Substituted pyrazolylpiperidine carboxylic acids

Abstract

The present invention relates to substituted pyrazolopiperidine carboxylic acids, salts thereof and processes for their preparation, and their use for 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), cardiorenal and renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiorespiratory 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), impaired wound healing such as diabetic foot ulcer (DFU).

Description

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

[0002] Furthermore, the same pathophysiological mechanisms described above are also effective when transfusions are given to patients with indications for transfusion (e.g., through storage, which increases the concentration of free Hb).

[0003] Furthermore, in the future, the combination of sGC activators with synthetic Hb-based oxygen carriers may alleviate the side effects observed to date due to reduced NO availability [Weiskopf, Anaesthesia & Analgesia, 110:3; 659-661, 2010], thereby allowing for clinical application.

[0004] One of the most important cell-transmitting systems in mammalian cells is cyclic guanosine monophosphate (cGMP). It forms the NO / cGMP system together with nitric oxide (NO), which is released from the endothelium and transmits hormones and mechanotransmitted signals. Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). Representatives of this family, as disclosed to date, can be divided into two categories based on structural features and ligand type: granular guanylate cyclases stimulated by natriuretic peptides and soluble guanylate cyclases stimulated by NO. Soluble guanylate cyclases consist of two subunits, and each heterodimer most likely contains a heme atom, 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. Conversely, 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 resulting phosphodiesterases, ion channels, and protein kinases, 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 diseases resulting from impaired processes. Under pathophysiological conditions, the NO / cGMP system can 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] Given their expected high efficiency and few side effects, potential treatments for such conditions that are not dependent on NO and aim to affect cGMP signaling pathways in organisms are promising approaches.

[0007] Its action is based on NO compounds, such as organic nitrates, which have so far been used only 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 important drawbacks of this treatment modality [OVEvgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

[0008] In recent years, substances that can directly stimulate soluble guanylate cyclases (sGCs), i.e., those that do not pre-release NO, have been discovered. The indazole derivative YC-1 is the first documented heme-dependent sGC stimulator that is independent of NO [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 identification 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 independence from NO and selective activation of heme-containing sGCs. Furthermore, based on the stability of the nitrosyl-heme complex, the binding of sGC stimulants to NO has a synergistic effect on the activation of sGC. 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 basic catalytic activity, i.e., it is still forming cGMP. None of the above stimulants can stimulate the remaining basic catalytic activity of heme-free enzymes [Evgenov et al., ibid.].

[0009] Furthermore, NO- and heme-independent sGC activators were identified, with BAY 58-2667 being the prototype of such activators. These substances share the characteristic that, upon binding with NO, they exhibit only an adductal effect on enzyme activation, and their 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 indicate that BAY 58-2667 replaces the oxidized heme groups that were only weakly attached to sGCs due to the weakening of the iron-histidine bond. The study also showed that the characteristic sGC heme-binding motif Tyr-x-Ser-x-Arg is essential for the interaction of the negatively charged propionic acid with the heme group and for the function of BAY 58-2667. In this context, it is believed that the binding site of BAY 58-2667 on sGC is the same as the binding site of the heme group [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 heme-free sGC enzyme activators, sGC activators may have broader therapeutic potential, but this potential awaits future identification and confirmation.

[0011] The compounds described in this invention are now also capable of activating the heme-free form of soluble guanylate cyclase. This is also supported by the fact that, firstly, these new 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] WO 2012 / 058132 discloses substituted pyrazolopyridine carboxylic acids as sGC activators. These compounds do indeed possess a heteroaromatic pyridine moiety linked to a pyrazolopyridine carboxylic acid, 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 administration.

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

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

[0015] This invention provides one of a compound of formula (I) or a salt thereof, a solvate thereof or a solvate thereof.

[0016]

[0017] in

[0018] R 1 Represents hydrogen or halogen,

[0019] R 2 Represents hydrogen or halogen,

[0020] R 3 Represents chloro or trifluoromethyl.

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

[0022] R 5 Groups representing the following formulas

[0023]

[0024] Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic group; where m is 0-4

[0025] R 6 represent

[0026] C1-C6-alkyl groups, optionally substituted by one or more substituents independently selected from: methyl, methoxy, trifluoromethoxy, nitrile, amido.

[0027] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0028] C3-C6-cycloalkyl,

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

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

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

[0032] (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, or C3-C6-cycloalkyl groups,

[0033] (C3-C6)-cycloalkoxy-carbonyl,

[0034] Mono-(C1-C4)-alkylaminocarbonyl,

[0035] (C1-C4)-alkylsulfonyl, or

[0036] Oxycyclic butyl,

[0037] Spiro[2.2]pentyl-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0038] R 7 Represents C1-C4-alkylcarbonyl and C3-C6-cycloalkyl-carbonyl.

[0039] R 8 Represents C2-C4 alkyl groups, C2-C4 haloalkyl groups substituted with 1 to 6 fluorine substituents.

[0040] X1 represents nitrogen, carbon, or CF.

[0041] X2 represents nitrogen or carbon.

[0042] The term "substitution" refers to the replacement of one or more hydrogen atoms on a specified atom or group with a group selected from the specified group, provided that the replacement does not exceed the normal valence state of the specified atom under normal conditions. Combinations of substituents and / or variables are permitted.

[0043] 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 particularly 1, 2 or 3, even more particularly 1 or 2”.

[0044] In the context of this invention, unless otherwise stated, substituents are defined as follows:

[0045] 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, and even more particularly a fluorine or chlorine atom.

[0046] The terms "C1-C4-alkyl", "C1-C5-alkyl", and "C1-C6-alkyl" refer to straight-chain or branched saturated monovalent hydrocarbon groups containing 1, 2, 3, or 4 carbon atoms, 1, 2, 3, 4, or 5 carbon atoms, and 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, etc. 1-Ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, or 1,3-dimethylbutyl, or isomers thereof. Specifically, the group has 1, 2, 3, or 4 carbon atoms (“C1-C4-alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, has 1, 2, or 3 carbon atoms (“C1-C3-alkyl”), such as methyl, ethyl, n-propyl, or isopropyl.

[0047] 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.

[0048] The terms "C1-C4-haloalkoxy" and "C1-C3-haloalkoxy" refer to straight-chain or branched saturated monovalent C1-C4-alkoxy or C1-C3-alkoxy (where C1-C4-alkoxy) are the alkoxy groups. Alkoxy This refers to a straight-chain or branched saturated monovalent alkoxy group having 1 to 4 or 1 to 3 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy), wherein one or more hydrogen atoms are substituted with 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.

[0049] The term "(C1-C4)-alkylcarbonyl" represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms, which is attached to the rest of the molecule via a carbonyl group [-C(=O)-]. Examples of such groups include, and are preferred to be mentioned, acetyl, propionyl, n-butyryl, isobutyryl, tert-butyryl, n-valeryl, and neovaleryl.

[0050] The term "mono-(C1-C4)-alkylaminocarbonyl" refers to an amino group that is bonded to the rest of the molecule via a carbonyl group [-C(=O)-] and has a straight-chain or branched alkyl substituent containing 1, 2, 3, or 4 carbon atoms, such as methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, and tert-butylaminocarbonyl.

[0051] The term "(C1-C4)-alkylsulfonyl" represents a straight-chain or branched, saturated monovalent group of the formula (C1-C4-alkyl)-S(=O)2-, wherein the term "C1-C4-alkyl" is as defined above, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl.

