between 1% and 4%. Depending on the chemical structure and / or the concentration of the compound being measured, setting the parameter "minimum height" <1% may be reasonable.

[0746] Chemical names are generated using ACD / Labs' ACD / Name software. In some cases, the generic name of a commercially available reagent is used instead of the name generated by ACD / Name.

[0747] Table 1 below lists the abbreviations used in this paragraph and the Examples section, unless they are explained in the text. Other abbreviations have the meanings that are customary to those skilled in the art.

[0748] Table 1: Abbreviations

[0749] The following table lists the abbreviations used in this article.

[0750] BH3·THF Borane-Tetrahydrofuran

[0751] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0752] br broad peak ( 1 H-NMR signal)

[0753] CI chemical ionization

[0754] d double peak ( 1 H-NMR signal)

[0755] d day

[0756] DAD Diode Array Detector

[0757] dd double peak

[0758] DMF N,N-dimethylformamide

[0759] DMSO (dimethyl sulfoxide)

[0760] ESI Electrospray (ES) Ionization

[0761] EtOAc (ethyl acetate)

[0762] h hours

[0763] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium

[0764] 3-Oxide hexafluorophosphate, CAS 148893-10-1

[0765] HPLC (High Performance Liquid Chromatography)

[0766] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0767] m multiplet ( 1 H-NMR signal)

[0768] M Moore

[0769] min minutes

[0770] MS mass spectrometry analysis

[0771] MTBE (methyl tert-butyl ether)

[0772] Sodium borohydride (NaBH4), sodium tetrahydroborate

[0773] NaHCO3 (Sodium bicarbonate)

[0774] Na2SO4 Sodium sulfate

[0775] NMR spectroscopy: Chemical shift (δ) is given in ppm. Unless

[0776] Unless otherwise specified, the dimethyl sulfoxide signal is set to 2.50 ppm.

[0777] To correct chemical shift.

[0778] PDA photodiode array

[0779] Pd2dba3 tris(dibenzylacetone)dipalladium(0), CAS 51364-51-3

[0780] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0), CAS14221-01-3

[0781] quant.

[0782] rac racemic

[0783] R t Rt Retention time (measured by HPLC or UPLC), in minutes.

[0784] RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-

[0785] 1,1'-Biphenyl)]Palladium(II) methanesulfonate, CAS 1445085-77-7

[0786] s Single peak ( 1 H-NMR signal)

[0787] SFC Supercritical Fluid Chromatography

[0788] SQD Single Quadrupole Detector

[0789] t triple peak ( 1 H-NMR signal)

[0790] td triplet peak ( 1 H-NMR signal)

[0791] TFA (trifluoroacetic acid)

[0792] THF Tetrahydrofuran

[0793] UPLC (Ultra-High Performance Liquid Chromatography)

[0794] X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0795] CAS 564483-18-7

[0796] The various aspects of the invention described in this application are illustrated by the following embodiments, which are not intended to limit the invention in any way.

[0797] The embodiments and test experiments described herein are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0798] All reagents not described in the experimental section are either commercially available, known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0799] Compounds and intermediates prepared according to the method of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several methods may be available for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, the compound may be purified by chromatography, particularly rapid column chromatography, for example using pre-packed silica columns, such as Biotage SNAP cartridges. or Combined with Biotage automated purification system ( or Isolera The compound can be purified by preparative HPLC, for example using a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, combined with a suitable pre-packed reversed-phase column and eluent (such as a gradient solution of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or ammonia).

[0800] In some cases, the purification methods described above can provide the compounds of the invention in the form of salts, which possess sufficient basic or acidic functionality, such as trifluoroacetate or formate salts for sufficiently basic compounds of the invention, or ammonium salts for sufficiently acidic compounds of the invention. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that the specific form (e.g., salt, free base, etc.) of the compounds of the invention isolated and described herein is not necessarily the only form in which the compounds can be used in bioassays to quantify specific biological activities.

[0801] In the synthetic intermediates and working examples of the invention described below, any compound described as a salt of a corresponding base or acid is generally a salt with an unknown exact stoichiometric composition, obtained by its respective preparation and / or purification methods. Therefore, unless otherwise specified, additional terms such as "hydrochloride," "trifluoroacetate," "sodium salt," or "x HCl," "x CF3COOH," "x Na" are used in names and structural formulas. + In the case of such salts, the term should not be understood in a stoichiometric sense, but rather should be interpreted only in a descriptive sense regarding the salt-forming components present.

[0802] This applies if the synthetic intermediate or working example or its salt is obtained by the described preparation and / or purification methods in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0803] HPLC and LC-MS methods:

[0804] Method 1 (LC-MS)

[0805] MS instrument type: SHIMADZU LCMS-2020, column: Kinetex EVO C18 30*2.1mm, 5um, mobile phase A: 0.0375% TFA aqueous solution (v / v), B: 0.01875% TFA acetonitrile solution (v / v), gradient: 0.0min 0% B → 0.8min 95% B → 1.2min 95% B → 1.21min 5% B → 1.55min 5% B, flow rate: 1.5ml / min, oven temperature: 50℃; UV detection: 220nm & 254nm.

[0806] Method 2 (LC-MS)

[0807] HPLC instrument model: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 50*4.6mm, 5um; Mobile phase A: 0.0375% TFA aqueous solution (v / v), B: 0.01875% TFA acetonitrile solution (v / v); Gradient: 0.0min 10% B → 2.4min 80% B → 3.7min 80% B → 3.71min 10% B → 4.0min 10% B; Flow rate: 1.5ml / min; Oven temperature: 50℃; UV detection: 220nm & 215nm & 254nm.

[0808] Method 3 (LC-MS)

[0809] Instruments: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.25ml formic acid, Eluent B: 1L acetonitrile + 0.25ml formic acid; Gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; Oven temperature: 50℃; Flow rate: 0.40ml / min; UV detection: 210nm.

[0810] Method 4 (LC-MS)

[0811] Instrument MS: Thermo Scientific FT-MS; Instrument type UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1 x 75 mm, C18 1.8 μm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven temperature: 50℃; Flow rate: 0.90 ml / min; UV detection: 210 nm / optimal integration path 210-300 nm.

[0812] Method 5 (LC-MS)

[0813] Instruments: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.25ml formic acid, Eluent B: 1L acetonitrile + 0.25ml formic acid; Gradient: 0.0min 95% A → 6.0min 5% A → 7.5min 5% A; Oven temperature: 50℃; Flow rate: 0.35ml / min; UV detection: 210nm.

[0814] Method 6 (LC-MS)

[0815] Instruments: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters AcquityUPLC HSS T3 1.8μm 50x 2.1mm; Eluent A: 1L water + 0.25ml formic acid, Eluent B: 1L acetonitrile + 0.25ml formic acid; Gradient: 0.0min 90% A → 0.3min 90% A → 1.7min 5% A → 3.0min 5% A; Oven temperature: 50℃; Flow rate: 1, 20ml / min; UV detection: 205–305nm.

[0816] Method 7 (LC-MS)

[0817] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: WatersAcquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.100ml 99% ig e formic acid; Eluent B: 1L acetonitrile + 0.100ml 99% ig e formic acid; Gradient: 0.0min 90% A → 1.2min 5% A → 2.0min 5% A; Oven temperature: 50℃; Flow rate: 0.40ml / min; UV detection: 210nm.

[0818] Method 8 (LC-MS)

[0819] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: WatersAcquity UPLC HSS T3 1.8μm 50x 1mm; Eluent A: 1L water + 0.01% formic acid, Eluent B: 1L acetonitrile + 0.01% formic acid; Gradient: 0.0min 2% B → 0.5min 2% B → 7.5min 95% B → 10.0min 95% B; Oven temperature: 50℃; Flow rate: 1.00ml / min; UV detection: 210nm.

[0820] Method 9 (Preparative HPLC)

[0821] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80 vol.% / 20 vol.%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 55 ml / min, Eluent B 15 ml / min; 2 to 10 minutes: Eluent A from 55 ml / min to 31 ml / min, Eluent B from 15 ml / min to 39 ml / min; 10 to 12 minutes: Eluent A 0 ml / min, Eluent B 70 ml / min; Eluent C and Eluent D maintained a constant flow rate of 5 ml / min throughout the run.

[0822] Method 10 (Preparative HPLC)

[0823] Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5μm 100x30 mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% ammonia solution; Eluent D: Acetonitrile / water (80 vol.% / 20 vol.%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 55 ml / min, Eluent B 15 ml / min; 2 to 10 minutes: Eluent A from 55 ml / min to 31 ml / min, Eluent B from 15 ml / min to 39 ml / min; 10 to 12 minutes: Eluent A 0 ml / min, Eluent B 70 ml / min; Eluent C and Eluent D maintained a constant flow rate of 5 ml / min throughout the run.

[0824] Method 11 (Preparative HPLC)

[0825] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80 vol.% / 20 vol.%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 47 ml / min, Eluent B 23 ml / min; 2 to 10 minutes: Eluent A from 47 ml / min to 23 ml / min, Eluent B from 23 ml / min to 47 ml / min; 10 to 12 minutes: Eluent A 0 ml / min, Eluent B 70 ml / min; Eluent C and Eluent D maintained a constant flow rate of 5 ml / min throughout the run.

[0826] Method 12 (Preparative HPLC)

[0827] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80 vol.% / 20 vol.%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Eluent A 23 ml / min, Eluent B 47 ml / min; 2 to 10 minutes: Eluent A from 23 ml / min to 0 ml / min, Eluent B from 47 ml / min to 70 ml / min; 10 to 12 minutes: Eluent A 0 ml / min, Eluent B 70 ml / min; Eluent C and Eluent D maintained a constant flow rate of 5 ml / min throughout the run.

[0828] Method 13 (Preparative HPLC)

[0829] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Eluent A: Water; Eluent B: Acetonitrile; Eluent C: 2% formic acid aqueous solution; Eluent D: Acetonitrile / water (80 vol.% / 20 vol.%); Flow rate: 80 ml / min; Gradient curve: Eluent A 0 to 2 minutes 70 ml / min, Eluent B 0 to 2 minutes 0 ml / min; Eluent A 2 to 10 minutes from 70 ml / min to 0 ml / min, Eluent B from 0 ml / min to 70 ml / min; 10 to 12 minutes, Eluent A 0 ml / min, Eluent B 70 ml / min; Eluent C and Eluent D maintained a constant flow rate of 5 ml / min throughout the run.

[0830] microwave: The microwave reactor used is The Initiator+ microwave system, with 60 robots.

[0831] When the compounds of the present invention are purified by preparative HPLC using the above-described method in which the eluent contains an additive (such as trifluoroacetic acid, formic acid, or ammonia), if the compounds of the present invention contain sufficient basic or acidic functionality, the compounds of the present invention can be obtained in the form of salts, such as trifluoroacetate salts, formate salts, or ammonium salts. Such salts can be converted into the corresponding free bases or acids by those skilled in the art using a variety of known methods.

[0832] In the synthetic intermediates and working examples of the invention described below, any compound described as a salt of a corresponding base or acid is generally a salt of unknown exact stoichiometric composition obtained by its respective preparation and / or purification methods. Therefore, unless otherwise specified, the additional terms in the name and structural formula, such as “hydrochloride,” “trifluoroacetate,” “sodium salt,” or “x HCl,” “xCF3COOH,” “x Na+,” should not be interpreted stoichiometrically in the case of such salts, but rather as descriptive of the salt-forming components present therein.

[0833] This applies if the synthetic intermediate or working example or its salt is obtained by the described preparation and / or purification methods in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0834] Enantiomer 1 It is the enantiomer that is first eluted from the column.

[0835] Enantiomer 2 It is the second enantiomer eluted from the column.

[0836] diastereomer mixture 1 A compound is defined as the starting material, which is defined as enantiomer 1, reacts with a structural unit containing at least one chiral center, and whose configuration is not defined.

[0837] diastereomer mixture 2 A compound is defined as the starting material, which is defined as enantiomer 2, reacts with a structural unit containing at least one chiral center, and whose configuration is not defined.

[0838] diastereomer 1 and diastereomer 2 Two compounds generated by the chiral separation of the above diastereomer mixture 1 are defined.

[0839] diastereomer 3 and diastereomer 4 Two compounds generated by the chiral separation of the above diastereomer mixture 2 are defined.

[0840] Stereoisomer 1 A compound is defined as the starting material, which is defined as enantiomer 1, reacts with a structural unit containing at least one chiral center, and its configuration is defined.

[0841] Stereoisomer 2 A compound is defined as the starting material, which is defined as enantiomer 2, reacts with a structural unit containing at least one chiral center, and its configuration is defined.

[0842] Example Section - Starting Materials and Intermediates

[0843] Example 1A

[0844] 3-{2-[(benzyloxy)carbonyl]hydrazinoyl}piperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[0845]

[0846] At 25°C, benzylhydrazine carboxylate [CAS No. 5331-43-1] (250 g, 1.51 mol) was added to a solution of 3-oxopiperidin-1-carboxylate [CAS No. 989-36-7] (300 g, 1.51 mol) in tetrahydrofuran (1.50 L) and methanol (300 mL). The mixture was stirred at 25°C for 1 hour. Then, sodium borohydride (114 g, 3.01 mol) was added in portions to the mixture at 25°C and stirred at 25°C for 2 hours. The reaction mixture was cooled to 10°C, and saturated NH4Cl was added dropwise to bring the pH to approximately 6. The mixture was extracted with ethyl acetate (EtOAc) (300 mL × 2) and concentrated under vacuum. The residue was dissolved in methyl tert-butyl ether (MTBE) (300 mL) and petroleum ether (300 mL) was added. The mixture was filtered and the precipitate was washed with petroleum ether (100 mL) to give the title compound as a white solid (400 g, 1.14 mol, 76.0% yield).

[0847] LC-MS: (Method 1) R t =0.832min, MS(M-100+1=250.4).

[0848] Example 2A

[0849] 3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester acetate adduct (racemate)

[0850]

[0851] In the presence of H2 (15Psi), acetic acid (415 g, 6.91 mol, 395 mL) and Pd / C (120 g, 20% purity) were added to an ethanol (11.0 L) solution of 3-{2-[(benzyloxy)carbonyl]hydrazinoyl}piperidine-1-carboxylic acid tert-butyl ester (prepared according to Example 1A, 1.20 kg, 3.43 mol). The mixture was stirred at 25 °C for 12 hours. The mixture was filtered, and the precipitate was washed with ethanol (11.0 L) to give an ethanol solution (945 g, acetate) of the title compound as a black liquid. The filtrate was used directly for the next step without purification.

[0852] 11 H-NMR (400MHz, CDCl3) δ [ppm]: 7.52 (s, 5H), 3.59 (d, J = 6.0Hz, 12H), 3.30-3.2 4(m,2H),2.75-2.71(m,2H),1.38-1.34(m,1H),1.20-1.18(m,1H),1.10(s,9H)

[0853] LC-MS: (Method 1) R t=0.263min, MS(M-56+1=160.2)

[0854] Example 3A

[0855] Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate

[0856]

[0857] A solution of ethyl 4,4-difluoro-3-oxobutyrate (120 g, 722 mmol) and (diethoxymethoxy)ethane (240 ml, 1.4 mol) in acetic anhydride (200 ml, 2.2 mol) was stirred overnight at 140 °C and evaporated to dryness to give 155 g (quantitative) of the title compound, which was used in the next step without further purification.

[0858] 11 H-NMR (600MHz, CDCl3) 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(2.0 0), 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).

[0859] Example 4A

[0860] 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[0861]

[0862] To a mixture of tert-butyl 3-hydrazinopyridine-1-carboxylic acid ester (Example 2A, 945 g, 3.43 mol) and ethanol (20.0 L), ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (prepared according to Example 3A, 840 g, 3.78 mol) was added. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated. The residue was poured into a saturated aqueous solution of NaHCO3 (10.0 L) and extracted with ethyl acetate (10.0 L * 2). The combined organic layers were washed with brine (10.0 L), dried over Na2SO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography using petroleum ether:ethyl acetate (50:1–25:1–10:1, R... f =0.3) Elution and purification yielded 530 g (41.4% yield) of the title compound.

[0863] 11 H-NMR (400MHz, CDCl3) δ [ppm]: 7.84 (s, 1H), 7.51 (t, J = 12.8Hz, 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)

[0864] LC-MS (Method 1)R t =0.992min, MS(M-56+1=318.0).

[0865] Example 5A

[0866] 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (racemic mixture)

[0867]

[0868] 3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (prepared according to Example 4A, 593 g, 1.59 mol) was added to a solution of dioxane (4 M, 2.50 L) containing hydrogen chloride, and 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 was 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 give 350 g (80.6% yield) of the title compound.

[0869] 1 H-NMR (400MHz, CDCl3) δ [ppm]: 7.87 (s, 1H), 7.54 (t, J = 12.8Hz, 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=7.2Hz,3H)

[0870] LC-MS: (Method 1) R t =0.644min, MS(M+1)=274.6.