[0052] The term "(C1-C4)-alkoxy-carbonyl" represents a straight-chain or branched alkoxy group containing 1, 2, 3, or 4 carbon atoms, which is bonded to the rest of the molecule via a carbonyl group [-C(=O)-], such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, and tert-butoxycarbonyl.

[0053] The term "(C3-C6)-cycloalkoxy-carbonyl" represents a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms. The C3-C6-cycloalkoxy group is, for example, cyclopropoxy, cyclobutoxy, cyclopentoxy, or cyclohexyloxy, which is bonded to the rest of the molecule via a carbonyl group [C(=O)-], such as cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentoxycarbonyl, or cyclohexyloxycarbonyl.

[0054] 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.

[0055] The compounds of the present invention are compounds of formula (I) and their salts, their solvates and their solvates, provided that the compounds covered by formula (I) and described in detail below are not salts, solvates and solvates of salts, and the compounds covered by formula (I) and described in detail below as examples, their salts, their solvates and their solvates.

[0056] 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.

[0057] This invention includes all possible tautomers of the compounds of this invention, in the form of a single tautomer or any mixture of said tautomers in any proportion.

[0058] In the context of this invention, the term "enantiomerically pure" should be understood to mean that the compound in question is present in excess of more than 95%, preferably more than 97%, of the enantiomers with respect to the absolute configuration of the chiral center. In this case, the enantiomer excess (ee value) is calculated by evaluating the corresponding HPLC chromatogram on the chiral phase using the following formula:

[0059] ee = [E A (Area%)-E B [(Area%)] x 100% / [E] A (Area%) + E B (area%)]

[0060] (E A Excessive enantiomers, E B (enantiomers of deficiency)

[0061] 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 to mean 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 include 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 incorporating one or more radioactive isotopes, can be beneficial for studies such as the mechanism of action or the distribution of active ingredients in vivo; they are also relatively easy to prepare and detect, especially using... 3 H or 14 Compounds labeled with the carbon isotope are suitable for this purpose. Furthermore, the incorporation of isotopes (e.g., deuterium) can lead to specific therapeutic effects due to enhanced metabolic stability of the compounds, such as prolonged half-life in vivo or reduced required active dose; therefore, in certain circumstances, such modification of the compounds of the present invention may also constitute a preferred embodiment of the invention. Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by means of appropriate isotopic modification of the corresponding reagents and / or starting compounds, as described further below and in the steps described in the working examples.

[0062] Preferred in the context of this invention SaltThese 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.

[0063] 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.

[0064] 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.

[0065] This invention includes all possible salts of the compounds of this invention, in the form of a single salt or any mixture of said salts in any proportion.

[0066] In the context of this invention solvates The compounds of the present invention are described in those forms, which form solid or liquid complexes by coordination with solvent molecules. The compounds of the present invention may contain a polar solvent, particularly such as water, methanol, or ethanol, as a structural unit of the compound's crystal lattice. A hydrate is a specific form of solvate in which coordination with water occurs. The amount of polar solvent (particularly water) may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvates, such as hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates are possible. The present invention includes all such hydrates or solvates.

[0067] Furthermore, the compounds of the present invention can exist as N-oxides, defined as compounds in which at least one nitrogen atom is oxidized in a known manner. The present invention includes all such possible N-oxides.

[0068] 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).

[0069] In which R can be represented 2In the formula for the group, in each case the endpoint of the line marked with # does not represent a carbon atom or a CH2 group, but rather is associated with R. 2 Part of the bond between the atoms.

[0070] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0071] R 1 Represents hydrogen or halogen,

[0072] R 2 Represents hydrogen or halogen,

[0073] R 3 Represents chloro or trifluoromethyl.

[0074] R 4 Represents hydrogen or, C1-C4-alkyl or halogen.

[0075] R 5 Groups representing the following formulas

[0076]

[0077] Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic group; where m is 0-4

[0078] R 6 represent

[0079] C1-C6-alkyl groups, which are substituted by one or more substituents independently selected from the following:

[0080] Methoxy, trifluoromethoxy, nitrile, amide

[0081] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0082] C3-C6-cycloalkyl,

[0083] C3-C6-cycloalkyl-methyl, optionally substituted with 1 to 5 fluorine substituents or a trifluoromethyl group,

[0084] C1-C6-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0085] C3-C6-cycloalkyl-carbonyl, which is optionally substituted with 1 to 3 fluorine substituents, or

[0086] (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, or C3-C6-cycloalkyl groups,

[0087] (C3-C6)-cycloalkoxy-carbonyl,

[0088] Mono-(C1-C4)-alkylaminocarbonyl,

[0089] (C1-C4)-alkylsulfonyl, or

[0090] Oxycyclic butyl,

[0091] Spiro[2.2]pentyl-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0092] R 7 Represents C1-C4-alkylcarbonyl and C3-C6-cycloalkyl-carbonyl.

[0093] R 8 Represents C2-C4 alkyl groups, C2-C4 haloalkyl groups substituted with 1 to 6 fluorine substituents.

[0094] X1 represents nitrogen, carbon, or CF.

[0095] X2 represents nitrogen or carbon.

[0096] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0097] R 1 Represents hydrogen and fluorine

[0098] R 2 Represents hydrogen and fluorine

[0099] R 3 Represents chloro or trifluoromethyl.

[0100] R 4 Represents hydrogen or methyl

[0101] R 5 Groups representing the following formulas

[0102]

[0103] Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic tribes; where m is 0.

[0104] R 6 represent

[0105] C1-C4-alkyl, optionally substituted by one or more substituents independently selected from: methyl, methoxy, trifluoromethoxy, nitrile, amide,

[0106] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents, or

[0107] C3-C6-cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0108] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0109] C3-C6-cycloalkyl-carbonyl,

[0110] (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy or C3-C4-cycloalkyl,

[0111] (C3-C6)-cycloalkoxy-carbonyl,

[0112] Mono-methylaminocarbonyl,

[0113] Methylsulfonyl,

[0114] R 7 C1-C3-alkyl carbonyl group, optionally substituted with a cyclopropyl group.

[0115] R 8 Represents C2-C4-haloalkyl groups, which are substituted with 1 to 3 fluorine substituents.

[0116] X1 represents nitrogen or carbon.

[0117] X2 represents nitrogen or carbon.

[0118] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0119] R 1 Represents hydrogen and fluorine

[0120] R 2 Represents hydrogen and fluorine

[0121] R 3 Represents chloro or trifluoromethyl.

[0122] R 4 Represents hydrogen or methyl

[0123] R 5 Groups representing the following formulas

[0124]

[0125] Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic tribes; where m is 0.

[0126] R 6 represent

[0127] C1-C4-alkyl groups, which are substituted by one or more substituents independently selected from the following:

[0128] Methoxy, trifluoromethoxy, nitrile, amide

[0129] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents, or

[0130] C3-C6-cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0131] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0132] C3-C6-cycloalkyl-carbonyl,

[0133] (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy or C3-C4-cycloalkyl,

[0134] (C3-C6)-cycloalkoxy-carbonyl,

[0135] Mono-methylaminocarbonyl,

[0136] Methylsulfonyl,

[0137] R 7 C1-C3-alkyl carbonyl group, optionally substituted with a cyclopropyl group.

[0138] R 8 Represents C2-C4-haloalkyl groups, which are substituted with 1 to 3 fluorine substituents.

[0139] X1 represents nitrogen or carbon.

[0140] X2 represents nitrogen or carbon.