[0871] Similar to Example 5A, ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (racemic mixture) was prepared using different protecting groups. The two enantiomers were separated by SFC [Sample preparation: 20 g dissolved in 500 ml methanol; injection volume: 15 ml; column: Daicel AZ SCF 20 μm, 400 x 50 mm; eluent: carbon dioxide / methanol / 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 the first-eluted enantiomer 1 (Example 6A) and 8.0 g of the second-eluted enantiomer 2 (Example 7A) were obtained.

[0872] Example 6A

[0873] Ethyl 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylate (enantiomer 1)

[0874] See Example 5A for separation conditions.

[0875] Analysis of SFC: R t =0.980 min, ee=100% [Chromatographic column Chiralpak IC-3: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.2% diethylamine]: 90:10; flow rate: 3.0 ml / min; temperature: 25℃; UV detection: 220 nm].

[0876] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:8.00(s,1H),7.75-7.44(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).

[0877] Example 7A

[0878] 5-(difluoromethyl)-1-(piperidin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0879] See Example 5A for separation conditions.

[0880] Analysis of SFC: R t =1.227 min, ee=97% [Chromatographic column Chiralpak IC-3: 50 x 4.6 mm; eluent: CO2 / [methanol + 0.2% diethylamine]: 90:10; flow rate: 3.0 ml / min; temperature: 25℃; UV detection: 220 nm].

[0881] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:8.01(s,1H),7.75-7.43(m,1H),4.50-4.37(m,1H),4.27(q,2H),3.09-2.97(m, 1H),2.94-2.81(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).

[0882] Example 8A

[0883] 2-Bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene

[0884]

[0885] A solution of 2-bromo-4-chlorophenol (10.0 g, 48.2 mmol) in acetone (75 mL) was treated with potassium carbonate (13.3 g, 96.4 mmol), potassium iodide (12.0 g, 72.3 mmol), and 1-(chloromethyl)-4-methoxybenzene (7.55 g, 48.2 mmol). The resulting mixture was stirred at 70 °C for approximately 19 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 13.78 g (86% yield) of the title compound.

[0886] LC-MS (Method 3): R t =2.48min; MS(ESIneg):m / z=324[MH] -

[0887] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:3.349(10.98),5.124(16.00),6.949(0.87 ),6.954(8.36),6.957(2.68),6.965(2.83),6.968(8.92),6.973(1.00),7.2 18(5.23),7.233(6.21),7.380(0.90),7.384(7.80),7.399(7.44),7.402(4 .47),7.406(3.89),7.417(3.04),7.421(3.07),7.697(6.51),7.702(6.34).

[0888] Example 9A

[0889] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0890]

[0891] Under argon atmosphere, a solution of 1,4-dioxane containing 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared according to Example 8A, 10.0 g, 30.5 mmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared according to Example 6A, enantiomer 1, 8.34 g, 30.5 mmol) 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) to treat the mixture. The resulting mixture was stirred overnight at 100 °C. The reaction mixture was combined with 500 mg of the test reactant, filtered through diatomaceous earth, washed with ethyl acetate, and evaporated. The residue was redissolved in water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 10.1 g (60% yield) of the title compound.

[0892] LC-MS (Method 4): R t =1.44min; MS(ESIpos): m / z=520[M+H] +

[0893] Example 10A

[0894] 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0895]

[0896] A solution of ethyl 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (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 redissolved in ethyl acetate and washed once with water, once with a saturated sodium bicarbonate solution, and finally once with a saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 7.17 g (83% purity, 77% yield) of the title compound.

[0897] LC-MS (Method 8): R t =1.26min; MS (ESIpos): m / z=400[M+H] +

[0898] Example 11A

[0899] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0900]

[0901] Under argon atmosphere, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (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 at 0 °C for 45 min. 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 rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 7.89 g (quantitative) of the title compound.

[0902] LC-MS (Method 4): R t =1.47min; MS (ESIpos): m / z=532[M+H] +

[0903] Example 12A

[0904] 4-(4'-chloro-2'-{3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (enantiomer 1)

[0905]

[0906] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 11A, enantiomer 1,665 mg, 1.25 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (583 mg, 1.50 mmol) in a toluene / ethanol mixture of 1:1 (14 ml) was treated with sodium carbonate aqueous solution (1.9 ml, 2.0 M, 3.8 mmol) and Pd(PPh3)4 (72.2 mg, 62.5 μmol) and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 760 mg (94% yield) of the title compound.

[0907] LC-MS (Method 3): R t =3.13min; MS (ESIpos): m / z=644[M+H] +

[0908] Example 13A

[0909] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (enantiomer 1)

[0910]

[0911] A solution of 4-(4'-chloro-2'-{3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Example 12A, enantiomer 1, 760 mg, 1.18 mmol) in dichloromethane (2.9 mL, 4.0 M, 12 mmol) was treated with dioxane (2.9 mL, 4.0 M, 12 mmol) and stirred at room temperature for 30 min. The reaction mixture was evaporated to give 626 mg (70% yield) of the title compound, which was used in subsequent steps without further purification.

[0912] LC-MS (Method 4): Rt = 0.98 min; MS (ESIpos): m / z = 544 [M+H]+

[0913] Example 14A

[0914] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0915]

[0916] Under argon atmosphere, a solution of ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared according to Example 7A, enantiomer 2, 43.6 g, 160 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared according 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 at 100 °C for 18 hours. The reaction mixture was diluted with ethyl acetate and 10% sodium chloride solution, filtered through diatomaceous earth and washed with ethyl acetate. The aqueous phase of the filtrate was extracted with ethyl acetate. The combined organic layers were washed with 10% sodium chloride solution, dried over sodium sulfate and evaporated. The residue was rapidly purified by silica gel (dichloromethane / petroleum ether 4:1) to give 42 g (82% yield) of the title compound.

[0917] LC-MS (Method 3): R t =2.78min; MS(ESIpos): m / z=520[M+H] +

[0918] 1H-NMR(400MHz,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), 4.2 69(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).

[0919] Example 15A

[0920] 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0921]

[0922] A solution of 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 14A, 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 10% sodium carbonate solution (450 mL) until no more carbon dioxide was produced. The organic phase was dried over sodium sulfate and evaporated to give 52 g (90% yield) of the title compound, which was used in the next step without further purification.

[0923] LC-MS (Method 3): R t =2.42min; MS (ESIpos): m / z=400[M+H] +

[0924] Example 16A

[0925] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0926]

[0927] A solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 15A, enantiomer 2, 52.0 g, 117 mmol) and triethylamine (49 mL, 350 mmol) in dichloromethane (330 mL) was cooled to -50 °C. Trifluoromethanesulfonic acid (28 mL, 160 mmol) was added dropwise, and the resulting mixture was stirred at -50 °C for 1 hour. 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 rapid chromatography (silica gel, dichloromethane / petroleum ether 6:4) to give 60 g (96% yield) of the title compound.

[0928] LC-MS (Method 3): R t =2.74min; MS(ESIpos): m / z=532[M+H] +

[0929] 1H-NMR(600MHz,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),1.787(0.63),1.793(0.66),1.801(0.62),1.808(0.60),1.910(1.25 ), 1.914(0.99), 1.927(0.67), 1.932(0.89), 2.068(0.72), 2.075(1.03), 2.086(2.45), 2.091(2.40), 2.100(1.41), 2.792(0.71), 2.796(0.83), 2.812(1.48), 2.816(1.50), 2.832(0.83), 2.836(0.72), 3.1 42(1.17),3.161(1.04),3.201(1.21),3.219(2.80),3.237(1.83),3.278(1.37),3.285(1.56),4.251(2.26),4.263(7.09),4.275(7.06),4.287(2.20),4.755(0.50),4.765(0.90),4.773(0.89),4.781(0 .90),4.791(0.49),5.734(2.17),7.261(2.19),7.265(2.27),7.275(2.69),7.279(2.82),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).

[0930] Example 17A

[0931] 4-(4'-chloro-2'-{3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (enantiomer 2)

[0932]

[0933] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 16A, enantiomer 2, 57.0 g, 107 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (49.9 g, 129 mmol) in toluene (600 ml) and ethanol (600 ml) was treated with sodium carbonate aqueous solution (160 ml, 2.0 M, 320 mmol) and Pd(PPh3)4 (6.19 g, 5.36 mmol). The resulting mixture was stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate 9:1 to 8:2) to give 62 g (89% yield) of the title compound.

[0934] LC-MS (Method 3): R t =3.15min; MS (ESIpos): m / z=644[M+H] +

[0935] Example 18A

[0936] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (enantiomer 2)

[0937]

[0938] A solution of 4-(4'-chloro-2'-{(3-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Example 17A, enantiomer 2, 60.0 g, 93.1 mmol) in dichloromethane (250 ml) was treated with a solution of dioxane (230 ml, 4.0 M, 930 mmol) containing hydrogen chloride. The resulting mixture was stirred at room temperature for 3 hours and then evaporated. The residue was evaporated twice with diethyl ether (250 ml × 2) and stirred in diisopropyl ether for 4 days. The suspension was filtered, and the solid was washed twice with diisopropyl ether to give 57 g (quantitative) of the title compound.

[0939] LC-MS (Method 3): Rt = 1.78 min; MS (ESIpos): m / z = 544 [M+H]+

[0940] 1H-NMR(400MHz,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(2.33), 3.063(1.24), 3.435(5.96), 3.448(7.25), 3.460(5.00), 3.570(5.78), 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(1.49),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(5.77),9.399(1.97).

[0941] Example 19A

[0942] 1-{1-[4-chloro-4'-(4-ethylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 1)

[0943]

[0944] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 11A, enantiomer 1, 100 mg, 96% purity, 180 μmol) and 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (68.5 mg, 217 μmol) were placed in 1.8 mL of DMF, mixed with tetrakis(triphenylphosphine)palladium(0) (10.4 mg, 9.02 μmol) and 2 M sodium carbonate solution (270 μl, 2.0 M, 540 μmol), and stirred at 130 °C for 2.5 h. The reaction mixture was filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA). The product fractions were combined, the acetonitrile was evaporated, and then lyophilized to give 51 mg of the title compound (41% of the theoretical value).

[0945] LC-MS (Method 3): R t =1.93min; MS(ESIpos):m / z=572[M+H] +

[0946] Example 20A

[0947] 1-{1-[4-chloro-4'-(4-ethylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0948]

[0949] A solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 300 mg, 95% purity, 536 μmol) and 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (203 mg, 643 μmol) in toluene / ethanol was treated with sodium carbonate aqueous solution (800 μl, 2.0 M, 1.6 mmol) and Pd(PPh3)4 (31.0 mg, 26.8 μmol) and stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by rapid chromatography (amino-phase silica gel, cyclohexane / ethyl acetate gradient) to give 236 mg (90% purity, 69% yield) of the title compound.

[0950] LC-MS (Method 3): R t =1.88min; MS(ESIpos):m / z=572[M+H] +

[0951] Example 21A

[0952] 1-Propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine

[0953]

[0954] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (300 mg, 1.04 mmol) was placed in 6.4 mL of tetrahydrofuran, and N,N-diisopropylethylamine (270 μl, 1.6 mmol) was added. Then propionaldehyde (242 mg, 4.16 mmol) was added, and the mixture was stirred for 10 min. Sodium triacetoxyborohydride (662 mg, 3.12 mmol) was then added, and the mixture was stirred at 55 °C for 1.5 h. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate was added. 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. The mixture was purified by silica gel chromatography (dichloromethane / methanol 100 / 1, then dichloromethane / methanol 50 / 1 without gradient). 186 mg of the title compound was given (53% of the theoretical value).

[0955] LC-MS (Method 6): R t =0.97min; MS(ESIpos):m / z=331[M+H] +

[0956] H-NMR(500MHz,DMSO-d6)δ[ppm]:0.856(1.10),0.871(2.41),0.886(1.18),1.070( 6.41),1.258(16.00),1.457(0.59),1.472(0.58),2.250(0.49),2.265(0.64),2.2 79(0.45),2.453(0.86),2.462(1.15),2.472(0.89),3.181(0.94),3.192(1.13),3.201(0.86),3.916(1.09),6.877(1.01),6.894(1.02),7.490(1.17),7.507(1.04).

[0957] Example 22A

[0958] 1-{1-[4-chloro-4'-(4-propylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[0959]

[0960] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomer 2, 90.0 mg, 169 μmol) and 1-propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 21A, 67.1 mg, 203 μmol) were placed in toluene / ethanol (940 μl / 940 μl), 2M sodium carbonate solution (250 μl) and tetra(triphenylphosphine)palladium(0) (9.78 mg, 8.46 μmol) were added, and the mixture was stirred overnight at 100 °C. Tetra(triphenylphosphine)palladium(0) (9.78 mg, 8.46 μmol) was added to the mixture, purged with argon, and stirred at 100 °C for 3 h. 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 residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% trifluoroacetic acid). 43 mg of the title compound was given (36% of the theoretical value).

[0961] LC-MS (Method 3): R t =2.07min; MS(ESIpos):m / z=586[M+H] +

[0962] Example 23A

[0963] 1-[1-{4-chloro-4'-[4-(propyl-2-yl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0964]

[0965] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomer 2, 100 mg, 184 μmol) and 1-(propyl-2-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (73.0 mg, 221 μmol) were dissolved in toluene / ethanol (1 / 1 ml). 2M sodium carbonate solution (280 μl) and tetrakis(triphenylphosphine)palladium(0) (10.6 mg, 9.21 μmol) were added, and the mixture was stirred overnight at 100 °C. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, washed thoroughly with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in acetonitrile / water / formic acid and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% formic acid). 20 mg (17% of theoretical value, 92% purity) of the title compound was obtained.

[0966] LC-MS (Method 4): R t =1.02min; MS(ESIpos):m / z=586[M+H] +

[0967] Example 24A

[0968] 1-Cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[0969]

[0970] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (700 mg, 2.43 mL) was dissolved in 12 mL of methanol. A 3A mol sieve (~200 mg), 1.4 mL of acetic acid, [(1-ethoxycyclopropyl)oxy](trimethyl)silane (2.9 mL, 15 mmol), and sodium cyanoborohydride (687 mg, 10.9 mmol) were added sequentially. The mixture was stirred at room temperature for 3 days. The molecular sieve was filtered through diatomaceous earth, thoroughly washed with ethyl acetate, and then washed twice with water. The organic phase was dried over sodium sulfate, filtered, and evaporated. The crude product was purified using silica gel (dichloromethane / methanol gradient: 100 / 1 to 50 / 1). 270 mg of the title compound was obtained (30% of the theoretical value, 88% purity).

[0971] LC-MS (Method 4): R t =0.66min; MS(ESIpos): m / z=329[M+H]+

[0972] Example 25A

[0973] 1-{1-[4-chloro-4'-(4-cyclopropylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 1)

[0974]

[0975] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 11A, enantiomer 1, 100 mg, 93% purity, 175 μmol) and 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 24A, 71.7 mg, 88% purity, 192 μmol) were dissolved in 1.7 mL of DMF, mixed with tetrakis(triphenylphosphine)palladium(0) (10.1 mg, 8.74 μmol) and 2 M sodium carbonate solution (260 μL), and stirred at 130 °C for 2.5 h. The reaction mixture was filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). 22 mg of the title compound as a TFA adduct was obtained (15% of theoretical value, 83% purity).

[0976] LC-MS (Method 4): R t =1.01min; MS(ESIpos): m / z=584[M+H] +

[0977] Example 26A

[0978] 1-[1-[5-chloro-2-[4-(4-cyclopropylpiperazin-1-yl)phenyl]phenyl]-3-piperidinyl]-5-(difluoromethyl)pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[0979]

[0980] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl]piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 11A, enantiomer 2, 100 mg, 95% purity, 179 μmol) and 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 24A, 73.3 mg, 88% purity, 196 μmol) were dissolved in 1.7 mL of DMF, mixed with tetrakis(triphenylphosphine)palladium(0) (10.3 mg, 8.93 μmol) and 2 M sodium carbonate solution (270 μl, 2.0 M), and stirred at 130 °C for 2.5 h. The reaction mixture was filtered through diatomaceous earth, washed with acetonitrile, and the filtrate was purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). 24.4 mg of the title compound as a TFA adduct was obtained (14% of theoretical value, purity ~71%).

[0981] LC-MS (Method 4): R t =1.05min; MS(ESIpos): m / z=584[M+H] +

[0982] Example 27A

[0983] 1-(cyclopropylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[0984]

[0985] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (380 mg, 1.32 mmol) was dissolved in 8 mL of THF, and N,N-diisopropylethylamine (340 μl, 2.0 mmol) was added. Cyclopropane formaldehyde (370 mg, 5.27 mmol) was then added, and the mixture was stirred for 10 min. Sodium triacetoxyborohydride (838 mg, 3.96 mmol) was then added, and the mixture was stirred at 55 °C for 4 h. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate was added. 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. 519 mg of the title compound was obtained (98% of theoretical value, 85% purity).

[0986] LC-MS (Method 3): R t =1.18min; MS (ESIpos): m / z=343[M+H] +

[0987] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:0.089(0.56),0.096(0.58),0.471(0.53),0.483(0.55),1.158(0.59),1.175(0.52),1.25 9(16.00),1.989(1.00),3.210(0.89),3.216(0.92),3.226(0.55),6.885(0.93),6.900(0.95),7.494(1.10),7.509(1.02).

[0988] Example 28A

[0989] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (enantiomer 2)

[0990]

[0991] An aqueous solution of lithium hydroxide (4.0 mL, 1.0 M, 4.0 mmol) was added to a 10:1 (8.8 mL) mixture of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 281 mg, 82% purity, 396 μmol) in THF / methanol. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with an aqueous solution of hydrogen chloride (2N) and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 175 mg (86% yield) of the title compound.

[0992] LC-MS (Method 4): R t =0.83min; MS (ESIpos): m / z=516[M+H] +

[0993] Example 29A

[0994] 1-(2,2-Dimethylpropyl)-4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[0995]

[0996] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (300 mg, 1.04 mmol) was placed in 6.4 mL of THF, and N,N-diisopropylethylamine (270 μl, 1.6 mmol) was added. Then 2,2-dimethylpropionaldehyde (450 μl, 4.2 mmol) was added, and the mixture was stirred for 10 min. Sodium triacetoxyborohydride (662 mg, 3.12 mmol) was then added, and the mixture was stirred at 55 °C for 4 h. The reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate was added. 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. 366 mg of the title compound was obtained (96% of the theoretical value).

[0997] LC-MS (Method 3): R t =1.38min; MS (ESIpos): m / z=359[M+H] +

[0998] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:0.874(11.03),1.259(16.00),1.358(0.55),2.094(2.28),2.582(1.32),2.589(1.7 4),2.598(1.38),3.177(1.08),3.186(1.41),3.193(1.12),6.868(1.03),6.882(1.05),7.490(1.08),7.504(0.99).

[0999] Example 30A

[1000] 1-[1-{4-chloro-4'-[4-(2,2-dimethylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 1)

[1001]

[1002] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 11A, enantiomer 1, 30.0 mg, 55.3 μmol) and 1-(2,2-dimethylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 29A, 21.8 mg, 60.8 μmol) were dissolved in toluene / ethanol (0.31 / 0.31 ml). Tetra(triphenylphosphine)palladium(0) (3.19 mg, 2.76 μmol) and 2M sodium carbonate solution (83 μl, 2.0 M, 170 μmol) were added, and the mixture was stirred at 100 °C for 2.5 hours. The reaction mixture was filtered through a Millipore filter, washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in acetonitrile / TFA / water and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with 0.1% TFA added). 26 mg of the title compound was given (64% of the theoretical value).

[1003] LC-MS (Method 3): R t =2.23min; MS (ESIpos): m / z=614[M-TFA+H] +

[1004] Example 31A

[1005] 1-[1-{4-chloro-4'-[4-(2,2--dimethylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[1006]

[1007] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomer 2, 50.0 mg, 93.1 μmol) and 1-(2,2-dimethylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 29A, 36.7 mg, 102 μmol) were dissolved in toluene / ethanol (0.52 / 0.52 ml). Tetra(triphenylphosphine)palladium(0) (5.38 mg, 4.65 μmol) and 2M sodium carbonate solution (140 μl, 280 μmol) were added, and the mixture was stirred at 100 °C for 2.5 h. The reaction mixture was filtered through a Millipore filter, washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in acetonitrile / TFA / water and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). 39 mg of the title compound was given (57% of the theoretical value).

[1008] LC-MS (Method 3): R t =2.24min; MS (ESIpos): m / z=614[M-TFA+H] +

[1009] Example 32A

[1010] 1-(cyclobutylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1011]

[1012] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (350 mg, 1.21 mmol) was placed in 7.4 mL of THF, and N,N-diisopropylethylamine (320 μl, 1.8 mmol) was added. Cyclobutyraldehyde (409 mg, 4.86 mmol) was then added, and the mixture was stirred for 10 min. 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, and saturated aqueous sodium bicarbonate solution was added, followed by extraction three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (dichloromethane / methanol: 50 / 1). 394 mg of the title compound was obtained (91% of the theoretical value).

[1013] LC-MS (Method 3): Rt =1.37min; MS (ESIpos): m / z=357[M+H] +

[1014] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.071(2.26),1.257(16.00),1.650(0.55),1.666(0.53),2.013(0.48),2.027(0.46),2.357(1.03),2.369(1.1 6),2.441(1.51),2.517(0.56),3.164(1.16),3.172(1.51),3.180(1.10 ),5.744(1.42),6.865(1.06),6.879(1.11),7.486(1.12),7.500(1.06).

[1015] Example 33A

[1016] 1-[1-{4-chloro-4'-[4-(cyclobutylmethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[1017]

[1018] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomer 2, 47.0 mg, 87.5 μmol) and 1-(cyclobutylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 32A, 34.3 mg, 96.2 μmol) were dissolved in toluene / ethanol (0.48 / 0.48 mL). Tetra(triphenylphosphine)palladium(0) (5.05 mg, 4.37 μmol) and 2M sodium carbonate solution (130 μl, 260 μmol) were added, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered through a Millipore filter, washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in acetonitrile / TFA / water and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). 43 mg of the title compound was obtained (68% of the theoretical value).

[1019] LC-MS (Method 3): R t=2.07min; MS (ESIpos): m / z=612[M-TFA+H] +

[1020] Example 34A

[1021] [4-[4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl]phenyl]boronic acid

[1022]

[1023] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (700 mg, 2.43 mmol) in N,N-dimethylformamide (30 mL) was treated with 3-(bromomethyl)-1,1-difluorocyclobutane (674 mg, 3.64 mmol) and potassium carbonate (1.01 g, 7.29 mmol). The resulting mixture was stirred overnight at 80 °C, then diluted with water and extracted with dichloromethane. The organic phase was washed with water, dried, concentrated, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 384 mg (88% purity, 45% yield) of the title compound.

[1024] LC-MS (Method 3): R t =0.60min; MS(ESIpos): m / z=311[M+H] +

[1025] Example 35A

[1026] 1-[1-(4-chloro-4'-{4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1027]

[1028] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 11A, enantiomer 1, 100 mg, 188 μmol) and (4-{4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl}phenyl)boronic acid (Example 34A, 79.5 mg, 88% purity, 226 μmol) in toluene / ethanol (1:1, 2.6 ml) was treated with Pd(PPh3)4 (10.9 mg, 9.40 μmol) and an aqueous solution of sodium carbonate (280 μl, 2N, 560 μmol) in toluene / ethanol. The reaction was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 49.0 mg (40% yield) of the title compound.

[1029] LC-MS (Method 3): R t =2.15min; MS (ESIpos): m / z=648[M+H] +

[1030] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.265(8.00),1.276(16.00),1.288(7.85),1.506(1.1 5),1.527(1.21),1.710(1.61),1.732(1.30),1.878(0.48),1.893(1.24),1.913(1.31) ,1.934(0.59),1.980(1.64),2.293(1.05),2.385(1.18),2.423(1.20),2.558(2.94),2.577(1.80),2.613(0.78),2.652(0.85),2.701(1.42),3.008(1.88),3.026(3.64),3.0 44(3.67),3.065(1.85),3.158(2.25),3.244(2.80),4.242(2.48),4.254(7.20),4.266(6.91),4.278(2.19),4.478(0.92),4.496(1.57),4.514(0.81),6.975(2.59),6.986(2 .60),7.055(4.85),7.086(2.34),7.100(3.21),7.151(5.87),7.165(3.90),7.382(1.58),7.443(3.94),7.456(3.77),7.469(3.40),7.556(1.45),7.996(7.92),8.131(0.44).

[1031] Example 36A

[1032] [4-(4-bromophenyl)piperazin-1-yl](1-fluorocyclobutyl)methyl ketone

[1033]

[1034] A solution of 1-fluorocyclobutane-1-carboxylic acid (269 mg, 2.28 mmol) in N,N-dimethylformamide (10 mL) was treated with HATU (788 mg, 2.07 mmol) and N,N-diisopropylethylamine (720 μl, 4.1 mmol) and stirred at room temperature for 10 min. Then, 1-(4-bromophenyl)piperazine (500 mg, 2.07 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with water and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 440 mg (62% yield) of the title compound.

[1035] LC-MS (Method 3): R t =2.15min; MS(ESIpos):m / z=341[M+H] +

[1036] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.486(1.46),1.501(2.95),1.515(3.10),1.519(2.12),1.530(1 .62),1.533(1.37),1.834(0.81),1.841(0.96),1.846(1.02),1.852(2.29),1.859(2.37),1.864(1 .39),1.870(2.33),1.876(2.27),1.883(1.00),1.887(0.92),1.894(0.81),2.069(1.17),2.348(1.27),2.353(0.79),2.365(2.52),2.370(2.33),2.380(2.35),2.385(3.91),2.403(3.62),2.408(2 .35),2.418(2.12),2.423(2.93),2.440(1.33),2.644(1.60),2.651(2.10),2.659(2.10),2.665(4.14),2.671(3.29),2.682(3.14),2.687(3.75),2.694(1.77),2.702(1.60),2.709(1.21),3.148(1 1.61), 3.156(16.00), 3.164(11.71), 3.260(0.42), 3.555(4.79), 3.634(4.79), 6.903(1.50), 6.909(14.56), 6.924(15.31), 6.930(1.50), 7.351(1.60), 7.356(15.88), 7.371(14.65), 7.377(1.29).

[1037] Example 37A

[1038] 1-(4-bromophenyl)-4-[(1-fluorocyclobutyl)methyl]piperazine

[1039]

[1040] Under argon atmosphere, a solution of 4-(4-bromophenyl)piperazin-1-yl](1-fluorocyclobutyl) ketone (Example 36A, 440 mg, 1.29 mmol) in THF (8.9 mL) was treated dropwise with a BH3·THF complex solution (26 mL, 1 N, 26 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with methanol and evaporated. The residue was dissolved in ethyl acetate and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 300 mg (71% yield) of the title compound.

[1041] LC-MS (Method 3): R t =1.18min; MS(ESIpos):m / z=327[M+H] +

[1042] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.493(1.79),1.508(1.95),1.764(2.01),2.184(7.41),2.383(0.42),2.604(13.67),2.65 9(5.19),3.111(16.00),3.245(0.40),3.256(0.53),3.323(0.56),6.868(7.05),6.882(7.58),7.3211(6.99),7.334(6.82).

[1043] Example 38A

[1044] 1-[(1-fluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1045]

[1046] A solution of 1-(4-bromophenyl)-4-[(1-fluorocyclobutyl)methyl]piperazine (Example 39A, 200 mg, 611 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxane (232 mg, 917 μmol) in 1,4-dioxane (6.0 mL) was treated under argon atmosphere with Pd2dba3 (16.8 mg, 18.0 μmol), X-Phos (17.5 mg, 37.0 μmol), and potassium acetate (180 mg, 1.83 mmol). The mixture was stirred overnight at 105 °C, then filtered through diatomaceous earth and concentrated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 228 mg (quantitative) of the title compound.

[1047] LC-MS (Method 3): R t =1.42min; MS(ESIpos):m / z=375[M+H] +

[1048] Example 39A

[1049] 1-[1-(4-chloro-4'-{4-[(1-fluorocyclobutyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1050]

[1051] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 92.0 mg, 173 μmol) and (4-{4-[(1-fluorocyclobutyl)methyl]piperazin-1-yl}phenyl)boronic acid (Example 38A, 60.6 mg, 208 μmol) in toluene / ethanol (1:1, 2.4 ml) was treated with Pd(PPh3)4 (9.99 mg, 8.65 μmol) and an aqueous solution of sodium carbonate (260 μl, 2N, 520 μmol), and the reaction was stirred at 100 °C for 3 hours. The reaction mixture was diluted with acetonitrile and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 73.0 mg (61% purity, 41% yield) of the title compound, which was used without further purification.

[1052] LC-MS (Method 3): R t =2.28min; MS(ESIpos):m / z=630[M+H]+

[1053] Example 40A

[1054] (3-Fluorobicyclo[1.1.1]pent-1-yl){4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl} methyl ketone

[1055]

[1056] A solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (248 mg, 1.91 mmol) in DMF (8.0 mL) was treated with HATU (660 mg, 1.73 mmol) and N,N-diisopropylethylamine (600 μl, 3.5 mmol) and stirred at room temperature for 10 min. Then, 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (500 mg, 1.73 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with water and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 450 mg (64% yield) of the title compound.

[1057] LC-MS (Method 3): R t =2.12min; MS(ESIpos):m / z=401[M+H] +

[1058] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.262(11.68),2.404(3.66),2.408(3.63),3.21 7(0.58),3.287(16.00),6.891(0.74),6.906(0.79),7.521(0.82),7.535(0.78).

[1059] Example 41A

[1060] 1-[(3-fluorobicyclo[1.1.1]pent-1-yl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine

[1061]

[1062] Under argon atmosphere, a solution of (3-fluorobicyclo[1.1.1]pent-1-yl){4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (Example 40A, 340 mg, 849 μmol) in THF (6.0 mL) was treated dropwise with a BH3·THF complex solution (17 mL, 1 N, 17 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with methanol and evaporated. The residue was dissolved in ethyl acetate and purified by rapid chromatography (silica gel-dichloromethane / methanol gradient) to give 353 mg (quantitative) of the title compound, which was used directly without further purification.

[1063] LC-MS (Method 3): R t =2.41min; MS(ESIpos):m / z=387[M+H] +

[1064] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.263(16.00),2.178(4.94),2.185(4.66),2.963(0.91),2.977(1.65),2.989(0.88),3.247(1.9 1),3.405(0.53),3.417(0.80),3.430(0.69),3.444(0.71),3.458(0.41),6.905(1.08),6.927(1.06),7.523(1.25),7.545(1.06).

[1065] Example 42A

[1066] 1-[1-(4-chloro-4'-{4-[(3-fluorobicyclo[1.1.1]pent-1-yl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1067]

[1068] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 180 mg, 338 μmol) and 1-[(3-fluorobicyclo[1.1.1]pent-1-yl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxanepentoborane-2-yl)phenyl]piperazine (Example 41A, 157 mg, 406 μmol) in toluene / ethanol (1:1 5.0 ml) was treated with Pd(PPh3)4 (19.6 mg, 16.9 μmol) and an aqueous sodium carbonate solution (510 μl, 2N, 1.0 mmol) in toluene / ethanol (1:1 5.0 ml) and stirred at 100 °C for 3 hours. The reaction mixture was concentrated, and the residue was purified by rapid chromatography (silica gel, dichloromethane / methanol, gradient). The product containing the fraction was then purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 64.0 mg (28% yield) of the title compound.

[1069] LC-MS (Method 3): R t =2.08min; MS(ESIpos):m / z=642[M+H] +

[1070] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.071(4.26),1.265(4.72),1.277(9.86),1.289(4.88),1.50 2(0.45),1.524(0.48),1.704(0.59),1.726(0.49),1.889(0.49),1.896(0.46),1.909(0.49), 1.979 (0.61), 2.016 (16.00), 2.020 (15.80), 2.559 (3.85), 2.568 (3.09), 2.667 (5.76), 3.010 (0.73), 3.027 (1.46), 3.045 (1.36), 3.061 (0.60), 3.158 (2.44), 3.164 (3.22), 3.168 (3.24), 3.1 75(2.33),3.250(0.75),3.262(0.77),3.268(0.80),3.899(0.66),4.243(1.32),4.254(4.04),4.266(3.85),4.278(1.21),4.485(0.42),4.502(0.66),6.953(3.26),6.968(3.39),7.045(2 .50),7.048(2.86),7.081(1.44),7.085(1.18),7.095(1.92),7.098(1.80),7.150(3.57),7.164(2.36),7.387(0.73),7.431(3.86),7.445(3.50),7.474(1.49),7.560(0.67),7.998(3.96).

[1071] Example 43A

[1072] 1-(2,2-Difluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1073]

[1074] Under argon atmosphere, a solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (500 mg, 1.73 mmol) in DMF (8.1 mL) was treated with N,N-diisopropylethylamine (940 μl, 5.4 mmol) and 2,2-difluoroethyltrifluoromethanesulfonate (1.04 g, 4.86 mmol). The mixture was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 582 mg (92% yield) of the title compound, which was ready for use without further purification.

[1075] LC-MS (Method 3): R t =2.03min; MS(ESIpos):m / z=353[M+H] +

[1076] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.257(16.00),2.636(1.04),2.644(1.30),2.653(1.08),2.772(0.61),2.7 79(0.61),3.194(1.08),3.202(1.25),3.210(0.99),6.887(1.05),6.902(1.05),7.496(1.17),7.511(1.05).

[1077] Example 44A

[1078] 1-[1-{4-chloro-4'-[4-(2,2-difluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1079]

[1080] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 11A, enantiomer 1, 113 mg, 213 μmol) and 1-(2,2-difluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 43A, 90.0 mg, 256 μmol) in toluene / ethanol (1:1, 3.0 mL) was treated with Pd(PPh3)4 (12.3 mg, 10.6 μmol) and an aqueous sodium carbonate solution (320 μl, 2.0 M, 640 μmol) in toluene / ethanol (1:1, 3.0 mL) and stirred at 100 °C for 3 hours. The reaction mixture was acidified with formic acid and filtered through an Extrulut filter. The filtrate was concentrated to give 87.0 mg (65% yield) of the title compound, which could be used without further purification.