[0141] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0142] R 1 Represents hydrogen

[0143] R 2 Represents hydrogen

[0144] R 3 Represents chlorine

[0145] R 4 Represents hydrogen

[0146] R 5 Groups representing the following formulas

[0147]

[0148] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0149] R 6 represent

[0150] C1-C4 alkyl groups, optionally substituted with trifluoromethoxy or nitrile groups,

[0151] C2-C3-haloalkyl groups, which are substituted with 1 to 2 fluorine substituents.

[0152] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0153] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0154] (C1-C3)-alkoxy-carbonyl,

[0155] Cyclopropoxy-carbonyl,

[0156] R 7 Represents a C1-C3 alkyl carbonyl group, which may optionally be substituted with a cyclopropyl group.

[0157] X1 represents carbon.

[0158] X2 represents carbon.

[0159] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0160] R 1 Represents hydrogen

[0161] R 2 Represents hydrogen

[0162] R 3 Represents chlorine

[0163] R 4 Represents hydrogen

[0164] R 5 Groups representing the following formulas

[0165]

[0166] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0167] R 6 represent

[0168] C1-C4 alkyl groups, which are substituted with trifluoromethoxy or nitrile groups.

[0169] C2-C3-haloalkyl groups, which are substituted with 1 to 2 fluorine substituents.

[0170] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0171] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0172] (C1-C3)-alkoxy-carbonyl,

[0173] Cyclopropoxy-carbonyl,

[0174] R 7 Represents a C1-C3 alkyl carbonyl group, which may optionally be substituted with a cyclopropyl group.

[0175] X1 represents carbon.

[0176] X2 represents carbon.

[0177] The preferred compound is one of the following: a salt thereof, a solvate thereof, or a solvate thereof.

[0178] R 1 Represents hydrogen

[0179] R 2 Represents hydrogen

[0180] R 3 Represents chloro or trifluoromethyl.

[0181] R 4 Represents hydrogen

[0182] R 5 Groups representing the following formulas

[0183]

[0184] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0185] R 7 Represents a C1-C3 alkyl carbonyl group, which may optionally be substituted with a cyclopropyl group.

[0186] X1 represents carbon or nitrogen.

[0187] X2 represents carbon.

[0188] Also preferred are compounds of formula (I), their salts, their solvates, and solvates of their salts, wherein

[0189] R 1 Represents hydrogen

[0190] R 2 Represents hydrogen

[0191] R 3 Represents chlorine

[0192] R 4 Represents hydrogen

[0193] R 5 Groups representing the following formulas

[0194]

[0195] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0196] R 6 represent

[0197] C1-C4 alkyl groups, optionally substituted with trifluoromethoxy or nitrile groups,

[0198] C2-C3-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0199] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0200] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0201] X1 represents carbon or nitrogen.

[0202] X2 represents carbon.

[0203] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0204] R 1 Represents hydrogen

[0205] R 2 Represents hydrogen

[0206] R 3 Represents chlorine

[0207] R 4 Represents hydrogen

[0208] R 5 Groups representing the following formulas

[0209]

[0210] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0211] R 6 represent

[0212] C1-C4 alkyl groups, which are substituted with trifluoromethoxy or nitrile groups.

[0213] C2-C3-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0214] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0215] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0216] X1 represents carbon or nitrogen.

[0217] X2 represents carbon.

[0218] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0219] R 1 Represents hydrogen

[0220] R 2 Represents hydrogen

[0221] R 3 Represents chlorine

[0222] R 4 Represents hydrogen

[0223] R 5 Groups representing the following formulas

[0224]

[0225] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0226] R 6 represent

[0227] C1-C4-alkyl groups, optionally substituted with trifluoromethoxy or nitrile groups, trifluoroethyl groups,

[0228] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0229] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0230] X1 represents carbon or nitrogen.

[0231] X2 represents carbon.

[0232] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0233] R 1 Represents hydrogen

[0234] R 2 Represents hydrogen

[0235] R 3 Represents chlorine

[0236] R 4 Represents hydrogen

[0237] R 5Groups representing the following formulas

[0238]

[0239] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0240] R 6 represent

[0241] C1-C4 alkyl groups, substituted with trifluoromethoxy or nitrile groups.

[0242] Trifluoroethyl,

[0243] C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group,

[0244] C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0245] X1 represents carbon or nitrogen.

[0246] X2 represents carbon.

[0247] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0248] R 1 Represents hydrogen

[0249] R 2 Represents hydrogen

[0250] R 3 Represents chlorine or trifluoromethyl

[0251] R 4 Represents hydrogen

[0252] R 5 Groups representing the following formulas

[0253]

[0254] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0255] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0256] X1 represents carbon or nitrogen.

[0257] X2 represents carbon.

[0258] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0259] R 1 Represents hydrogen

[0260] R 2 Represents hydrogen

[0261] R 3 Represents chlorine or trifluoromethyl

[0262] R 4 Represents hydrogen

[0263] R 5 Groups representing the following formulas

[0264]

[0265] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0266] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0267] X1 represents carbon or nitrogen.

[0268] X2 represents carbon.

[0269] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0270] R 1 Represents hydrogen

[0271] R 2 Represents hydrogen

[0272] R 3 Represents chlorine

[0273] R 4 Represents hydrogen

[0274] R 5 Groups representing the following formulas

[0275]

[0276] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0277] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0278] X1 represents carbon or nitrogen.

[0279] X2 represents carbon.

[0280] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0281] R 1 Represents hydrogen

[0282] R 2 Represents hydrogen

[0283] R 3 Represents chlorine

[0284] R 4 Represents hydrogen

[0285] R 5 Groups representing the following formulas

[0286]

[0287] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0288] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0289] X1 represents carbon or nitrogen.

[0290] X2 represents carbon.

[0291] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0292] R 1 Represents hydrogen

[0293] R 2 Represents hydrogen

[0294] R 3 Represents chlorine

[0295] R 4 Represents hydrogen

[0296] R 5 Groups representing the following formulas

[0297]

[0298] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0299] R 6 Represents n-propyl, trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0300] X1 represents carbon.

[0301] X2 represents carbon.

[0302] Also preferred are compounds of formula (I) and their salts, their solvates and solvates of their salts, wherein

[0303] R 1 Represents hydrogen

[0304] R 2 Represents hydrogen

[0305] R 3 Represents chlorine

[0306] R 4 Represents hydrogen

[0307] R 5 Groups representing the following formulas

[0308]

[0309] Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes.

[0310] R 6 Represents trifluoroethyl, (cyclopropyl)-methyl, acetyl, and 1-propionyl.

[0311] X1 represents carbon.

[0312] X2 represents carbon.

[0313] Compounds of the following formula are also preferred.

[0314]

[0315] Compounds of the following formula are also preferred.

[0316]

[0317] Its salts, its solvates and solvates of its salts.

[0318] 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

[0319] In the first step [B], the compound of formula (III) is made

[0320]

[0321] Where R 1 R 2 and R 3 As defined above,

[0322] Compounds of formula (IV)

[0323]

[0324] Where R 4 R 5 And X1 and X2 are as defined above,

[0325] And R 9 Represents hydrogen, methyl, or two Rs 94,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane is formed via adjacent oxygen atoms.

[0326] The reaction, in the presence of a palladium source, a suitable ligand, and a base, yields a compound of formula (II).

[0327]

[0328] Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are defined as above.

[0329] and

[0330] In the second step [A],

[0331] The compound of formula (II) reacts with a base to produce the compound of formula (I).

[0332]

[0333] Where R 1 R 2 R 3 R 4 R 5 As defined above, X1 and X2,

[0334] Optionally, in the third step [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.