[1081] LC-MS (Method 3): R t =2.90min; MS(ESIpos):m / z=608[M+H] +

[1082] Example 45A

[1083] 1-[1-{4-chloro-4'-[4-(2,2-difluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1084]

[1085] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 113 mg, 213 μmol) and 1-(2,2-difluoroethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 43A, 90.0 mg, 256 μmol) in toluene / ethanol (1:1 3.0 ml) was treated with Pd(PPh3)4 (12.3 mg, 10.6 μmol) and an aqueous sodium carbonate solution (320 μl, 2.0 M, 640 μmol) in toluene / ethanol (1:1 3.0 ml) and stirred at 100 °C for 3 hours. The reaction mixture was acidified with formic acid and filtered through an Extrulut filter. The filtrate was concentrated to give 93.0 mg (91% purity, 65% yield) of the title compound, which could be used without further purification.

[1086] LC-MS (Method 3): R t =2.91min; MS(ESIpos):m / z=608[M+H] +

[1087] Example 46A

[1088] 4-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[1089]

[1090] A suspension of 2-bromo-4-chloro-1-iodobenzene (518 mg, 1.63 mmol), {4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}boronic acid (500 mg, 1.63 mmol), and Pd(PPh3)4 (94.4 mg, 81.7 μmol) was treated with an aqueous sodium carbonate solution (2.4 mL, 2.0 M, 4.9 mmol) under argon atmosphere and heated overnight at 85 °C. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 390 mg (52% yield) of the title compound.

[1091] LC-MS (Method 3): R t =2.82min; MS(ESIpos):m / z=451[M+H] +

[1092] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.43),0.008(0.47),1.419(1.16),1.428(16 .00),3.166(0.88),3.179(1.25),3.192(1.05),3.458(0.93),3.471(1.13),3.483(0.7 8), 7.006(1.04), 7.028(1.24), 7.258(1.42), 7.280(1.16), 7.355(0.92), 7.376(1.19), 7.488(0.68), 7.493(0.69), 7.508(0.50), 7.514(0.52), 7.820(1.11), 7.826(1.09).

[1093] Example 47A

[1094] 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine hydrochloride

[1095]

[1096] A solution of 4-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (prepared according to Example 46A, 664 mg, 1.47 mmol) in dichloromethane was treated with a solution of hydrogen chloride in dioxane (3.7 mL, 4.0 M, 15 mmol), stirred for 2.5 h, and evaporated. The residue was ground in diethyl ether. The solid was filtered off to give 602 mg (quantitative) of the title compound.

[1097] LC-MS (Method 3): R t =1.46min; MS(ESIpos):m / z=351[M+H] +

[1098] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:0.146(0.66),1.596(1.27),2.329(0.80),2.671(0.82),3.360(1. 28),3.437(12.88),3.451(14.96),3.463(10.26),3.568(1.96),4.670(3.35),5.756(2.57),7.002( 0.87), 7.055(12.43), 7.077(14.87), 7.294(16.00), 7.315(12.89), 7.362(11.21), 7.382(14.09), 7.502(7.29), 7.507(7.43), 7.522(5.26), 7.528(5.74), 7.835(12.20), 7.840(11.66), 9.202(2.59).

[1099] Example 48A

[1100] 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine

[1101]

[1102] Under argon atmosphere, a solution of 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine hydrochloride (Example 47A, 600 mg, 1.55 mmol) in DMF (7.8 mL) was treated with N,N-diisopropylethylamine (1.6 mL, 9.3 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (670 μL, 4.6 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 536 mg (80% yield) of the title compound.

[1103] LC-MS (Method 4): R t =1.42min; MS(ESIpos):m / z=433[M+H] + (Isotope 1) m / z = 435 [M+H] + (isotope 2)

[1104] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.007(1.98),0.008(2.22),2.740(0.98),2.758(11.29),2.770(14.79),2.782(12.18) ,3.115(0.79),3.128(0.89),3.140(0.72),3.205(12.89),3.212(13.88),3.218(16.00),3.230(12.50),3.236(11.79),3. 262(9.39),3.288(3.13),6.914(0.51),6.935(0.60),6.990(11.06),7.011(13.08),7.204(0.54),7.246(13.70),7.267(11.56),7.354(8.19),7.375(10.92),7.485(5.59),7.490(5.77),7.506(4.15),7.511(4.36),7.817(7.70),7.823(7.57).

[1105] Example 49A

[1106] 1-[1-{4-chloro-4'-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1107]

[1108] Under argon atmosphere, a solution of 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine (Example 48A, 150 mg, 346 μmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared according to Example 6A, enantiomer 1, 94.5 mg, 346 μmol) in toluene (3.0 mL) was treated with cesium carbonate (282 mg, 865 μmol) and RuPhos Pd G3 (57.9 mg, 69.2 μmol) and stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.5% formic acid gradient) to give 62.7 mg (29% yield) of the title compound.

[1109] LC-MS (Method 4): R t =1.58min; MS(ESIpos):m / z=626[M+H] +

[1110] Example 50A

[1111] 1-[1-{4-chloro-4'-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1112]

[1113] Under argon atmosphere, a solution of 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)-4-(2,2,2-trifluoroethyl)piperazine (Example 48A, 150 mg, 346 μmol) and ethyl 5-(difluoromethyl)-1-[piperidin-3-yl]-1H-pyrazole-4-carboxylate (prepared according to Example 7A, enantiomer 2, 94.5 mg, 346 μmol) in toluene (3.0 mL) was treated with cesium carbonate (282 mg, 865 μmol) and RuPhos Pd G3 (57.9 mg, 69.2 μmol) and stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.5% formic acid gradient) to give 66.6 mg (30% yield) of the title compound.

[1114] LC-MS (Method 4): R t =1.58min; MS(ESIpos):m / z=626[M+H] +

[1115] Example 51A

[1116] 3,3-Difluoropropyl 4-methylbenzene-1-sulfonic acid

[1117]

[1118] Under argon atmosphere, a solution of 3,3-difluoroprop-1-ol (100 mg, 1.04 mmol) in dichloromethane (970 μl) and pyridine (680 μl) was stirred at room temperature for 30 min and cooled to -10 °C. Then, 4-methylbenzene-1-sulfonyl chloride (238 mg, 1.25 mmol) was slowly added, and the resulting mixture was stirred at 0 °C for 2.5 h and then overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed once with water, and then washed with a saturated sodium chloride solution. The organic layer was dried over sodium sulfate and evaporated to give 202 mg (77% yield) of the title compound, which was used directly in subsequent steps without further purification.

[1119] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:2.173(0.86),2.181(0.93),2.192(1.13),2.202(1.71),2.209(1.72),2.220(1.14),2.230(0.86),2.238( 0.85),2.287(7.61),2.431(16.00),4.126(3.53),4.136(6.70),4.14 6(3.44),4.800(0.70),4.811(1.36),4.823(0.67),6.006(0.79),6.0 92(0.79),6.099(1.59),6.106(0.78),6.192(0.81),6.200(0.42),7.103(1.84),7.116(1.98),7.467(2.27),7.480(2.14),7.494(3.88),7.508(4.20),7.798(5.08),7.812(4.60),8.170(0.48),8.182(0.75),8.193(0.51),8.629(0.50),8.845(0.48),9.123(0.91),9.132(0.90).

[1120] Example 52A

[1121] 1-(3,3-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1122]

[1123] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (80.0 mg, 278 μmol) in acetonitrile (3.5 mL) was treated with 3,3-difluoropropyl 4-methylbenzene-1-sulfonic acid (Example 51A, 83.4 mg, 333 μmol), potassium carbonate (192 mg, 1.39 mmol), and potassium iodide (4.61 mg, 27.8 μmol) and stirred overnight at 70 °C. The reaction mixture was combined with 100 mg of the test reactant, filtered through diatomaceous earth, and washed with acetonitrile. The filtrate was evaporated, and the residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 152 mg (66% yield) of the title compound.

[1124] LC-MS (Method 3): R t =1.20min; MS(ESIpos):m / z=367[M+H] +

[1125] Example 53A

[1126] 1-[1-{4-chloro-4'-[4-(3,3-difluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1127]

[1128] Under argon atmosphere, solutions of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 91.4 mg, 172 μmol) and 1-(3,3-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 52A, 75.5 mg, 206 μmol) in toluene (960 μl) and ethanol (960 μl) were treated with sodium carbonate aqueous solution (260 μl, 2.0 M, 520 μmol) and Pd(PPh3)4 (9.93 mg, 8.59 μmol) and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate. The filtrate was evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 76.0 mg (71% yield) of the title compound.

[1129] LC-MS (Method 3): R t =2.19min; MS(ESIpos):m / z=622[M+H] +

[1130] Example 54A

[1131] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-(3,3,3-trifluoropropyl)piperazine

[1132]

[1133] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]piperazine (300 mg, 1.04 mmol) in THF (6.4 mL) was treated with N,N-diisopropylethylamine (270 μl, 1.6 mmol) and 3,3,3-trifluoropropanal (481 mg, 4.16 mmol). The resulting mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (662 mg, 3.12 mmol) was added, and the resulting mixture was stirred at 55 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to give 482 mg (73% purity, 88% yield) of the title compound, which was used directly for the next step without further purification.

[1134] LC-MS (Method 3): R t=1.54min; MS(ESIpos):m / z=385[M+H] +

[1135] Example 55A

[1136] 1-[1-{4-chloro-4'-[4-(3,3,3-trifluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1137]

[1138] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 100 mg, 188 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-(3,3,3-trifluoropropyl)piperazine (Example 54A, 119 mg, 73% purity, 226 μmol) in a toluene / ethanol 1:1 mixture was treated with sodium carbonate aqueous solution (280 μl, 2.0 M, 560 μmol) and Pd(PPh3)4 (10.9 mg, 9.40 μmol) and stirred at 100 °C for 4 hours. The reaction mixture was cooled to room temperature, acidified with formic acid, and filtered using an EXtrelut NT 3 filter cartridge. The filtrate was evaporated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 66.0 mg (55% yield) of the title compound.

[1139] LC-MS (Method 3): R t =2.54min; MS(ESIpos):m / z=640[M+H] +

[1140] Example 56A

[1141] 2,2-Difluoro-1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]piperazin-1-yl}prop-1-one

[1142]

[1143] A solution of 2,2-difluoropropionic acid (147 mg, 1.34 mmol) in dichloromethane (5.0 mL) was treated with HATU (462 mg, 1.21 mmol) and N,N-diisopropylethylamine (420 μl, 2.4 mmol), followed by the addition of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (350 mg, 1.21 mmol). The resulting mixture was stirred overnight at room temperature and then diluted with water and dichloromethane. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 287 mg (62% yield) of the title compound.

[1144] LC-MS (Method 3): R t =2.25min; MS(ESIpos):m / z=381[M+H] +

[1145] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.263(16.00),1.795(0.88),1.829(1.80),1.863(0.81),3.2 84(1.31),3.670(0.58),3.771(0.57),6.920(1.05),6.935(1.14),7.526(1.12),7.540(1.11).

[1146] Example 57A

[1147] 1-(2,2-Difluoropropyl)-4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1148]

[1149] Under argon atmosphere, a solution of 2,2-difluoro-1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl}prop-1-one (Example 56A, 286 mg, 752 μmol) in THF (1.4 mL) was added dropwise with a BH3·THF complex solution (7.5 mL, 1 N, 7.5 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by rapid chromatography (silica gel cyclohexane / ethyl acetate gradient) to give 212 mg (77% yield) of the title compound.

[1150] LC-MS (Method 3): R t=2.19min; MS(ESIpos):m / z=367[M+H] +

[1151] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.260(16.00),1.612(0.81),1.644(1.67),1.676(0.77),2.648(1.06),2.656(1.41),2.664(1.20),2.7 39(0.48),2.762(0.99),2.786(0.47),3.197(1.10),3.206(1.37),3 .214(1.12),6.882(1.02),6.897(1.09),7.497(1.10),7.511(1.06).

[1152] Example 58A

[1153] 1-[1-{4-chloro-4'-[4-(2,2-difluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1154]

[1155] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 11A, enantiomer 1, 84.7 mg, 159 μmol) and 1-(2,2-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 57A, 70.0 mg, 191 μmol) in toluene / ethanol (1:1, 2.3 ml) was treated with Pd(PPh3)4 (9.20 mg, 7.96 μmol) and an aqueous sodium carbonate solution (240 μl, 2N, 480 μmol) in toluene / ethanol. The reaction was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 70 mg (71% yield) of the title compound.

[1156] LC-MS (Method 3): R t =3.00min; MS(ESIpos):m / z=622[M+H] +

[1157] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.022(1.04),0.025(0.49),1.235(3.16),1.264(8.16),1 .276(16.00),1.288(7.88),1.504(1.18),1.524(1.27),1.546(0.60),1.710(2.76),1.731(1 0.97), 1.880(0.53), 1.895(1.20), 1.916(1.31), 1.936(0.62), 1.980(1.68), 2.384(0.45), 2.423(0.60), 2.559(1.72), 2.577(0.97), 2.613(0.46), 2.652(0.81), 2.707(1.27), 3.012(1.8 4), 3.030(3.65), 3.047(3.25), 3.061(1.76), 3.195(2.81), 3.246(2.79), 3.265(2.79), 4.243(2.44), 4.255(7.22), 4.266(7.02), 4.278(2.26), 4.481(0.92), 4.499(1.60), 4.517(0.83) ),6.987(2.89),6.999(3.04),7.057(4.82),7.089(2.23),7.102(3.20),7.155(5.91),7.168(3.92),7.391(1.48),7.451(3.77),7.464(3.69),7.478(3.34),7.565(1.34),7.998(7.89).

[1158] Example 59A

[1159] 1-[1-{4-chloro-4'-[4-(2,2-difluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1160]

[1161] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 84.7 mg, 159 μmol) and 1-(2,2-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 57A, 70.0 mg, 191 μmol) in toluene / ethanol (1:1, 2.3 ml) was treated with Pd(PPh3)4 (9.20 mg, 7.96 μmol) and an aqueous sodium carbonate solution (240 μl, 2N, 480 μmol) in toluene / ethanol. The reaction was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 74.0 mg (75% yield) of the title compound.

[1162] LC-MS (Method 3): R t =2.99min; MS(ESIpos):m / z=622[M+H] +

[1163] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.175(0.61),1.235(0.79),1.264(7.86),1.276(16.00),1.288(8.01),1.50 5(0.90),1.526(0.99),1.628(4.72),1.660(9.79),1.692(4.44),1.707(1.32),1.728(1.05),1.891(0.96),1. 897(0.91),1.911(1.03),1.917(1.01),1.932(0.52),1.987(2.08),2.423(0.51),2.567(1.06),2.612(0.43),2.652(0.56),2.681(5.88),2.689(8.80),2.697(6.56),2.758(2.80),2.781(5.55),2.804(2.59),3.011(1.4 9), 3.028(2.94), 3.046(2.77), 3.063(1.25), 3.174(5.36), 3.184(6.96), 3.190(5.25), 3.250(1.68), 3.271(1.80), 4.242(2.38), 4.254(7.08), 4.266(6.88), 4.277(2.19), 4.485(0.83), 4.503(1.32), 4.521(0.76), 6.96 6(6.15),6.980(6.44),7.046(4.64),7.049(5.19),7.083(2.44),7.086(1.98),7.097(3.30),7.100(2.99),7.153(5.92),7.166(4.02),7.388(1.38),7.436(7.03),7.451(6.40),7.475(2.81),7.562(1.17),7.998(7.50).

[1164] Example 60A

[1165] 1-[1-(4-chloro-4'-{4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1166]

[1167] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 18A, enantiomer 2, 150 mg, 276 μmol) in DMF (2.7 mL) was treated with 1-bromo-2-(trifluoromethoxy)ethane (48 μl, 410 μmol) and potassium carbonate (114 mg, 827 μmol). The resulting mixture was stirred overnight at room temperature. A further portion of potassium carbonate (38.1 mg, 276 μmol) and 1-bromo-2-(trifluoromethoxy)ethane (16 μl, 140 μmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 31.9 mg (18% yield) of the title compound.