[0335]

[0336] Reaction [A]* (salt formation)

[0337] The reaction [A]* is usually carried out in an inert solvent in the presence of an acid, preferably at atmospheric pressure and at a temperature range of 0°C to 60°C.

[0338] 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, wherein water is optionally added. Hydrogen chloride, hydrogen bromide, toluenesulfonic acid, methanesulfonic acid, or sulfuric acid are preferred.

[0339] Suitable inert solvents for salt formation include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether, or other solvents such as acetone, ethyl acetate, ethanol, n-propanol, isopropanol, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethylacrylamide (DMPU), or N-methylpyrrolidone (NMP). Mixtures of the above solvents may also be used. Diethyl ether, dioxane, tetrahydrofuran, or mixtures of these solvents are preferred.

[0340] Reaction [A] (Ester hydrolysis)

[0341] In compounds of Formula II, the hydrolysis of the ester group is carried out by conventional methods by treating the ester with an acid or base in an inert solvent. In the latter variant, 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.

[0342] 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.

[0343] 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.

[0344] Acids suitable for ester hydrolysis are typically sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid, or mixtures thereof, wherein water is optionally added. 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.

[0345] 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.

[0346] The compound of formula (II) is new.

[0347]

[0348] Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are defined as above.

[0349] Compounds of formula (II) can be synthesized from the corresponding starting compounds of formula (III) via the following steps.

[0350] [B] Compounds of formula (III)

[0351]

[0352] Where R 1 R 2 and R 3 As defined above,

[0353] In the presence of a suitable palladium catalyst, a base, and a suitable solvent

[0354] Compounds of formula (IV)

[0355]

[0356] Where R 4 R 5 R 9 As defined above, X1 and X2,

[0357] The reaction, in the presence of a palladium source, a suitable ligand, and a base, yields the compound of formula (II).

[0358] Reaction [B] (Suzuki coupling)

[0359] The reaction [B] is typically carried out in an inert solvent in the presence of a suitable palladium catalyst and a suitable base, preferably at atmospheric pressure in the range of room temperature to solvent reflux temperature.

[0360] 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'-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile, or water. Mixtures of the above solvents may also be used. A mixture of dimethylformamide / water and toluene / ethanol is preferred.

[0361] 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. The preferred base is sodium carbonate or potassium carbonate.

[0362] 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]palladium(II) dichloride-dichloromethane complex [see, for example, Hassan J. et al., Chem. Rev.]. 102 ,1359-1469(2002)).

[0363] 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.

[0364] The compound of formula (IV) is new.

[0365]

[0366] Where R 4 R 5 R 9 X1 and X2 are defined as above.

[0367] and

[0368] in

[0369] R 5 Groups representing the following formulas

[0370]

[0371] Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic group; and where m is 0-4.

[0372] R 6 represent

[0373] C1-C6-alkyl, optionally substituted by one or more substituents independently selected from: methyl, trifluoromethoxy, nitrile, amide,

[0374] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0375] C3-C6-cycloalkyl,

[0376] C3-C6-cycloalkyl-methyl, optionally substituted with 1 to 5 fluorine substituents or a trifluoromethyl group,

[0377] C1-C6-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents,

[0378] C3-C6-cycloalkyl-carbonyl, which is optionally substituted with 1 to 3 fluorine substituents, or

[0379] (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, or C3-C6-cycloalkyl groups,

[0380] (C3-C6)-cycloalkoxy-carbonyl,

[0381] Mono-(C1-C4)-alkylaminocarbonyl,

[0382] (C1-C4)-alkylsulfonyl, or

[0383] Oxycyclic butyl,

[0384] Spiro[2.2]pentyl-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl,

[0385] R 7 Represents C1-C4-alkylcarbonyl and C3-C6-cycloalkyl-carbonyl.

[0386] R 8 Represents C2-C4-alkyl, C2-C4-haloalkyl substituted with 1 to 6 fluorine substituents.

[0387] The compound of formula (IVb) is new.

[0388]

[0389] Where R 4 R 6 R 9 As defined above, X1 and X2 are, and

[0390] It can be prepared by the following steps

[0391] [C] Compounds of formula (IVa)

[0392]

[0393] Where R 4 R 9 X1 and X2 are defined as above.

[0394] Compounds of formula (XV)

[0395] R 6a-CHO (XV)

[0396] in

[0397] R 6a Represents a C1-C5-alkyl group, optionally substituted by one or more substituents independently selected from the following: methyl, methoxy, trifluoromethoxy, nitrile, amide.

[0398] C2-C5-haloalkyl groups, substituted with 1 to 5 fluorine substituents.

[0399] C3-C6 cycloalkyl groups, optionally substituted with 1 to 5 fluorine substituents or a trifluoromethyl group,

[0400] Spiro[2.2]but-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]butyl)methyl, reacted in the presence of a reducing agent, a base and a suitable solvent,

[0401] or alternative

[0402] [D] Compounds of formula (IVa)

[0403]

[0404] Where R 4 R 9 X1 and X2 are defined as above.

[0405] Compounds of formula (XVI)

[0406] R 6 -X (XVI)

[0407] in

[0408] R 6 As defined above, and X is Br, OTs, or OTf.

[0409] The reaction occurs in the presence of a base and a suitable solvent.

[0410] or alternative

[0411] [F] First, the compound of formula (IVa) is used.

[0412]

[0413] Where R 4 R 9 X1 and X2 are defined as above.

[0414] Compounds with formula (XVII)

[0415]

[0416] in

[0417] R 10 Represents a C1-C6 alkyl group, which may optionally be selected independently from one or more of the following.

[0418] Substitution groups: methyl, methoxy, trifluoromethoxy, nitrile, amide.

[0419] C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents.

[0420] C3-C6-cycloalkyl groups, optionally substituted with 1 to 5 fluorine substituents or a trifluoromethyl group,

[0421] Spiro[2.2]but-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]butyl)methyl, reacted in the presence of a base and a suitable solvent.

[0422] Compounds with generative formula (IVc)

[0423]

[0424] in

[0425] R 4 R 9 R 10 And X1 and X2 as defined above, and [E] further make the compound of formula (IVc)

[0426]

[0427] in

[0428] R 4 R 9 R 10 X1 and X2 are defined as above.

[0429] The reaction occurs in the presence of a reducing agent and a suitable solvent.

[0430] Compounds with generative formula (IVd)

[0431]

[0432] in

[0433] R 4 R 9 R 10 X1 and X2 are defined as above.

[0434] The compound of formula (IVc) will also be used in the above reaction [B] (Suzuki coupling).

[0435] Reaction [C] (reductive amination)

[0436] The reaction [C] is usually carried out in an inert solvent in the presence of a reducing agent, and where 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.

[0437] 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.

[0438] Adding acids, especially acetic acid, and / or dehydrating agents, such as molecular sieves, trimethyl orthoformate, or triethyl orthoformate, to these reactions may be advantageous.

[0439] The base is, for example, an organic base such as a trialkylamine, such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, or diisopropylethylamine or pyridine. Bases, especially N,N-diisopropylethylamine and triethylamine, may be advantageous in these reactions.

[0440] 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.

[0441] The reaction is usually carried out in a temperature range of 0°C to +60°C.

[0442] The aldehyde in formula (XV) is commercially available or can be synthesized from known starting materials using known processes.

[0443] The starting material for formula (IVa) is commercially available, known, or obtainable by known methods.

[0444] [D] (alkylation) reaction

[0445] Reaction [D] is typically carried out in a temperature range of 0°C to +120°C, preferably +20°C to +80°C, and may be carried out in a microwave oven where appropriate. The reaction can be carried out at atmospheric pressure, under pressure or under reduced pressure (e.g., 0.5 to 5 bar).