[1168] LC-MS (Method 3): R t =2.47min; MS(ESIpos):m / z=656[M+H] +

[1169] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.021(0.71),1.235(1.56),1.263(7.61),1.275(16.00),1.287(7.76),1.5 11(0.79),1.532(0.83),1.710(1.05),1.733(0.88),1.891(0.81),1.896(0.76),1.911(0.92),1.917(0.86),1 .982(1.06),2.423(0.42),2.557(1.82),2.576(0.90),2.600(5.04),2.608(7.34),2.616(5.61),2.652(0.40),2.691(2.72),2.700(5.27),2.710(2.88),3.009(1.30),3.027(2.50),3.045(2.29),3.068(1.14),3.176(4.8 0), 3.185(6.06), 3.192(4.72), 3.245(1.41), 3.262(1.57), 3.309(1.81), 4.198(3.71), 4.207(7.14), 4.216(3.71), 4.242(2.15), 4.254(6.35), 4.266(6.09), 4.277(1.92), 4.482(0.68), 4.501(1.15), 4.519(0.64), 6.97 1(5.57),6.985(5.81),7.048(4.20),7.051(4.88),7.083(2.32),7.086(1.88),7.097(3.15),7.100(2.91),7.153(5.77),7.166(3.91),7.382(1.20),7.436(6.44),7.450(5.93),7.469(2.60),7.556(1.03),7.995(6.66).

[1170] LC-MS (Method 3): R t =2.46min; MS(ESIpos):m / z=656[M+H] +

[1171] Example 61A

[1172] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomeric mixture 1)

[1173]

[1174] A solution of 2,2-difluorocyclopropane-1-carboxylic acid (43.5 mg, 357 μmol) in dichloromethane (1.3 mL) was treated with HATU (123 mg, 324 μmol) and N,N-diisopropylethylamine (230 μl, 1.3 mmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 1, 200 mg, 324 μmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 136 mg (64% yield) of the title compound.

[1175] LC-MS (Method 4): R t =1.45min; MS(ESIpos):m / z=648[M+H] +

[1176] Two diastereomers were separated by preparative chiral HPLC [Sample preparation: 136 mg dissolved in 4 ml ethanol + 2 ml n-heptane; injection volume: 360 μl; column: Daicel Chiralpak IH 5 μm, 250 x 20 mm; eluent: n-heptane / ethanol 75:25; flow rate: 18 ml / min; temperature: 35 °C; UV detection: 235 nm]. After separation, 62 mg of diastereomer 1 (Example 62A) and 63 mg of diastereomer 2 (Example 63A) were separated.

[1177] Example 62A

[1178] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 1)

[1179] See Example 61A for separation conditions.

[1180] Analytical chiral HPLC: Rt = 5.518 min, ee = 100% [Column: Daicel Chiralpak IH 5 μm, 250 x 4.6 mm; Eluent: n-heptane / ethanol 75:25 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 35 °C; UV detection: 235 nm].

[1181] Example 63A

[1182] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 2)

[1183] See Example 61A for separation conditions.

[1184] Chiral HPLC analysis: Rt = 7.122 min, ee = 100% [Column: Daicel Chiralpak IH 5 μm, 250 x 4.6 mm; Eluent: n-heptane / ethanol 75:25 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 35 °C; UV detection: 235 nm].

[1185] Example 64A

[1186] 1-{1-[4-chloro-4'-(4-{[2,2-difluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 1)

[1187]

[1188] Under argon atmosphere, a solution of 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl]piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 62A, non-corresponding isomer 1, 62 mg, 96.9 μmol) in THF (940 μl) was added dropwise to a solution of the BH3·THF complex in THF (970 μl, 1.0 M, 970 μmol), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was carefully quenched with water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 19.0 mg (31% yield) of the title compound.

[1189] LC-MS (Method 4): Rt = 1.11 min; MS (ESIpos): m / z = 634 [M+H] +

[1190] Example 65A

[1191] 1-{1-[4-chloro-4'-(4-{[2,2-difluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 2)

[1192]

[1193] Under argon atmosphere, a solution of 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 63A, non-corresponding isomer 2, 63 mg, 97.7 μmol) in THF (950 μl) was added dropwise to a solution of the BH3·THF complex in THF (980 μl, 1.0 M, 980 μmol), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was carefully quenched with water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 21.0 mg (34% yield) of the title compound.

[1194] LC-MS (Method 4): Rt = 1.11 min; MS (ESIpos): m / z = 634 [M+H] +

[1195] Example 66A

[1196] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomeric mixture 2)

[1197]

[1198] A solution of 2,2-difluorocyclopropane-1-carboxylic acid (54.4 mg, 446 μmol) in dichloromethane (1.6 mL) was treated with HATU (154 mg, 405 μmol) and N,N-diisopropylethylamine (280 μl, 1.6 mmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 250 mg, 405 μmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 191 mg (73% yield) of the title compound.

[1199] LC-MS (Method 3): Rt = 2.79 min; MS (ESIpos): m / z = 648 [M+H]+

[1200] Another batch of Example 66A (diastereomer mixture 2) was prepared, and the two diastereomers were separated by preparative chiral HPLC [Sample preparation: 108 mg was dissolved in 3 ml ethanol + 3.5 ml n-heptane; injection volume: 440 μl; column: Daicel Chiralpak IG 5 μm, 250 x 20 mm; eluent: n-heptane / ethanol 80:20; flow rate: 17 ml / min; temperature: 40 °C; UV detection: 220 nm]. After separation, 52 mg of diastereomer 3 (Example 67A) eluted first and 53 mg of diastereomer 4 (Example 68A) eluted later were separated.

[1201] Example 67A

[1202] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 3)

[1203] See Example 66A for separation conditions.

[1204] Analytical chiral HPLC: Rt = 10.834 min, ee = 100% [Column: Daicel Chiralpak IG 5 μm, 250 x 4.6 mm; Eluent: n-heptane / ethanol 80:20 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[1205] Example 68A

[1206] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 4)

[1207] See Example 66A for separation conditions.

[1208] Analytical chiral HPLC: Rt = 12.298 min, ee = 100% [Column: Daicel Chiralpak IG 5 μm, 250 x 4.6 mm; Eluent: n-heptane / ethanol 80:20 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 40 °C; UV detection: 235 nm].

[1209] Example 69A

[1210] 1-{1-[4-chloro-4'-(4-{[2,2-difluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 2)

[1211]

[1212] Under argon atmosphere, a solution of 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 66A, diastereomer mixture 2, 191 mg, 295 μmol) in THF (17 ml) was added dropwise with a BH3·THF complex solution (2.9 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with water and evaporated. The residue was redissolved in water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 140 mg (75% yield) of the title compound.

[1213] LC-MS (Method 3): Rt = 2.07 min; MS (ESIpos): m / z = 634 [M+H] +

[1214] Example 70A

[1215] 1-{1-[4-chloro-4'-(4-{[2,2-difluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 3)

[1216]

[1217] Under argon atmosphere, a solution of 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 67A, non-corresponding isomer 3, 85.3 mg, 132 μmol) in THF (7.4 ml) was added dropwise to the solution of the BH3·THF complex in THF (1.3 ml, 1.0 M, 1.3 mmol), and the resulting mixture was stirred overnight at room temperature. A second portion of the BH3·THF complex solution in THF (1.3 ml, 1.0 M, 1.3 mmol) was then added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 35.0 mg (42% yield) of the title compound.

[1218] LC-MS (Method 4): Rt = 1.07 min; MS (ESIpos): m / z = 634 [M+H] +

[1219] Example 71A

[1220] 1-{1-[4-chloro-4'-(4-{[2,2-difluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 4)

[1221]

[1222] Under argon atmosphere, a solution of 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 68A, diastereomeric 4, 88.1 mg, 136 μmol) in THF (7.7 ml) was added dropwise to the solution of the BH3·THF complex in THF (1.4 ml, 1.0 M, 1.4 mmol), and the resulting mixture was stirred overnight at room temperature. A second portion of the BH3·THF complex solution in THF (1.4 ml, 1.0 M, 1.4 mmol) was then added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with water and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 58.8 mg (68% yield) of the title compound.

[1223] LC-MS (Method 3): Rt = 2.07 min; MS (ESIpos): m / z = 634 [M+H] +

[1224] Example 72A

[1225] 1-[1-(4-chloro-4'-{4-[trans-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomeric mixture 2)

[1226]

[1227] A solution of trans-2-fluorocyclopropane-1-carboxylic acid (25.3 mg, 243 μmol) in DMF (2.3 mL) was treated with HATU (126 mg, 331 μmol) and N,N-diisopropylethylamine (120 μl, 660 μmol). After stirring at room temperature for 10 min, ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (prepared according to Example 18A, enantiomer 2, 120 mg, 221 μmol) was added, and the resulting mixture was stirred overnight at room temperature. Purification by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) yielded 96.0 mg (69% yield) of the title compound.

[1228] LC-MS (Method 3): Rt = 2.77 min; MS (ESIpos): m / z = 630 [M+H] +

[1229] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.153(0.62),1.164(1.73),1.174(2.23),1.185(2.28),1.195(1.65),1.206(0.61),1.235(0.40),1.263(7.77),1.274(16.00),1.286(7.88),1.382(0.61),1.387(0.60),1.392(0.73),1.399(0.84),1.405(0.71),1.410(0.68),1.415(0.69),1.419(0.73),1.424(0.62),1.429(0.72),1.436(0.85),1.441(0.72),1.447(0.64),1.452(0.55),1.511(0.88),1.532(0.97),1.553(0.44),1.711(1.17),1.734(0.98),1.895(0.96),1.901(0.85),1.915(0.96),1.922(0.93),1.936(0.49),1.982(1.17),1.999(0.79),2.559(1.72),2.563(1.72),2.579(0.84),2.624(0.67),2.638(0.68),2.642(0.75),2.655(1.24),2.666(0.72),2.673(0.74),2.684(0.67),3.014(1.40),3.032(2.80),3.049(2.64),3.065(1.19),3.171(1.28),3.245(2.32),3.264(2.54),3.312(0.92),3.614(2.10),3.847(2.47),4.241(2.34),4.253(7.07),4.265(6.83),4.276(2.15),4.484(0.72),4.503(1.26),4.521(0.69),4.759(0.75),4.764(0.90),4.768(0.95),4.772(0.86),4.777(0.73),4.878(0.92),4.881(0.89),5.744(0.77),7.012(6.39),7.027(6.73),7.057(4.80),7.061(5.61),7.091(2.70),7.094(2.18),7.104(3.67),7.108(3.33),7.162(6.64),7.175(4.54), 7.390(1.15), 7.463(7.58), 7.477(9.06), 7.564(1.01), 7.996(7.65).

[1230] Two diastereomers were separated by preparative chiral HPLC [Sample preparation: 96 mg; Injection volume: 40 μl; Column: Daicel Chiralcel OX-H 5 μm, 250 x 20 mm; Eluent: n-heptane / ethanol 92.5:7.5; Flow rate: 20 mL / min; Temperature: 30 °C; UV detection: 220 nm]. After separation, 37 mg of diastereomer 3 (Example 73A) eluted first and 38 mg of diastereomer 4 (Example 74A) eluted later were obtained.

[1231] Example 73A

[1232] 1-[1-(4-chloro-4'-{4-[trans-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 3)

[1233] See Example 72A for separation conditions.

[1234] Analytical chiral HPLC: Rt = 3.505 min, ee = 100% [Column: Daicel Chiralpak OX 3 μm, 50 x 4.6 mm; Eluent: n-heptane / ethanol 90:10 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 23℃; UV detection: 220 nm].

[1235] LC-MS (Method 3): Rt = 2.77 min; MS (ESIpos): m / z = 630 [M+H] +

[1236] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.128(1.25),1.141(2.63),1.153(1.70),1.162(1.51),1.173(1.93),1.184(1.96),1.194(1.49),1.204(0.54),1.235(0.45),1.262(7.66),1.273(16.00),1.285(7.73),1.381(0.54),1.387(0.47),1.392(0.65),1.399(0.77),1.404(0.61),1.409(0.59),1.415(0.59),1.418(0.62),1.423(0.52),1.428(0.63),1.436(0.79),1.441(0.61),1.446(0.55),1.451(0.53),1.510(0.77),1.531(0.81),1.710(1.02),1.733(0.83),1.894(0.78),1.902(0.74),1.915(0.85),1.936(0.43),1.981(1.03),2.559(1.51),2.580(0.79),2.624(0.60),2.634(0.68),2.641(0.68),2.655(1.09),2.665(0.65),2.672(0.65),2.683(0.56),2.875(0.79),2.887(0.80),3.013(1.22),3.031(2.42),3.049(2.28),3.064(1.04),3.167(1.86),3.249(2.41),3.314(0.87),3.318(0.89),3.613(2.19),3.847(2.41),4.240(2.07),4.252(6.22),4.263(5.92),4.275(1.83),4.484(0.67),4.502(1.11),4.520(0.60),4.764(0.80),4.767(0.83),4.772(0.75),4.877(0.79),4.880(0.79),7.011(5.48),7.026(5.65),7.057(4.17),7.060(4.70),7.090(2.36),7.094(1.90),7.104(3.13),7.107(2.82),7.162(5.68),7.175(3.85),7.391(1.14),7.462(6.47),7.477(8.05), 7.564(0.96), 7.996(6.51).

[1237] Example 74A

[1238] 1-[1-(4-chloro-4'-{4-[trans-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 4)

[1239] See Example 72A for separation conditions.

[1240] Chiral HPLC analysis: Rt = 3.935 min, ee = 100% [Column: Daicel Chiralpak OX 3 μm, 50 x 4.6 mm; eluent: n-heptane / ethanol 90:10 + 0.2% diethylamine; flow rate: 1.0 ml / min; temperature: 23℃; UV detection: 220 nm].

[1241] LC-MS (Method 3): Rt = 2.77 min; MS (ESIpos): m / z = 630 [M+H] +

[1242] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.129(1.63),1.141(3.35),1.153(2.12),1.163(1.46),1.174(1.89),1.185(1.91),1.195(1.43),1.206(0.54),1.262(7.70),1.274(16.00),1.286(7.61),1.382(0.52),1.387(0.47),1.392(0.61),1.399(0.68),1.405(0.57),1.409(0.56),1.415(0.56),1.418(0.58),1.424(0.49),1.429(0.60),1.436(0.72),1.442(0.57),1.447(0.55),1.452(0.48),1.510(0.73),1.531(0.76),1.711(0.92),1.733(0.74),1.894(0.75),1.901(0.68),1.915(0.76),1.921(0.72),1.983(0.93),1.998(0.60),2.559(1.32),2.563(1.29),2.579(0.71),2.624(0.58),2.627(0.55),2.635(0.60),2.638(0.56),2.642(0.64),2.645(0.58),2.655(1.02),2.666(0.63),2.669(0.58),2.673(0.63),2.676(0.56),2.684(0.55),2.863(0.41),2.875(1.20),2.887(1.19),2.899(0.41),3.013(1.20),3.031(2.33),3.048(2.18),3.065(0.91),3.149(0.79),3.185(0.83),3.247(1.99),3.265(2.36),3.615(1.39),3.847(1.77),4.241(2.03),4.252(6.08),4.264(5.82),4.276(1.79),4.483(0.64),4.494(0.64),4.501(1.04),4.508(0.66),4.519(0.59),4.759(0.63),4.761(0.71),4.764(0.75),4.767(0.75),4.772(0.72),4.777(0.56),4.867(0.61),4.870(0.70), 4.872(0.70), 4.875(0.74), 4.880(0.72), 4.882(0.64), 4.885(0.59), 7.011(5.34), 7.026(5.48), 7.057(4.07), 7.060(4.66), 7.090(2.38), 7.094(1.80), 7.104(3.08), 7.107(2.76), 7.162(5.68), 7.175(3.81), 7.389(1.14), 7.462(6.38), 7.477(7.35), 7.563(0.96), 7.995(6.41).

[1243] Example 75A

[1244] 1-{1-[4-chloro-4'-(4-{[trans-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 3)

[1245]

[1246] A solution of 1-[1-(4-chloro-4'-{4-[trans-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 73A, diastereomeric 3, 37.0 mg, 58.7 μmol) in THF (1.4 mL) was treated with a solution of the BH3·THF complex in THF (1.2 mL, 1.0 M, 1.2 mmol) and stirred overnight at 35 °C. The reaction mixture was quenched with methanol, diluted with ethyl acetate, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 16.0 mg (44% yield) of the title compound.

[1247] LC-MS (Method 3): Rt = 1.96 min; MS (ESIpos): m / z = 616 [M+H] +

[1248] Example 76A

[1249] 1-{(1-[4-chloro-4'-(4-{[trans-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 4)

[1250]

[1251] A solution of 1-[1-(4-chloro-4'-{4-[trans-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 74A, diastereomeric 4, 38.0 mg, 60.3 μmol) in THF (1.4 mL) was treated with a solution of the BH3·THF complex in THF (1.2 mL, 1.0 M, 1.2 mmol) and stirred overnight at 35 °C. The reaction mixture was quenched with methanol, diluted with ethyl acetate, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 22.0 mg (59% yield) of the title compound.

[1252] LC-MS (Method 3): Rt = 1.98 min; MS (ESIpos): m / z = 616 [M+H] +

[1253] Example 77A

[1254] [(1S,2S)-2-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl}methyl ketone

[1255]

[1256] A solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (278 mg, 2.67 mmol) in DMF (10 mL) was treated with HATU (924 mg, 2.43 mmol) and N,N-diisopropylethylamine (850 μl, 4.9 mmol) and stirred at room temperature for 10 min. Then, 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (700 mg, 2.43 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with water and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 759 mg (79% yield) of the title compound.