[0446] Suitable inert solvents for alkylation include, 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'-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of the mentioned solvents may also be used. Dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran are preferred.

[0447] 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, 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 amines such as sodium amide or lithium bis(trimethylsilyl)amide. Or bis(trimethylsilyl)aminopotassium or diisopropylaminolithium, 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.

[0448] The alkylating agent of formula ((XVI)) is known, commercially available, or obtainable by known methods.

[0449] The starting material for formula (IVa) is commercially available, known, or obtainable by known methods.

[0450] Reaction [E] (reduction) )

[0451] 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, where appropriate, in a microwave. The reaction can be carried out at atmospheric pressure, under pressure, or under reduced pressure (e.g., 0.5 to 5 bar).

[0452] Suitable inert solvents for reduction reactions include, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene, or chlorobenzene; ethers such as diethyl ether, dioxane, or tetrahydrofuran; and hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane, or mineral oil fractions. Mixtures of the mentioned solvents may also be used. Tetrahydrofuran is preferred.

[0453] Suitable reducing agents for the amide reduction in the process steps are, for example, lithium aluminum hydride or borane tetrahydrofuran complexes. Borane tetrahydrofuran complexes are preferred.

[0454] The starting materials for formula (IVc) are commercially available, known, or obtainable by known methods or reactions [F].

[0455] Reaction [F] (Amide formation)

[0456] 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, more preferably 0°C to +60°C. The reaction can be carried out at atmospheric pressure, under pressure or reduced pressure (e.g., 0.5 to 5 bar). Typically, the reaction is carried out at atmospheric pressure.

[0457] The 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'-dimethylacrylurea (DMPU), or N-methylpyrrolidone (NMP). Mixtures of the mentioned solvents may also be used. Dichloromethane, tetrahydrofuran, dimethylformamide, or mixtures of these solvents are preferred.

[0458] Suitable condensing agents for amide formation are, for example, carbodiimides such as N,N'-diethylcarbodiimide, N,N'-dipropylcarbodiimide, N,N'-diisopropylcarbodiimide, 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-thio Salts or 2-tert-butyl-5-methylisoxazole perchlorate, amide compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline or isobutyl chloroformate, propionic anhydride (T3P), 1-chloro-N,N,2-trimethylpropen-1-amine, diethyl cyanophosphonate, bis-(2-oxo-3-oxazolyl)phosphonyl chloride, benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytris(pyrrolidinyl)phosphonium hexafluorophosphate ( PyBOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethylurea tetrafluoroborate (TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HAT) U) or O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TCTU), in combination where appropriate with other auxiliaries, such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and alkali metal carbonates as bases, such as sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, such as triethylamine, N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine. Preferably, TBTU is used in combination with N-methylmorpholine, 1-chloro-N,N,2-trimethylprop-1-en-1-amine, or HATU in combination with N,N-diisopropylethylamine.

[0459] Alternatively, the carboxylic acid may first be converted to the corresponding carboxyl chloride, which can then be reacted directly or in a separate reaction with an amine to obtain the compound of the present invention. The formation of carboxyl chloride from carboxylic acid is carried out by methods known to those skilled in the art, for example by treatment with thionyl chloride, sulfonyl 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.

[0460] The starting materials for formula (IVc) are commercially available, known, or obtainable by known methods or reactions [F].

[0461] The acylating agent of formula (XVII) is commercially available, known, or obtainable by known methods.

[0462] The compound of formula (IVf) is new.

[0463]

[0464] Where R 4 R 9 As defined above, X1 and X2,

[0465] And R 7a Represents C1-C2-alkyl and cyclopropyl.

[0466] They can be accessed

[0467] [G] Compounds of formula (IVe)

[0468]

[0469] Where R 4 R 9 X1 and X2 are defined as above.

[0470] Compounds of formula (XVIII)

[0471]

[0472] Where R 7a As defined above

[0473] It is obtained by reaction in the presence of a base and a suitable solvent.

[0474] [G] (acylation) reaction

[0475] 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, where appropriate, in a microwave. The reaction can be carried out at atmospheric pressure, under pressure, or under reduced pressure (e.g., 0.5 to 5 bar).

[0476] Suitable inert solvents for acylation include, 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'-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of the mentioned solvents may also be used. Dimethylformamide or dichloromethane is preferred.

[0477] 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, 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 amines such as sodium amide or lithium bis(trimethylsilyl)amide. Or bis(trimethylsilyl)aminopotassium or diisopropylaminolithium, 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.

[0478] Compounds of formula (IVe)

[0479]

[0480] Where R 4 R 9 X1 and X2 are defined as above.

[0481] It is known, commercially available, or obtainable by known methods.

[0482] Compounds of formula (XVIII)

[0483]

[0484] Where R 7a As defined above

[0485] It is known, commercially available, or obtainable by known methods.

[0486] Compounds of formula (IVi)

[0487]

[0488] Where R 4 R 8 R 9 As defined above, X1 and X2 are new and can be obtained in the following ways.

[0489] [I] First, the compound of formula (IVg) is used.

[0490]

[0491] Where R 4 R 9 X1 and X2 are defined as above.

[0492] Reaction with acids in a suitable solvent

[0493] To obtain a compound of formula (IVh)

[0494]

[0495] Where R 4 R 9 X1 and X2 are defined as above.

[0496] as well as

[0497] [H] Secondly, compounds of formula (IVh)

[0498]

[0499] Where R 4 R 9 X1 and X2 are defined as above.

[0500] Compounds of formula ((XIX))

[0501] XR 8 (XIX)

[0502] Where X represents I and OTf

[0503] And R 8 As defined above

[0504] The reaction occurs in the presence of a base and a suitable solvent.

[0505] To obtain a compound of formula (IVi)

[0506]

[0507] Where R 4 R 8 R 9 X1 and X2 are defined as above.

[0508] [H] (alkylation) reaction

[0509] The reaction [H] is typically carried out in a temperature range of 0°C to +120°C, preferably +20°C to +80°C, and may be carried out in a microwave oven where appropriate. The reaction can be carried out at atmospheric pressure, under pressure or under pressure (e.g., 0.5 to 5 bar).

[0510] Suitable inert solvents for alkylation include, 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'-dimethylacrylurea (DMPU), N-methylpyrrolidone (NMP), or pyridine. Mixtures of the mentioned solvents may also be used. Dimethylformamide, dimethyl sulfoxide, or tetrahydrofuran are preferred.

[0511] 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 alkaline earth 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, 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 amines such as sodium amide or lithium bis(trimethylsilyl)amide. Or bis(trimethylsilyl)aminopotassium or diisopropylaminolithium, 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.

[0512] Reaction [I] (Deprotection)

[0513] The reaction [I] is usually carried out in an inert solvent in the presence of a suitable acid, preferably at atmospheric pressure in the temperature range of 0°C to 60°C.

[0514] 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.

[0515] 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.

[0516] The reaction is usually carried out in a temperature range of 0°C to +60°C.

[0517] The alkylating agent of formula ((XVI)) is known, commercially available, or obtainable by known methods.

[0518] The starting material for formula (IVa) is commercially available, known, or obtainable by known methods.

[0519] The compounds of formula (IVg) are known, commercially available, or can be obtained from known starting materials by known methods.

[0520] The compounds of formula (XIX) are known, commercially available, or can be obtained from known starting materials by known methods.

[0521] Compounds of formula (III)

[0522]

[0523] Where R 1 R 2 and R 3 As defined above, it is new and can

[0524] [J] By making the compound of formula (V)

[0525]

[0526] in

[0527] R 1 R 2 and R 3 As defined above,

[0528] It is prepared by reacting with trifluoromethanesulfonic anhydride in the presence of a base and an inert solvent.

[0529] Reaction [J] (triflatization)

[0530] 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.

[0531] The base is, for example, an organic base such as a basic amine or pyridine, or an inorganic base such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or an alkali metal carbonate such as cesium carbonate, sodium carbonate or potassium carbonate, or an alkoxide such as potassium tert-butoxide or sodium tert-butoxide, or a pyridine such as pyridine or 2,6-dimethylpyridine, or a basic amine such as triethylamine or N,N-diisopropylethylamine; preferably triethylamine.

[0532] 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.

[0533] The compound of formula (V) is new.

[0534]

[0535] Where R 1 R 2 and R 3 As defined above.

[0536] Compounds of formula (V) can

[0537] [K] by making the compound of formula (VI)

[0538]

[0539] Where R 1 R 2 and R 3 As defined above,

[0540] It is prepared by reacting with an acid, optionally in an inert solvent.

[0541] Reaction [K] (acidic deprotection)

[0542] 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.

[0543] The inert solvent is, for example, a halogenated hydrocarbon such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, an alcohol such as methanol or ethanol, an ether 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 a mixture of solvents; preferably dichloromethane or dioxane.

[0544] 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.

[0545] The compound of formula (VI) is new.

[0546]

[0547] in

[0548] R 1 R 2 and R 3 As defined above.

[0549] Compounds of formula (VI) can

[0550] [L] By making the compound of formula (VII)

[0551]

[0552] in

[0553] R 1 and R 2 As defined above,

[0554] Compounds of formula (VIII)

[0555]

[0556] Where R 3 As defined above,

[0557] It is prepared by reaction in the presence of a palladium source, a suitable ligand, and a base.

[0558] The reaction [L] (Buchwald Hartwig coupling)

[0559] 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.

[0560] 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]palladium(II) dichloride and the corresponding dichloromethane complexes, optionally combined with other phosphane ligands such as 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino] 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-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, CAS-No: 657408-07) -6), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos, CAS-No: 787618-22-8), 2-(di-tert-butylphosphino)-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl (RockPhos) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tert-ButylXPhos). 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).

[0561] Preferably, it is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), tris(dibenzylideneacetone)palladium (0), or combined with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthocyanidin (Xantphos) or dicyclohexyl[2',4',6'-tris(1-methylethyl)biphenyl-2-yl]phosphine (XPhos).

[0562] 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, amines such as sodium amide, lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino or potassium bis(trimethylsilyl)amino or lithium diisopropylamino, 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.

[0563] The inert solvent is, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, di-n-butyl ether, cyclopentylmethyl ether, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as tert-butanol or pentanol, or dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, toluene or acetonitrile or a mixture of said solvents; preferably tert-butanol, 1,4-dioxane and toluene.

[0564] The compounds in formula (VIII) are known or can be synthesized by known methods from the corresponding commercially available starting compounds.

[0565] The compound of formula (VII) is new.

[0566]

[0567] Where R 1 and R 2 As defined above.

[0568] The compound of formula (VII) can

[0569] [M] by making the compound of formula (IX)

[0570]

[0571] Where R 1 and R 2 As defined above,

[0572] It is prepared by reacting with an acid in an inert solvent.

[0573] Reaction [M] (debocylation)

[0574] 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.

[0575] 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.

[0576] 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.

[0577] The compound of formula (IX) is new.

[0578]

[0579] Where R 1 and R 2 As defined above.

[0580] Compounds of formula (IX) can

[0581] [N] by making the compound of formula (X)

[0582]

[0583] in

[0584] R1 and R2 are defined above.

[0585] Compounds of formula (XI)

[0586]

[0587] Prepared by reaction in solvent

[0588] Reaction [N] (Pyrazole formation)

[0589] The reaction [L] is usually carried out in a solvent at room temperature to reflux temperature.

[0590] 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.

[0591] The compounds of formula (XI) are known or can be synthesized from the corresponding starting compounds by known methods.

[0592] The compound of formula (X) is new.

[0593]

[0594] Where R 1 and R 2 As defined above.

[0595] Compounds of formula (X) can

[0596] [O] By making the compound of formula (XII)

[0597]

[0598] Where R 1 and R 2 As defined above

[0599] It is prepared by reacting palladium on carbon in the presence of hydrogen in a suitable solvent.

[0600] The reaction [O](Z deprotection)

[0601] The reaction [O] is typically carried out in a suitable solvent in the presence of palladium on carbon at room temperature to reflux, preferably at 1 bar.

[0602] Suitable solvents include alcohols such as methanol, ethanol, or isopropanol; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane, dichloromethane; and polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), NMP, acetic acid, or water, or mixtures of such solvents; preferably ethanol / acetic acid.

[0603] The compound of formula (XII) is new.

[0604]

[0605] Where R 1 and R 2 As defined above.

[0606] Compounds of formula (XII) can

[0607] [P] By making the compound of formula (XIIII)

[0608]

[0609] Where R 1 and R 2 As defined above

[0610] Compounds of formula (XIV)

[0611]

[0612] Prepared by reaction in the presence of a reducing agent and a suitable solvent.

[0613] The compounds of formula (XIV) are known and commercially available, or can be synthesized from the corresponding starting compounds by known methods.

[0614] The compounds of formula (XIII) are known and commercially available, or can be synthesized from the corresponding starting compounds by known methods.

[0615] The preparation of the starting compound and the compound of formula (I) can be described by the following synthetic schemes 1 to 4.

[0616] Option 1

[0617]

[0618] Option 2

[0619]

[0620] Option 3

[0621]

[0622] Option 4

[0623]

[0624]

[0625] The compounds of this invention have important pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0626] 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 blood flow. These effects are mediated by direct, heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP.

[0627] Furthermore, the compounds of the present invention have favorable pharmacokinetic properties, specifically in terms of their bioavailability and / or duration of action after intravenous or oral administration.

[0628] Compared with compounds according to the prior art (WO 2012 / 058132), the compounds of the present invention have similarly excellent pharmacokinetic (PK) characteristics, for example, a lower plasma clearance (CL) in rats compared to, for example, Example 174 of WO2012 / 058132 (see Tables 3 and 4, Experimental Section). 血浆 Furthermore, the half-life and mean residence time (MRT) of the compounds of the present invention after intravenous (iv) administration are within a comparable range compared to the corresponding values ​​of compounds disclosed in the prior art (WO 2012 / 058132). After oral (po) administration, the compounds of the present invention, such as those in Example 7, show similar exposure levels but lower bioavailability.

[0629] 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.

[0630] In the context of this invention, the term "treatment" or "treating" includes the suppression, delay, inhibition, relief, mitigation, limitation, weakening, prevention, resistance, or cure of a disease, condition, ailment, 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".

[0631] In the context of this invention, “prevention,” “prophylaxis,” and “preclusion” are used synonymously and refer to avoiding or reducing the risk of developing or progressing an infection, experiencing, suffering from, or having a disease, condition, ailment, injury, or health problem, or the symptoms of these conditions.

[0632] Treatment or prevention of diseases, conditions, symptoms, injuries, or health problems can be partial or complete.

[0633] In addition, the compounds of the present invention have other advantageous properties, particularly in terms of their lung-selective effect (compared to systemic effect) after intrapulmonary administration, lung retention time and / or duration of effect.