[1257] LC-MS (Method 3): Rt = 1.92 min; MS (ESIpos): m / z = 375 [M+H] +

[1258] H-NMR (400MHz, DMSO-d6) δ [ppm]: 1.263 (16.00), 6.922 (1.07), 6.944 (1.07), 7.518 (1.24), 7.540 (1.07).

[1259] Example 78A

[1260] 1-{[(1S,2S)-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1261]

[1262] Under argon atmosphere, a solution of [(1S,2S)-2-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (Example 77A, 759 mg, 2.03 mmol) in THF (18 ml) was treated dropwise with a BH3·THF complex solution (41 ml, 1 N, 41 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with methanol and evaporated. The residue was dissolved in ethyl acetate and purified by rapid chromatography (silica gel-dichloromethane / methanol gradient) to give 250 mg (31% yield) of the title compound, which was used directly without further purification.

[1263] LC-MS (Method 3): Rt = 1.23 min; MS (ESIpos): m / z = 361 [M+H] +

[1264] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.853(0.99),0.865(2.16),0.877(1.05),1.159( 2.02),1.260(16.00),1.264(10.64),1.290(0.41),3.041(0.44),3.220(0.52),3.3 78(0.65),3.387(0.66),4.281(0.72),6.481(0.97),6.892(0.54),6.907(0.57),6.918(0.64),6.932(0.63),7.498(0.74),7.512(0.70),7.526(0.69),7.540(0.64).

[1265] Example 79A

[1266] 1-{1-[4-chloro-4'-(4-{[(1S,2S)-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1267]

[1268] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, stereoisomer 2, 120 mg, 226 μmol) and 1-{[(1S,2S)-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 78A, 97.5 mg, 271 μmol) in toluene / ethanol (1:1, 3.3 ml) was treated with Pd(PPh3)4 (13.0 mg, 11.3 μmol) and an aqueous sodium carbonate solution (340 μl, 2N, 680 μmol) in toluene / ethanol (1:1, 3.3 ml) and stirred overnight at 100 °C. The reaction mixture was concentrated, the residue was dissolved in dichloromethane, and purified by rapid chromatography (silica gel, dichloromethane / methanol, gradient) to give 78.0 mg (91% purity, 51% yield) of the title compound, which was ready for use without further purification.

[1269] LC-MS (Method 3): Rt = 1.90 min; MS (ESIpos): m / z = 616 [M+H] +

[1270] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.539(0.54),0.543(0.53),0.550(1.02),0.554(0.99),0.562(0.61),0.567(0.59),0.577(0.54),0.581(0.54),0.588(1.04),0.593(0.98),0.600(0.60),0.605(0.56),0.810(0.52),0.821(0.96),0.830(0.88),0.838(1.40),0.847(0.99),0.857(1.10),0.867(0.58),1.009(0.46),1.022(0.92),1.032(1.02),1.048(0.78),1.263(7.72),1.275(16.00),1.286(7.87),1.515(0.86),1.536(0.92),1.558(0.41),1.713(1.18),1.735(0.92),1.888(0.91),1.894(0.84),1.908(0.95),1.915(0.93),1.929(0.45),1.984(1.17),1.999(0.77),2.378(1.49),2.391(1.46),2.399(1.64),2.412(1.60),2.564(2.03),2.574(3.14),2.583(3.18),2.591(1.58),2.624(1.51),2.632(3.16),2.640(3.90),2.651(3.32),2.661(1.87),2.670(1.32),3.007(1.38),3.024(2.76),3.042(1.75),3.053(1.26),3.073(1.19),3.189(5.38),3.198(9.13),3.206(5.27),3.249(2.17),4.241(2.12),4.253(6.37),4.265(6.18),4.276(1.93),4.483(0.75),4.501(1.26),4.520(0.72),4.724(0.64),4.728(0.68),4.734(1.19),4.738(1.20),4.744(0.65),4.748(0.60),4.834(0.58),4.839(0.62),4.844(1.18),4.848(1.16),4.854(0.67),4.858(0.58),6.973(5.96), 6.988(6.14), 7.048(4.50), 7.051(5.15), 7.083(2.36), 7.087(1.90), 7.097(3.29), 7.101(2.94), 7.152(5.84), 7.166(3.97), 7.385(1.33), 7.438(6.88), 7.45 2(6.26), 7.472(2.72), 7.540(0.42), 7.549(1.11), 7.560(1.63), 7.566(0.92), 7.604(1.13), 7.616(1.14), 7.624(1.51), 7.637(0.97), 7.995(7.28), 8.142(1.00).

[1271] Example 80A

[1272] [trans-2-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (racemic mixture)

[1273]

[1274] A solution of trans-2-fluorocyclopropane-1-carboxylic acid (278 mg, 2.67 mmol) in N,N-dimethylformamide (10 mL) was treated with HATU (924 mg, 2.43 mmol) and N,N-diisopropylethylamine (850 μl, 4.9 mmol) and stirred at room temperature for 10 min. 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (700 mg, 2.43 mmol) was added, and the mixture was stirred overnight at room temperature. Water was then added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 696 mg (74% yield) of the title compound.

[1275] LC-MS (Method 3): Rt = 2.04 min; MS (ESIpos): m / z = 375 [M+H] +

[1276] H-NMR(400MHz,DMSO-d6)δ[ppm]:1.264(16.00),3.210(0.41),3.583(0.5 6),3.821(0.61),6.919(1.02),6.941(1.11),7.518(1.18),7.539(1.10).

[1277] Example 81A

[1278] 1-{[trans-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (racemic mixture)

[1279]

[1280] In an argon atmosphere, a solution of [2-trans-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (Example 80A, racemic, 696 mg, 1.86 mmol) in THF (17 ml) was treated dropwise with a BH3·THF complex solution (37 ml). The resulting mixture was stirred at room temperature for 30 minutes. The reactants were carefully quenched and concentrated with methanol. The residue was dissolved in ethyl acetate and purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 422 mg (57% yield) of the title compound.

[1281] LC-MS (Method 3): Rt = 2.29 min; MS (ESIpos): m / z = 361 [M+H] +

[1282] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.260(3.81),1.264(16.00),3.024(0.51),3.034(0.82),3.042(0.5 5),3.448(0.58),3.455(0.40),3.461(0.51),6.919(1.01),6.933(1.04),7.526(1.15),7.541(1.04).

[1283] Example 82A

[1284] 1-{1-[4-chloro-4'-(4-{[trans-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 2)

[1285]

[1286] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 120 mg, 226 μmol) and 1-{[trans-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 81A, racemic, 97.5 mg, 271 μmol) in toluene / ethanol (1:1, 3.3 ml) was treated with Pd(PPh3)4 (13.0 mg, 11.3 μmol) and an aqueous sodium carbonate solution (340 μl, 2N, 680 μmol) in toluene / ethanol (1:1, 3.3 ml). The reaction was stirred at 100 °C for 3 hours. The reaction mixture was concentrated, and the residue was purified by rapid chromatography (silica gel, dichloromethane / methanol, gradient) followed by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 41.0 mg (27% yield) of the title compound.

[1287] LC-MS (Method 3): Rt = 1.97 min; MS (ESIpos): m / z = 616 [M+H] +

[1288] H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.55),0.146(1.56),0.499(0.43),0.515(1.24),0.531(1.32),0.541(1.33),0.557(1.24),0.574(0.47),1.000(0.52),1.005(0.48),1.016(0.55),1.027(0.70),1.033(0.64),1.044(0.61),1.050(0.65),1.055(0.68),1.061(0.53),1.072(0.56),1.083(0.72),1.089(0.62),1.099(0.60),1.105(0.56),1.235(0.47),1.257(7.43),1.275(16.00),1.293(7.59),1.339(0.43),1.369(0.53),1.386(0.65),1.404(0.57),1.433(0.42),1.504(0.64),1.537(0.74),1.706(1.00),1.738(0.77),1.879(0.72),1.909(0.77),1.977(1.03),2.114(0.83),2.133(0.84),2.141(1.18),2.160(1.11),2.269(1.06),2.285(0.86),2.300(0.75),2.323(0.70),2.327(0.89),2.366(1.53),2.524(4.07),2.570(4.57),2.586(4.85),2.598(2.54),2.614(0.97),2.665(0.69),2.669(0.89),2.674(0.69),2.710(1.53),2.999(1.03),3.025(2.21),3.051(2.20),3.075(0.98),3.180(4.13),3.192(7.38),3.204(4.11),3.247(1.45),4.233(2.08),4.251(6.42),4.268(6.17),4.286(1.92),4.472(1.44),4.487(1.58),4.501(1.06),4.633(0.98),4.648(1.01),5.754(3.02),6.970(5.05),6.993(5.42),7.048(3.87),7.053(4.77),7.082(2.09),7.087(1.47), 7.102(3.29), 7.107(2.99), 7.151(5.99), 7.171(3.40), 7.350(1.34), 7.437(6.12), 7.459(5.46), 7.480(2.70), 7.547(0.95), 7.556(0.77), 7.565(1.08), 7.573(0.91), 7.597(1.36), 7.610(1.78), 7.626(1.56), 7.643(0.77), 8.003(5.40).

[1289] Example 83A

[1290] 1-[1-(4-chloro-4'-{4-[(1R,2R)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 2)

[1291]

[1292] A solution of (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (24.1 mg, 232 μmol) in DMF (930 μl) was treated with HATU (120 mg, 316 μmol) and N,N-diisopropylethylamine (110 μl, 630 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 130 mg, 211 μmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 104 mg (78% yield) of the title compound.

[1293] LC-MS (Method 3): Rt = 2.71 min; MS (ESIpos): m / z = 630 [M+H] +

[1294] H-NMR(400MHz,DMSO-d6)δ[ppm]:0.993(0.50),1.008(1.06),1.016(0.71),1.024(1.19),1.032(1.20),1.039(1.17),1.047(1.22),1.055(0.76),1.063(1.04),1.078(0.55),1.253(7.69),1.271(16.00),1.289(7.91),1.503(1.33),1.512(1.71),1.521(1.80),1.530(1.69),1.539(1.34),1.553(1.04),1.561(1.07),1.571(1.46),1.579(1.22),1.588(0.71),1.596(0.57),1.706(1.34),1.738(1.00),1.881(0.91),1.911(1.04),1.976(1.41),2.086(0.43),2.182(0.59),2.199(1.52),2.217(1.65),2.222(1.68),2.240(1.43),2.256(0.47),2.328(0.45),2.366(0.58),2.523(2.15),2.587(1.07),2.670(0.50),2.710(0.60),2.998(1.32),3.024(3.00),3.051(2.73),3.069(1.96),3.151(1.22),3.168(1.16),3.239(2.24),3.257(1.47),3.604(1.09),3.622(1.08),3.688(1.16),3.819(2.78),4.229(2.26),4.247(7.11),4.264(6.98),4.282(2.21),4.466(0.78),4.493(1.40),4.520(0.71),4.840(0.63),4.848(0.73),4.856(1.10),4.864(1.07),4.871(0.68),4.879(0.57),5.007(0.56),5.015(0.65),5.022(1.09),5.030(1.05),5.038(0.71),5.046(0.58),5.754(8.09),7.012(6.34),7.034(6.84),7.057(4.80),7.062(5.75),7.089(2.36),7.094(1.63),7.110(3.75), 7.114(3.23), 7.160(6.56), 7.181(3.72), 7.340(1.64), 7.460(7.72), 7.470(4.11), 7.481(6.85), 7.600(1.38), 8.002(6.29).

[1295] Example 84A

[1296] 1-{1-[4-chloro-4'-(4-{[(1R,2R)-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 2)

[1297]

[1298] A solution of 1-[1-(4-chloro-4'-{4-[(1R,2R)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 84A, stereoisomer 2, 62.0 mg, 98.4 μmol) in THF (2.1 mL) was treated with a solution of the BH3·THF complex in THF (2.0 mL, 1.0 M, 2.0 mmol). The resulting mixture was stirred overnight at 35 °C and cooled to room temperature. The reaction mixture was quenched with methanol, diluted with ethyl acetate and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 17.5 mg (29% yield) of the title compound.

[1299] LC-MS (Method 3): Rt = 1.94 min; MS (ESIpos): m / z = 616 [M+H] +

[1300] Example 85A

[1301] [4-(4-bromophenyl)piperazin-1-yl][cis-2-(trifluoromethyl)cyclopropyl] (racemate)

[1302]

[1303] A solution of cis-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (351 mg, 2.28 mmol) in N,N-dimethylformamide (10 mL) was treated with HATU (788 mg, 2.07 mmol) and N,N-diisopropylethylamine (720 μl, 4.1 mmol) and stirred at room temperature for 10 min. Then, 1-(4-bromophenyl)piperazine (500 mg, 2.07 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with water and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 462 mg (59% yield) of the title compound.

[1304] LC-MS (Method 3): Rt = 2.09 min; MS (ESIpos): m / z = 377 [M+H] +

[1305] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.195(1.56),1.204(4.03),1.213(5.13),1.219(6.66),1.228(5.40),1.235(3.81),1 .243(1.35),1.400(16.00),1.987(0.48),2.194(0.97),2.205(1.74),2.215(2.30),2.226(1.93),2.238(1.09),2.558 (2.88),2.652(0.43),3.117(3.10),3.125(3.67),3.131(3.34),3.202(5.17),3.210(5.18),3.250(0.76),3.262(0.89),3.326(3.03),3.607(4.94),3.614(4.98),3.814(6.01),6.916(12.83),6.931(13.62),7.358(13.72),7.373(12.99).

[1306] Example 86A

[1307] 1-(4-Bromophenyl)-4-{[cis-2-(trifluoromethyl)cyclopropyl]methyl}(racemate)

[1308]

[1309] Under argon atmosphere, a solution of [4-(4-bromophenyl)piperazin-1-yl][cis-2-(trifluoromethyl)cyclopropyl] methyl ketone (Example 85A, racemic, 461 mg, 1.22 mmol) in 2.4 ml of THF was added dropwise with a BH3·THF complex solution (12 ml, 1 M, 12 mmol), and the resulting mixture was stirred overnight at room temperature. The second portion of the BH3·THF complex (6.1 ml, 1 M, 6.1 mmol) was added, and the reaction mixture was stirred for another 4 hours at room temperature. The third portion of the BH3·THF complex (6.1 ml, 1 M, 6.1 mmol) was added, and the reaction mixture was stirred for another 24 hours at room temperature. The reaction mixture was carefully quenched and concentrated with methanol. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) and then by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 44.9 mg (10% yield) of the title compound.

[1310] LC-MS (Method 3): Rt = 1.25 min; MS (ESIpos): m / z = 363 [M+H] +

[1311] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.718(1.40),0.727(2.91),0.741(2.96),0.751(1.56),0.941(1.94),0.950(3.74),0.957(3 .35),0.965(4.00),0.973(1.93),1.281(0.51),1.291(1.50),1.302(2.21),1.309(2.19),1.314(2.12),1.324(1.38),1.335(0 .44),1.721(2.29),2.283(1.55),2.295(1.73),2.305(2.35),2.315(2.17),2.383(2.74),2.393(2.58),2.403(1.83),2.414(1.69),3.123(11.54),3.131(16.00),3.139(10.92),6.880(14.22),6.895(15.05),7.314(1.64),7.320(15.65),7.335(14.39).

[1312] Example 87A

[1313] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[cis-2-(trifluoromethyl)cyclopropyl]methyl}(racemate)

[1314]

[1315] Under argon atmosphere, a solution of 1-(4-bromophenyl)-4-[[cis-2-(trifluoromethyl)cyclopropyl]methyl]piperazine (prepared according to Example 86A, racemic, 193 mg, 531 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxacyclopentaborane (202 mg, 797 μmol), Pd2dba3 (14.6 mg, 15.9 μmol), X-Phos (15.2 mg, 31.9 μmol), and potassium acetate (156 mg, 1.59 mmol) in cyclopentylmethyl ether (5.9 mL) was stirred overnight at 105 °C. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to give 451 mg (75% purity, quantitative) of the title compound, which was used directly without further purification.

[1316] LC-MS (Method 3): Rt = 1.45 min; MS (ESIpos): m / z = 411 [M+H] +

[1317] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.072(0.65),1.160(16.00),1.168(9.14),1.259(7.01),1.295(2.53),1.897(0.44),2.5 68(0.51),3.150(0.78),3.206(0.54),3.214(0.71),3.223(0.51),6.889(0.46),6.903(0.47),7.495(0.51),7.509(0.47).

[1318] Example 88A

[1319] 1-{1-[4-chloro-4'-(4-{[cis-2-(trifluoromethyl)cyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 2)

[1320]

[1321] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomers 2, 70.0 mg, 1...) was treated with Pd(PPh3)4 (7.60 mg, 6.58 μmol) and sodium carbonate aqueous solution (200 μl, 2N, 390 μmol) under argon atmosphere. A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-[[cis-2-(trifluoromethyl)cyclopropyl]methyl]piperazine (Example 87A, racemic, 86.4 mg, 75% purity, 158 μmol) in toluene / ethanol (1:1, 1.9 mL) was prepared and the reaction was stirred overnight at 100 °C. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 39.0 mg (44% yield) of the title compound.

[1322] LC-MS (Method 3): Rt = 2.09 min; MS (ESIpos): m / z = 666 [M+H] +

[1323] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.761(0.51),0.987(0.63),1.263(7.71),1.275(16.00),1.287( 7.84),1.347(0.47),1.510(0.81),1.531(0.86),1.713(1.15),1.734(1.17),1.890(0.85),1.898 (0.78), 1.911(0.89), 1.932(0.42), 1.982(1.09), 1.997(0.73), 2.384(0.52), 2.423(0.71), 2.558(1.79), 2.574(1.62), 2.609(1.62), 2.652(0.74), 3.009(1.34), 3.026(2.57), 3.044(2.29), 3.0 68(1.12),3.189(2.33),3.247(1.53),3.259(1.46),3.333(0.83),4.242(2.12),4.253(6.34),4.265(6.03),4.277(1.84),4.481(0.65),4.499(1.12),4.516(0.62),6.982(2.31),6.996(2.40),7 .050(3.60),7.054(3.99),7.086(2.02),7.089(1.66),7.099(2.79),7.103(2.50),7.153(5.69),7.166(3.76),7.385(1.24),7.442(3.62),7.456(3.37),7.472(2.51),7.559(1.02),7.998(6.89).

[1324] Example 89A

[1325] {4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl}[1-(trifluoromethyl)cyclopropyl]methyl ketone

[1326]

[1327] A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (206 mg, 1.34 mmol) in dichloromethane (5.0 mL) was treated with HATU (462 mg, 1.21 mmol) and N,N-diisopropylethylamine (420 μl, 2.4 mmol), followed by the addition of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (350 mg, 1.21 mmol). The resulting mixture was stirred overnight at room temperature, then water was added and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried, and concentrated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 347 mg (67% yield) of the title compound.

[1328] LC-MS (Method 3): Rt = 2.22 min; MS (ESIpos): m / z = 425

[1329] Example 90A

[1330] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine

[1331]

[1332] Under argon atmosphere, a solution of {4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl}[1-(trifluoromethyl)cyclopropyl]methyl ketone (Example 89A, 346 mg, 816 μmol) in THF (1.4 mL) was treated dropwise with a BH3·THF complex solution (8.2 mL, 1 N, 8.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by rapid chromatography (silica gel cyclohexane / ethyl acetate gradient) to give 265 mg (79% yield) of the title compound.

[1333] LC-MS (Method 4): Rt = 0.87 min; MS (ESIpos): m / z = 411

[1334] Example 91A

[1335] 1-{1-[4-chloro-4'-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1336]

[1337] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 100 mg, 188 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine (prepared according to Example 90A, 145 mg, 86% purity, 282 μmol) in toluene / ethanol (1:1, 2.3 ml) was treated with Pd(PPh3)4 (10.9 mg, 9.40 μmol) and an aqueous sodium carbonate solution (280 μl, 2.0 M, 560 μmol), and the reaction was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 10.4 mg (8% yield) of the title compound.

[1338] LC-MS (Method 3): Rt = 2.96 min; MS (ESIpos): m / z = 666 [M+H] +

[1339] Example 92A

[1340] 1-[1-{4-chloro-4'-[4-(spirocyclic[2.2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1341]

[1342] A solution of spirocyclic [2,2]pentane-1-carboxylic acid (30.0 mg, 267 μmol) in dichloromethane (980 μmol) was treated with HATU (102 mg, 267 μmol) and N,N-diisopropylethylamine (170 μl, 970 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 150 mg, 243 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 123 mg (80% yield) of the title compound.

[1343] LC-MS (Method 3): R t =2.86min; MS(ESIpos):m / z=638[M+H] +

[1344] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.690(1.40),0.781(0.76),0.789(1.36),0.796(1.89),0.804(2.42),0.811(1.46),0.830(0.90),0.841(1.57),0.845(1.40),0.850(1.43),0.918(1.01),0.926(1.70),0.933(1.84),0.941(1.52),0.948(0.71),1.200(1.85),1.206(2.28),1.212(2.17),1.218(2.04),1.262(7.84),1.274(16.00),1.286(8.01),1.414(1.96),1.420(3.36),1.427(1.94),1.511(0.92),1.531(1.02),1.554(0.42),1.713(1.30),1.734(1.06),1.890(1.01),1.896(0.96),1.910(1.08),1.916(1.04),1.931(0.52),1.979(1.32),1.996(0.88),2.354(1.65),2.365(1.89),2.373(1.60),2.565(1.84),2.584(0.90),3.007(1.21),3.024(2.60),3.043(3.03),3.065(2.40),3.182(0.81),3.237(1.82),3.254(2.13),3.320(0.74),3.580(0.88),3.627(0.85),3.678(1.79),4.241(2.07),4.252(6.24),4.264(6.15),4.276(2.02),4.473(0.67),4.491(1.24),4.507(0.67),6.991(6.64),7.006(7.01),7.057(4.98),7.060(5.89),7.088(2.81),7.092(2.29),7.102(3.82),7.105(3.49),7.156(6.63),7.170(4.46),7.377(0.89),7.381(0.91),7.454(7.90),7.469(8.63),7.554(0.83),7.993(8.04)。

[1345] Example 93A

[1346] 1-[1-(4-chloro-4'-{4-[(spirocyclic[2,2]pent-1-yl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomeric mixture 2)

[1347]

[1348] Under argon atmosphere, a solution of 1-[1-{4-chloro-4'-[4-(spirocyclo[2,2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 92A, enantiomer 2, 120 mg, 188 μmol) in THF (11 ml) was treated dropwise with a solution of the BH3·THF complex trihydro(tetrahydrofuran)boron (1.9 ml, 1 N, 1.9 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was carefully quenched with water and evaporated. The residue was redissolved in water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 76.0 mg (62% yield) of the title compound.

[1349] LC-MS (Method 9):R t =5.80min; MS(ESIpos):m / z=624[M+H] +

[1350] H-NMR(600MHz,DMSO-d6)δ[ppm]:0.702(0.82),0.711(0.67),0.724(1.00),0.732(1.76),0.739(1.00),0.786(1.31),0.797(1 .35),0.826(0.92),0.831(0.86),0.838(0.92),0.846(0.62),1.121(0.96),1.235(0.68),1.262(4.01),1.274(7.86),1.285( 3.99), 1.357(9.69), 1.398(16.00), 1.505(0.65), 1.526(0.74), 1.732(1.34), 1.896(0.48), 1.917(0.55), 1.978(0.73), 2.183(1.35), 2.562(1.01), 2.582(0.50), 2.749(0.65), 2.762(0.67), 2.770(0.85), 2.783(0.80), 2.898(0.67), 2.917(0.52), 2.9 70(1.76),3.010(0.70),3.027(1.40),3.045(1.59),3.066(1.84),3.071(1.86),3.238(0.77),3.251(0.81),3.257(0.83),3.426(1.04),3.434(1.60),3.443(2.01),3.451(1.58),3.462(1.09),4.239(1.11),4.250(3.39),4.262(3.33),4.274(1.12),4 .496(0.62),6.600(0.53),6.871(0.84),6.998(2.91),7.013(3.05),7.057(2.26),7.060(2.57),7.091(1.21),7.095(1.10),7.105(1.66),7.108(1.53),7.162(2.82),7.176(1.95),7.384(0.66),7.462(3.44),7.477(3.38),7.559(0.59),7.998(3.44).

[1351] Example 94A

[1352] 1-(oxecyclobutane-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxecyclopentaborane-2-yl)phenyl]piperazine

[1353]

[1354] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (80.0 mg, 278 μmol) was placed in 1.7 mL of THF, and N,N-diisopropylethylamine (73 μl, 420 μmol) was added. Then, oxetane-3-one (100 mg, 1.39 mmol) was added, and the mixture was stirred for 10 min. Next, sodium triacetoxyborohydride (176 mg, 833 μmol) 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 dried over sodium sulfate, filtered, and evaporated. 89 mg of the title compound was given (92% of the theoretical value).

[1355] LC-MS (Method 3): R t =1.26min; MS(ESIpos):m / z=345[M+H] +

[1356] H-NMR(500MHz,DMSO-d6)δ[ppm]:1.259(16.00),2.370(0.91),2.379(1.14),2.389(0.92),3.219(0.94),3.230(1.08),3.239(0.87),4.4 53(0.62),4.465(1.23),4.477(0.73),4.548(0.78),4.561(1.30),4 .574(0.59),6.891(0.99),6.909(1.02),7.497(1.16),7.515(1.05).

[1357] Example 95A

[1358] 1-[1-{4-chloro-4'-[4-(oxetane-3-yl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 1)

[1359]

[1360] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 11A, enantiomer 1, 150 mg, 93% purity, 262 μmol) and 1-(oxetane-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (prepared according to Example 94A, 99.3 mg, 288 μmol) were placed in 2.6 mL of DMF. Tetra(triphenylphosphine)palladium(0) (15.2 mg, 13.1 μmol) and 2 M sodium carbonate solution (390 μl, 790 μmol) were added, and the mixture was stirred at 130 °C for 2.5 h. The reaction mixture was made slightly acidic with 6 M hydrochloric acid and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in acetonitrile / water / TFA and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). The product fraction was further purified by thick-layer chromatography (dichloromethane / methanol / formic acid: 10 / 1 / 0.1). 120 mg of the title compound was given (54% of theoretical value, 85% purity).

[1361] LC-MS (Method 3): R t =2.29min; MS(ESIpos):m / z=600[M-TFA+H] +

[1362] Example 96A

[1363] 1-[1-{4-chloro-4'-[4-(oxecyclobutan-3-yl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[1364]

[1365] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylate (prepared according to Example 16A, enantiomer 2, 200 mg, 95% purity, 357 μmol) and 1-(oxecyclobutane-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxecyclopentaborane-2-yl)phenyl]piperazine (prepared according to Example 94A, 135 mg, 393 μmol) were placed in 3.5 mL of DMF. Tetra(triphenylphosphine)palladium(0) (20.6 mg, 17.9 μmol) and 2 M sodium carbonate solution (540 μl, 1.1 mmol) were added, and the mixture was stirred at 130 °C for 2.5 h. The reaction mixture was made slightly acidic with 6 M hydrochloric acid and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in acetonitrile / water / TFA and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA). The product fraction was purified by thick-layer chromatography (dichloromethane / methanol / formic acid: 10 / 1 / 0.1). 108 mg of the title compound was given (41% of theoretical value, 96% purity).

[1366] LC-MS (Method 3): R t =2.28min; MS(ESIpos):m / z=600[M+H] +

[1367] Example 97A

[1368] 1-{1-[4-chloro-4'-(pyrrolidone-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1369]

[1370] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 11A, enantiomer 1, 38.5 mg, 69.7 μmol, purity 49.7 μmol) in DMF (550 μl) was treated with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]pyrrolidine (16.3 mg, 59.7 μmol), sodium carbonate (75 μl, 2.0 M, 150 μmol), and Pd(PPh3)4 (3 mg, 2.0 μmol). The resulting mixture was stirred at 130 °C for 1.5 h and cooled to room temperature. The reaction mixture was diluted with water (30 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 10.0 mg (84% purity, 32% yield) of the title compound.

[1371] LC-MS (Method 3): R t =3.21min; MS(ESIpos):m / z=529[M+H] +

[1372] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.251(16.00),1.264(3.28),1.276(6.28),1.288(3.22),1.39 8(1.39),1.528(0.41),1.550(0.46),1.695(0.60),1.717(0.47),1.895(0.46),1.917(0.53),1. 938(1.22),1.948(2.52),1.958(2.74),1.968(4.72),1.978(2.08),3.020(0.64),3.038(1.22),3.055(0.72),3.073(0.62),3.092(0.55),3.198(0.43),3.226(1.14),3.236(2.50),3.255(4.2 0), 3.265(1.85), 3.703(0.40), 4.242(0.91), 4.253(2.64), 4.265(2.62), 4.277(0.86), 4.539(0.59), 5.747(1.01), 6.483(1.07), 6.497(1.07), 6.581(2.60), 6.596(2.56), 7.012(1.94), 7.01 6(2.04),7.063(0.95),7.067(0.79),7.077(1.31),7.080(1.15),7.136(2.34),7.150(1.66),7.382(0.65),7.415(2.87),7.429(2.67),7.454(1.15),7.468(2.07),7.555(0.55),8.001(2.85).

[1373] Example 98A

[1374] Ethyl 1-{1-[4-chloro-4'-(pyrrolidone-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (enantiomer 2)

[1375]

[1376] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 167 mg, 300 μmol) in DMF (3.3 mL) was treated with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]pyrrolidine (98.3 mg, 360 μmol), sodium carbonate (17.3 mg, 15.0 μmol), and Pd(PPh3)4 (17.3 mg, 15.0 μmol). The resulting mixture was stirred at 130 °C for 1.5 h and then cooled to room temperature. The reaction mixture was diluted with water (30 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 70.2 mg (44% yield) of the title compound.

[1377] LC-MS (Method 3): R t =3.20min; MS(ESIpos):m / z=529[M+H] +

[1378] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.229(0.96),1.263(7.73),1.276(16.00),1.287(7.94),1.525(0.79), 1.546(0.86),1.690(1.09),1.712(0.86),1.891(0.87),1.897(0.83),1.911(0.92),1.918(0.90),1.932 (0.51), 1.939(0.55), 1.955(3.56), 1.961(4.53), 1.966(9.65), 1.977(4.12), 1.987(1.48), 2.005(0.79), 2.484(0.88), 2.520(1.06), 3.020(1.31), 3.037(2.56), 3.055(1.50), 3.072(1.17), 3.091(1.11), 3.2 42(3.36),3.253(8.27),3.264(3.41),3.280(1.36),3.295(1.10),4.241(2.14),4.253(6.27),4.265(5.95),4.277(1.87),4.525(0.68),4.536(0.73),4.543(1.17),4.550(0.74),4.561(0.66),6.581(5.73),6 .595(5.89),7.013(4.40),7.016(4.85),7.068(2.30),7.072(1.97),7.082(3.20),7.085(2.99),7.137(5.89),7.151(3.95),7.399(1.23),7.423(6.61),7.438(6.18),7.485(2.44),7.572(1.00),8.016(6.96).

[1379] Example 99A

[1380] 3-[4-(4-bromophenyl)piperazin-1-yl]propionitrile

[1381]

[1382] A solution of 1-bromo-4-iodobenzene (500 mg, 1.77 mmol) and 3-(piperazin-1-yl)propionitrile (295 mg, 2.12 mmol) in 1,4-dioxane (8.0 mL) was treated with Pd₂dba₃ (40.5 mg, 44.2 μmol), Xantphos (77.7 mg, 134 μmol), and cesium carbonate (806 mg, 2.47 mmol) under argon atmosphere and stirred overnight at 100 °C. The reaction mixture was cooled, diluted with water, extracted three times with ethyl acetate, and concentrated. The crude residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 94 mg (18% yield) of the title compound.

[1383] LC-MS (Method 3): R t =1.10min; MS(ESIpos):m / z=294[M+H] +

[1384] H-NMR(400MHz,DMSO-d6)δ[ppm]:2.366(0.59),2.567(14.25),2.593(4.36),2.610(12.81),2.625(9.11), 2.670(0.45),2.694(9.38),2.710(14.56),2.726(4.38),2.729(4.12),3.113(13.70),3.126(15.62),3.13 8(12.62),3.276(0.51),5.754(0.55),6.877(1.51),6.885(14.59),6.890(4.73),6.902(5.25),6.908(16.00),6.916(1.60),7.314(1.61),7.323(15.82),7.328(4.62),7.340(4.66),7.345(14.13),7.354(1.24).

[1385] Example 100A

[1386] 3-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl}propionitrile

[1387]

[1388] Under argon atmosphere, a solution of 3-[4-(4-bromophenyl)piperazin-1-yl]propionitrile (prepared according to Example 99A, 579 mg, 1.97 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxane (750 mg, 2.95 mmol) in 1,4-dioxane (14 ml) was treated with Pd2dba3 (54.1 mg, 59.0 μmol), X-Phos (56.3 mg, 118 μmol), and potassium acetate (579 mg, 5.90 mmol). The reaction was stirred overnight at 105 °C and then filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) and then by preparative HPLC (RP18 column, eluent: acetonitrile / water, gradient) to give 321 mg (48% yield) of the title compound.

[1389] LC-MS (Method 3): R t =1.37min; MS(ESIpos):m / z=342[M+H] +

[1390] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.260(16.00),2.560(1.06),2.600(0.43),2.612(1.09),2.623(0.70),2.695(0.75),2.7 06(1.19),2.718(0.46),3.203(1.05),3.211(1.29),3.219(1.00),6.894(1.03),6.908(1.07),7.498(1.13),7.512(1.05).