[0634] The compounds of the present invention are particularly suitable for the treatment and / or prevention of cardiovascular and heart diseases, heart and kidney diseases, cardiopulmonary and pulmonary diseases, neurodegenerative diseases, thromboembolic diseases, fibrotic conditions and / or wound healing disorders.

[0635] 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 renal diseases, preferably chronic kidney disease and diabetic kidney disease (CKD and DKD), cardiopulmonary and pulmonary diseases, preferably pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementia, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), and wound healing disorders such as diabetic foot ulcers (DFU).

[0636] Therefore, the compounds of the present invention can be used in medicaments for the treatment and / or prevention of cardiovascular, cardiopulmonary, and cardiorenal conditions, such as hypertension (Hypertension), heart failure, coronary artery disease, stable and unstable angina, pulmonary arterial hypertension (PAH) and secondary pulmonary arterial hypertension (PH), chronic thromboembolic pulmonary hypertension (CTEPH), renal hypertension, renovascular hypertension and refractory hypertension, peripheral and cardiovascular conditions, arrhythmias, atrial and ventricular arrhythmias and conduction impairment, 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, AV junctional premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome ( Acute cardiovascular disease (ACS), autoimmune heart disease (pericarditis, endocarditis, valvular heart disease, aortitis, cardiomyopathy), Boxer cardiomyopathy, aneurysm, shock such as cardiogenic shock, septic shock, and anaphylactic shock; in addition, it is used to treat and / or prevent thromboembolic diseases and local ischemia such as myocardial ischemia, myocardial infarction, stroke, myocardial hypertrophy, transient and local ischemic attacks, preeclampsia, inflammatory cardiovascular disease, coronary and peripheral artery spasm, formation of edema such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral perfusion impairment, reperfusion injury, arterial and venous thrombosis, microalbuminuria, heart failure, endothelial dysfunction, microvascular and large vessel injury (vasculitis), and to prevent restenosis, such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), and restenosis after heart transplantation and bypass surgery.

[0637] In the context of this invention, the term "pulmonary hypertension" includes two subtypes: primary and secondary, as defined below according to their respective etiologies by the Dana Point classification [see D. Montana and G. Simonneau, in: AJPeacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3]. rd [edition, Hodder Arnold Publ., 2011, pp. 197-206; M.M. Hoeper et al., J. Am. Coll. Cardiol. 2009, 54(1), S85-S96]. Specifically, this includes Group 1 pulmonary arterial hypertension (PAH), particularly idiopathic and familial forms (IPAH and FPAH, respectively). In addition, PAH also includes persistent pulmonary arterial hypertension in newborns and associated pulmonary arterial hypertension (APAH) associated with the following conditions: collagen diseases, congenital systemic pulmonary shunts, portal hypertension, HIV infection, intake of certain drugs and agents (e.g., appetite suppressants), conditions with significant venous / capillary components such as pulmonary venous occlusion and pulmonary capillary hemangioma, or other conditions such as thyroid disorders, glycogen storage diseases, Gaucher disease, hereditary teleangiectasia, hemoglobinopathies, myeloproliferative disorders, and splenectomy. Group 2 of the Dana Point classification includes pulmonary hypertension (PH) patients with left ventricular conditions (e.g., ventricular, atrial, or valvular conditions). Group 3 includes forms of pulmonary hypertension associated with lung conditions (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 PH patients with chronic thrombotic and / or embolic conditions, such as proximal and distal pulmonary thromboembolic occlusion (CTEPH) or non-thrombotic embolisms (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.

[0638] 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 intermediate 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.

[0639] 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.

[0640] Furthermore, the compounds of the present invention can be used to treat and / or prevent primary and secondary Raynaud's phenomena, such as 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.

[0641] Furthermore, the compounds of this invention can be used to treat sickle cell disease (SCD), sickle cell anemia, and other SCD-related symptoms (e.g., end-organ damage affecting the lungs, brain, kidneys, or heart), as well as malaria, thalassemia, hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, drug-induced hemolytic anemia, or vascular occlusive events or pain crises such as rhabdomyopathies, achalasia, and hemolytic angiopathy. Moreover, since similar pathophysiological mechanisms are effective in transfusing blood to patients with transfusion indications (e.g., by increasing free Hb concentration through storage), these compounds can be used in patients receiving transfusions. Finally, in the future, the combination of sGC activators with synthetic Hb-based oxygen carriers may alleviate the side effects observed to date caused by reduced NO availability [Weiskopf, Anesthesia &

[0642] [Analgesia, 110:3; 659-661, 2010], thus allowing for further clinical application.

[0643] 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 for perfusion and preservation solutions of organs, organ parts, tissues or tissue parts in humans or animals, particularly in the fields of surgical intervention or transplant medicine.

[0644] 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, the terms 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, nephropathy such as primary and congenital nephropathy, nephritis, immune-mediated nephropathy such as kidney transplant rejection and immune complex-induced nephropathy, toxic substance-induced nephropathy, and contrast agent-induced nephropathy. This invention relates to diabetic and non-diabetic nephropathy, diabetic nephropathy (DKD), pyelonephritis, renal cysts and polycystic kidney disease, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, characterized by features such as abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme (e.g., gamma-glutamyl synthase) activity, altered urine osmolality or urine volume, increased microalbuminuria or macroalbuminuria, glomerular and arteriolar damage, renal tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The invention also covers the use of the compounds of this invention for the treatment and / or prevention of 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.

[0645] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of urinary system disorders such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), prostatitis, neurogenic overactive bladder (OAB), urinary incontinence such as mixed, urge, stress, or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, interstitial cystitis (IC), as well as erectile dysfunction and female sexual dysfunction.

[0646] 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).

[0647] The compounds described in this invention are also active compounds for controlling central nervous system disorders characterized by NO / cGMP system disorders. They are particularly suitable for improving perception, attention, learning, or memory following cognitive impairment, such as those associated with: mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia, post-traumatic brain injury, general attention deficit, attention deficit in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, frontal lobe degenerative dementia including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, corticobasal degenerative dementia, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating diseases, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia, or Korsakoff psychosis. They are also applicable to the treatment and / or prevention of central nervous system disorders, such as anxiety, tension and depression, CNS-related dysfunction and sleep disorders, as well as pathological disorders for controlling the intake of food, stimulants and addictive substances.

[0648] Furthermore, the compounds of this invention are also suitable for regulating cerebral blood flow, and are therefore effective agents for controlling migraines. They are also suitable for preventing and controlling sequelae of stroke, such as cerebral ischemia and traumatic brain injury. The compounds of this invention can also be used to control pain states.

[0649] 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 arthritis, inflammatory skin diseases, and inflammatory eye diseases.

[0650] Furthermore, the compounds of the present invention are also suitable for treating and / or preventing fibrotic conditions of internal organs such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatological fibrosis and ocular fibrosis. In the context of this invention, the term "fibrotic condition" specifically includes conditions 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 conditions, 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.

[0651] 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, microcirculatory impairment, renal insufficiency, fibrotic diseases and arteriosclerosis.

[0652] The present invention also provides the use of the compounds of the present invention for treating and / or preventing diseases, particularly the aforementioned diseases.

[0653] 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.

[0654] The present invention also provides a medicine comprising at least one compound of the present invention for treating and / or preventing conditions, particularly the aforementioned conditions.

[0655] 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.

[0656] 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.

[0657] Therefore, they are suitable for use as medicines for the treatment and / or prevention of diseases in humans and animals.