[1391] Example 101A

[1392] 1-[1-{4-chloro-4'-[4-(2-cyanoethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1393]

[1394] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (prepared according to Example 16A, enantiomer 2, 90.0 mg, 169 μmol) and 3-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl}propionitrile (Example 100A, 69.3 mg, 203 μmol) in toluene / ethanol (1:1, 2.5 ml) was treated with Pd(PPh3)4 (9.78 mg, 8.46 μmol) and an aqueous solution of sodium carbonate (250 μl, 2N, 510 μmol) in toluene / ethanol (1:1, 2.5 ml) and stirred at 100 °C for 3 hours. The reaction mixture was diluted with dichloromethane and purified by rapid chromatography (silica gel, dichloromethane / methanol, gradient) to give 100 mg (89% yield) of the title compound.

[1395] LC-MS (Method 3): R t =2.41min; MS(ESIpos):m / z=597[M+H] +

[1396] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.071(16.00),1.160(1.32),1.236(0.73),1.264(3.39),1.275(6.57),1.287(3 .37),1.508(0.49),1.530(0.49),1.708(0.60),1.731(0.50),1.890(0.44),1.910(0.49),1.981(0.69),1.998(0. 47), 2.579(3.06), 2.587(4.61), 2.594(3.52), 2.622(1.40), 2.633(3.17), 2.644(2.11), 2.694(0.48), 2.714(2.24), 2.725(3.34), 2.737(1.32), 2.953(0.42), 3.010(0.64), 3.028(1.28), 3.046(1.28), 3.066(0.59), 3.189(3.6 0), 3.250(0.70), 3.263(0.72), 3.897(2.68), 4.242(0.93), 4.254(2.74), 4.266(2.70), 4.277(0.86), 4.502(0.62), 5.747(1.90), 6.979(2.78), 6.993(2.86), 7.048(2.04), 7.051(2.26), 7.084(1.02), 7.087(0.86), 7.098(1.43) ),7.101(1.27),7.154(2.44),7.168(1.64),7.385(0.65),7.439(3.07),7.454(2.79),7.472(1.23),7.540(0.44),7.549(0.78),7.560(1.02),7.604(0.75),7.616(0.79),7.624(1.02),7.637(0.68),7.997(3.14),8.765(0.48).

[1397] Example 102A

[1398] 1-[1-{4-chloro-4'-[4-(2-methylpropionyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1399]

[1400] A solution of 2-methylpropionic acid (15 μl, 160 μmol) in DMF (1.4 mL) was treated with HATU (55.5 mg, 146 μmol) and N,N-diisopropylethylamine (76 μl, 440 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 90.0 mg, 146 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 71 mg (79% yield) of the title compound.

[1401] LC-MS (Method 3): R t =2.84min; MS(ESIpos):m / z=614[M+H] +

[1402] Example 103A

[1403] 1-[1-{4-chloro-4'-[4-(2-fluoro-2-methylpropionyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1404]

[1405] A solution of 2-fluoro-2-methylpropionic acid (17.0 mg, 160 μmol) in DMF (700 μl) was treated with HATU (55.5 mg, 146 μmol) and N,N-diisopropylethylamine (76 μl, 440 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 90.0 mg, 146 μmol) was added, and the resulting mixture was stirred overnight at room temperature. A solution of 2-fluoro-2-methylpropionic acid (17.0 mg, 160 μmol), HATU (55.5 mg, 146 μmol), and N,N-diisopropylethylamine (76 μl, 440 μmol) in DMF (0.5 mL) was added and pre-stirred (10 min). The resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 68.0 mg (72% yield) of the title compound.

[1406] LC-MS (Method 3): Rt =2.91min; MS(ESIpos):m / z=632[M+H] +

[1407] Example 104A

[1408] 1-[1-{4-chloro-4'-[4-(cyclopropanecarbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1409]

[1410] A solution of cyclopropanecarboxylic acid (13 μl, 160 μmol) in DMF (1.4 mL) was treated with HATU (55.5 mg, 146 μmol) and N,N-diisopropylethylamine (76 μl, 440 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (prepared according to Example 18A, enantiomer 2, 90.0 mg, 146 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 74.0 mg (83% yield) of the title compound.

[1411] LC-MS (Method 3): R t =2.79min; MS(ESIpos):m / z=612[M+H] +

[1412] Example 105A

[1413] 1-[1-{4-chloro-4'-[4-(3-methylbutyryl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1414]

[1415] A solution of 3-methylbutyric acid (18 μl, 160 μmol) in DMF (1.4 mL) was treated with HATU (55.5 mg, 146 μmol) and N,N-diisopropylethylamine (76 μl, 440 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylate hydrochloride (prepared according to Example 18A, enantiomer 2, 90.0 mg, 146 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 64.0 mg (70% yield) of the title compound.

[1416] LC-MS (Method 3): R t =2.91min; MS(ESIpos):m / z=628[M+H] +

[1417] Example 106A

[1418] 5-{2-[(benzyloxy)carbonyl]hydrazinoyl}-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[1419]

[1420] A solution of tert-butyl 3,3-difluoro-5-oxopiperidin-1-carboxylic acid (7.00 g, 29.8 mmol) in methanol (280 mL) was treated with benzyl hydrazide (4.95 g, 29.8 mmol) and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C, and sodium triacetoxyborohydride was added. The resulting mixture was slowly heated to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 6.30 g (51% yield) of the title compound.

[1421] LC-MS (Method 5): R t =3.14min; MS(ESIneg):m / z=384[MH] -

[1422] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.163(0.75),1.175(1.46),1.187(0.75),1.381(16.00),1.396(2.96),1.406(1.75),1. 415(0.91),1.419(1.19),1.427(0.52),1.432(0.48),1.986(2.73),2.258(0.47),2.985(0.42),4.013(0.49),4.025(0.9 7), 4.036(1.00), 4.048(0.61), 4.960(1.05), 5.062(5.04), 5.137(0.48), 7.302(0.48), 7.307(0.55), 7.313(1.17), 7.317(0.87), 7.324(0.89), 7.327(0.98), 7.343(1.20), 7.353(8.44), 7.364(2.81), 7.377(0.68), 7.391(0.52), 8.676(0.44).

[1423] Example 107A

[1424] 3,3-Difluoro-5-hydrazinopiperidine-1-carboxylic acid tert-butyl ester hydrochloride (racemic mixture)

[1425]

[1426] A solution of 5-{2-[(benzyloxy)carbonyl]hydrazinoyl}-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (Example 106A, 6.30 g, 16.3 mmol) in ethanol (350 ml) was treated with 10% Pd / C and stirred at 1 hydrogen pressure for 48 hours. The reaction mixture was filtered through diatomaceous earth. A solution of hydrogen chloride in dioxane (4.9 ml, 4.0 M, 20 mmol) was added to the filtrate, and the resulting solution was evaporated. The residue was co-evaporated three times with diethyl ether to give 4.23 g (89% yield) of the title compound, which was used in the next step without further purification.

[1427] H-NMR(600MHz,DMSO-d6)δ[ppm]:1.378(0.48),1.386(0.76),1.396(4.76),1.411(16.00),1.4 32(0.50),1.496(0.45),3.436(0.62),3.447(0.53),7.186(0.46),7.270(0.52),7.356(0.45).

[1428] Example 108A

[1429] 5-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[1430]

[1431] A solution of 3,3-difluoro-5-hydrazinopiperidine-1-carboxylic acid tert-butyl hydrochloride (prepared according to Example 3A, 770 μl, 4.1 mmol) in ethanol (32 mL) was treated with 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate (prepared according to Example 3A, 1.07 g, 3.72 mmol) and N,N-diisopropylethylamine (1.3 mL, 7.4 mmol). The resulting mixture was stirred at 80 °C for 1 hour and then evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 717 mg (44% yield) of the title compound.

[1432] Two enantiomers were separated by preparative chiral HPLC [Sample preparation: 717 mg dissolved in 9.5 mL acetonitrile / ethanol (1:1); injection volume: 80 μL; column: Daicel Chiralpak AY-H 5 μm, 250 x 20 mm; eluent: n-heptane / ethanol 85:15; flow rate: 20 mL / min; temperature: 30 °C; UV detection: 220 nm]. After separation, 289 mg of enantiomer 1 (Example 109A) eluted first and 249 mg of enantiomer 2 (Example 110A) eluted later were obtained.

[1433] Example 109A

[1434] 5-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (enantiomer 1)

[1435] See Example 108A for separation conditions.

[1436] Analytical chirality HPLC: Rt = 0.752 min, ee = 99% [Column: Daicel Chiralpak AY 3 μm, 50 x 4.6 mm; Eluent: n-heptane / ethanol 70:30; Flow rate: 1.0 ml / min; Temperature: 30 °C; UV detection: 220 nm].

[1437] LC-MS (Method 3): R t =2.33min; MS(ESIpos):m / z=410[M+H] +

[1438] Example 110A

[1439] 5-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (enantiomer 2)

[1440] See Example 108A for separation conditions.

[1441] Chiral HPLC analysis: Rt = 0.943 min, ee = 98% [Column: Daicel Chiralpak AY 3 μm, 50 x 4.6 mm; eluent: n-heptane / ethanol 70:30; flow rate: 1.0 ml / min; temperature: 30 °C; UV detection: 220 nm].

[1442] LC-MS (Method 3): R t =2.33min; MS(ESIpos):m / z=410[M+H] +

[1443] Example 111A

[1444] 5-(difluoromethyl)-1-[5,5-difluoropiperidin-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (enantiomer 1)

[1445]

[1446] A solution of 5-[5-(difluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazol-1-yl]-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester (Example 109A, enantiomer 1, 289 mg, 706 μmol) in dichloromethane (7.0 mL) was treated with a solution of hydrogen chloride in dioxane (1.8 mL), and stirred at room temperature for 3 hours. The reaction mixture was co-evaporated three times with acetonitrile to give 249 mg (quantitative) of the title compound, which was used in the next step without further purification.

[1447] LC-MS (Method 3): R t =1.38min; MS(ESIpos):m / z=310[M+H] +

[1448] Example 112A

[1449] 5-(difluoromethyl)-1-[5,5-difluoropiperidin-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1450]

[1451] A solution of ethyl 5-(difluoromethyl)-1-[5,5-difluoropiperidin-3-yl]-1H-pyrazole-4-carboxylic acid hydrochloride (Example 110A, enantiomer 1, 179 mg, 518 μmol) in dichloromethane was washed once with saturated sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 153 mg (96% yield) of the title compound, which was used in the next step without further purification.

[1452] H-NMR(400MHz,DMSO-d6)δ[ppm]:1.271(7.41),1.289(16.00),1.307(7.62),1.407(0.55),2.572(0.55),2.582(0. 51),2.602(0.64),2.613(0.62),2.821(0.40),2.846(0.63),2.879(0.98),2.900(1.18),2.927(1.97),2.954(3.3 5), 2.978(0.94), 3.060(1.48), 3.090(1.90), 4.250(2.32), 4.268(7.13), 4.286(7.06), 4.304(2.21), 4.653(0.55), 4.666(0.72), 4.679(0.95), 4.692(0.81), 4.706(0.51), 7.472(1.79), 7.602(3.47), 7.732(1.63), 8.066(5.92).

[1453] Example 113A

[1454] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}-5,5-difluoropiperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1455]

[1456] Under argon atmosphere, a solution of 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared according to Example 8A, 161 mg, 491 μmol) and ethyl 5-(difluoromethyl)-1-[5,5-difluoropiperidin-3-yl]-1H-pyrazole-4-carboxylate (Example 112A, enantiomer 1, 152 mg, 491 μmol) in 1,4-dioxane (5.1 mL) was treated with Pd2dba3 (225 mg, 246 μmol), rac-BINAP (306 mg, 491 μmol), and cesium carbonate (400 mg, 1.23 mmol). The resulting mixture was stirred overnight at 100 °C. Additional 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (Example 8A, 81 mg, 246 μmol), Pd2dba3 (90 mg, 98 μmol), rac-BINAP (122 mg, 196 μmol), and cesium carbonate (200 mg, 0.61 mmol) were added to the reaction mixture, and the resulting mixture was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 134 mg (87% purity, 42% yield...

Claims

1. A compound of formula (I), or a salt thereof. in R 1 Represents hydrogen or halogen, R 2 Represents hydrogen or halogen, R 3 Represents chloro or trifluoromethyl. R 4 Represents hydrogen or C1-C4-alkyl. R 5 Groups representing the following formulas The # symbol represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes. R 6 represent C1-C6-alkyl groups independently substituted with one or more of the following substituents: trifluoromethoxy, nitrile, amino. C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl groups optionally substituted with 1 to 5 fluorine substituents or trifluoromethyl groups, C1-C6-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents, C3-C6-cycloalkyl-carbonyl groups optionally substituted with 1 to 3 fluorine substituents, Oxycyclic butyl, Spirocyclic [2.2]pentyl-2-methyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl, R 7 Represents a C1-C4 alkyl carbonyl group optionally substituted with a C3-C6-cycloalkyl group. R 8 Represents C2-C4-haloalkyl groups substituted with 1 to 6 fluorine substituents. X1 represents nitrogen or CH4 X2 represents nitrogen or CH.

2. The compound according to claim 1, or one of its salts, characterized in that, R 1 Represents hydrogen and fluorine R 2 Represents hydrogen and fluorine R 3 Represents chlorine or trifluoromethyl R 4 Represents hydrogen or methyl R 5 Groups representing the following formulas The # symbol represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes. R 6 represent C1-C4-alkyl groups substituted by one or more substituents selected from the following: trifluoromethoxy, nitrile; C2-C6-haloalkyl groups substituted with 1 to 5 fluorine substituents C3-C6-cycloalkyl-methyl groups optionally substituted with one or two fluorine substituents or trifluoromethyl groups, C1-C3-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents, C3-C6-cycloalkyl-carbonyl, R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group. R 8 Represents a C2-C4-haloalkyl group optionally substituted with 1 to 3 fluorine substituents. X1 represents nitrogen or CH4 X2 represents nitrogen or CH.

3. The compound according to claim 1 or 2, or a salt thereof, characterized in that, R 1 Represents hydrogen R 2 Represents hydrogen R 3 Represents chlorine R 4 Represents hydrogen R 5 Groups representing the following formulas The # symbol represents the connection point with the 6-ring system of the Aromatic or Hybrid Aromatic tribes. R 6 Represents C1-C4-alkyl groups substituted with trifluoromethoxy or nitrile groups, C2-C3-haloalkyl groups substituted with 1 to 5 fluorine substituents, and C3-C4-cycloalkyl-methyl groups optionally substituted with 1 to 2 fluorine substituents or trifluoromethyl groups. C1-C3-alkyl carbonyl groups optionally substituted with 1 to 3 fluorine substituents, Cyclopropyl-carbonyl, R 7 Represents a C1-C3-alkyl carbonyl group optionally substituted with a cyclopropyl group. X1 represents CH X2 represents CH.

4. A method for preparing a compound of formula (I) according to any one of claims 1 to 3, or a salt thereof, characterized in that, In step [B], in the presence of a palladium source, a suitable ligand, and a base, the compound of formula (III) is reacted with the compound of formula (IV) to generate the compound of formula (II). Where R 1 R 2 and R 3 The definition is as defined in any one of claims 1 to 3. Where R 4 R 5 X1 and X2 are defined as defined in any one of claims 1 to 3. and Where R 9 Represents hydrogen, methyl, or two Rs 9 4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane is formed via adjacent oxygen atoms. Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are defined as defined in any one of claims 1 to 3. and In the second step [A] The compound of formula (II) reacts with a base to produce the compound of formula (I). Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are defined as defined in any one of claims 1 to 3. Optionally, in step three [A]*, the compound of formula (I) is converted into the salt of the corresponding formula (Ia) in a suitable solvent in the presence of a suitable acid. 。 5. Use of the compound according to any one of claims 1 to 3 in the preparation of a medicament for the treatment and / or prevention of the following diseases: heart failure, hypertension (HTN), chronic kidney disease (CKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcer (DFU).

6. The use according to claim 5, wherein the heart failure is HFrEF, HFmrEF, or HFpEF.

7. The use according to claim 5, wherein the chronic kidney disease (CKD) is diabetic kidney disease (DKD).

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

9. Use of the medicament according to claim 8 in the preparation of a medicament for the treatment and / or prevention of the following diseases: heart failure, hypertension (HTN), chronic kidney disease (CKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcer (DFU).

10. The use according to claim 9, wherein the heart failure is HFrEF, HFmrEF, or HFpEF.

11. The use according to claim 9, wherein the chronic kidney disease (CKD) is diabetic kidney disease (DKD).

12. Use of the compound of any one of claims 1 to 3, the medicament of claim 8, or the medicament obtained according to any one of claims 5-7 and 9 in the preparation of a medicament for the treatment and / or prevention of the following diseases in humans or animals, by administration of a therapeutically effective amount of at least one of the compounds or the medicament: heart failure, hypertension (HTN), chronic kidney disease (CKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), and diabetic foot ulcer (DFU).

13. The use according to claim 12, wherein the heart failure is HFrEF, HFmrEF, or HFpEF.

14. The use according to claim 12, wherein the chronic kidney disease (CKD) is diabetic kidney disease (DKD).

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