[0658] The present invention further provides the use of the compounds of the present invention for the treatment and / or prevention of conditions, particularly cardiovascular conditions, preferably thrombotic conditions or thromboembolic conditions 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 conditions, especially those associated with these conditions.

[0659] For the purposes of this invention, "thrombotic conditions or thromboembolic conditions" include conditions preferably occurring within arterial vessels and treatable with the compounds of this invention, particularly conditions leading to peripheral artery occlusion and conditions 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, and coronary interventions (such as angioplasty, stent implantation, or main coronary intervention). Reocclusion and restenosis after coronary artery bypass grafting (CABG), as well as thrombotic or thromboembolic conditions in cerebral arteries, such as transient ischemic attack (TIA), ischemic stroke including cardiogenic stroke such as stroke caused by atrial fibrillation, non-cardiogenic stroke such as lacunar stroke, stroke caused by disease of large or small arteries, or stroke due to uncertain factors, cryptogenic stroke, embolic stroke, embolic stroke of unknown origin, or thrombotic and / or thromboembolic origin events leading to stroke or TIA.

[0660] Furthermore, the compounds of the present invention are particularly suitable for treating and / or preventing conditions 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 conditions such as myocarditis.

[0661] Furthermore, the compounds of the present invention are suitable for the treatment and / or prevention of urogenital tract conditions such as overactive bladder, interstitial cystitis, and bladder pain syndrome.

[0662] 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.

[0663] Furthermore, the compounds of the present invention are particularly suitable for the treatment and / or prevention of neurological conditions such as neuropathic pain, neurodegenerative diseases, and dementias such as vascular dementia or Alzheimer's disease and Parkinson's disease.

[0664] Furthermore, the compounds of the present invention are particularly suitable for the treatment and / or prevention of lung conditions such as chronic cough, asthma, and COPD.

[0665] The present invention further provides the use of the compounds of the present invention for treating and / or preventing diseases, especially the aforementioned diseases.

[0666] 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.

[0667] 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.

[0668] The present invention further provides a method for using the compound of the present invention to treat and / or prevent diseases, especially the aforementioned diseases, by using a therapeutically effective amount of the compound of the present invention.

[0669] The present invention specifically provides a method for using the compounds of the present invention in a therapeutically effective amount to treat and / or prevent thrombotic or thromboembolic, especially atherosclerotic thrombotic, conditions.

[0670] The present invention also provides a medicament comprising the compound of the present invention and one or more other active compounds.

[0671] 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.

[0672] The present invention also provides a method for preventing in vitro blood clotting, particularly in bank blood or biological samples that may contain factor XIa or plasma kallikrein or both of these enzymes, characterized by the addition of an anticoagulant amount of the compound of the present invention.

[0673] 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.

[0674] For these routes of administration, the compounds of the present invention can be administered in a suitable form.

[0675] For oral administration, the compounds of the present invention can be formulated into dosage forms known in the art that can deliver the compounds of the present invention rapidly and / or in an improved manner, such as tablets (uncoated or coated tablets, e.g., enteric or controlled-release coatings with delayed dissolution or insolubility), orally disintegrating tablets, films / capsules, films / lyophilized forms, capsules (such as hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. The compounds according to the present invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved forms.

[0676] 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.

[0677] 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).

[0678] Intraocular drug delivery includes intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar, and subconjunctival administration. Suitable forms of administration for intraocular drug delivery are those that operate according to existing technology, enabling rapid and / or modified or controlled release of the active compound, and containing the active compound in crystalline and / or amorphous and / or dissolved forms, such as injectable formulations and concentrates 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), gels of injectable formulations (semi-solid formulations, such as hydrogels, in-situ hydrogels), and implants (solid formulations, such as biodegradable and non-biodegradable implants, implantation pumps).

[0679] Oral administration is preferred.

[0680] Examples of other routes of administration include inhaled drug forms [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / capsules / sacs for administration to the tongue, sublingually, or buccally; suppositories; eye drops, eye ointments, eye washes, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear plugs; vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapy systems (e.g., patches), lotions, pastes, foams, powders, implants, or stents.

[0681] 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,

[0682] • Fillers and carriers (e.g., cellulose, microcrystalline cellulose) ), lactose, mannitol, starch, calcium phosphate (e.g.) )),

[0683] • Ointment base (e.g., petroleum jelly, paraffin, triglycerides, waxes, lanolin, lanolin alcohol, hydrophilic ointments, polyethylene glycol),

[0684] • Suppository base (e.g., polyethylene glycol, cocoa butter, stearin),

[0685] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0686] Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g.) ), sorbitan 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., ),

[0687] • Buffers, acids, and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, thiamin, triethanolamine),

[0688] • Isotonic agents (e.g., glucose, sodium chloride),

[0689] • Adsorbent (e.g., highly dispersed silica),

[0690] • Tackifiers, gelling agents, thickeners and / or adhesives (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g.) (alginate, gelatin),

[0691] • Disintegrants (e.g., modified starch, sodium carboxymethyl cellulose, sodium glycolate starch (e.g.) ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g.) )),

[0692] • Flow conditioners, lubricants, flow aids, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g.) )),

[0693] • Coating materials (e.g., sugar, shellac) and film-forming agents that dissolve rapidly or in a modified manner in the form of thin or diffused films (e.g., polyvinylpyrrolidone). Polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate, etc. ),

[0694] • Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[0695] • 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),

[0696] Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerin, triacetyl triacetate, triacetyl citrate, dibutyl phthalate),

[0697] • Penetration enhancer

[0698] • Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[0699] • Preservatives (such as parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0700] • Colorants (e.g., inorganic pigments, such as iron oxide and titanium dioxide),

[0701] • Flavoring agents, sweeteners, flavor and / or odor masking agents.

[0702] The present invention also relates to pharmaceutical compositions comprising at least one compound of the present invention, typically together with one or more pharmaceutically suitable excipients, and to their use according to the present invention.

[0703] 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.

[0704] According to another aspect, the present invention covers pharmaceutical compositions, particularly medicines, which comprise at least one compound of 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 conditions, preferably thrombotic conditions or thromboembolic conditions and diabetes, as well as genitourinary and ophthalmic conditions.

[0705] 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-parts.

[0706] In this invention, "fixed combination" is used as is known to those skilled in the art and is defined as a combination in which, for example, a first active ingredient such as one or more compounds of general formula (I) 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 for simultaneous administration, such as in a formulation. 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.

[0707] The non-fixed combination or "kit" 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 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 may be administered individually, sequentially, simultaneously, concurrently, or in a time-sequential manner.

[0708] 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 for treating and / or preventing the aforementioned conditions. Preferred examples of suitable combinations of active ingredients include:

[0709] • Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0710] • Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterases (PDEs) 1, 2, 5 and / or 9, especially PDE 5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, mirodenafil, lodenafil or PF-00489791;

[0711] • Compounds that inhibit the breakdown of cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterase (PDE) 3 and 4, especially cilostatzole, milrinone, roflumilast, apremilast, or crisaborole.

[0712] • Active ingredients that lower blood pressure, such as and preferably calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, angiopeptidase inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, and diuretics;

[0713] • Antiarrhythmic drugs, such as and preferably sodium channel blockers, beta-blockers, potassium channel blockers, calcium channel blockers, If-channel blockers, digitalis, parasympathomimetic drugs, sympathomimetic drugs and other antiarrhythmic drugs such as adenosine, adenosine receptor agonists and vernakalant;

[0714] • Positive cardiotonic agents, such as cardiac glycosides (Dogoxin), β-adrenergic and dopaminergic agonists, such as isoproterenol, epinephrine, noradrenaline, dopamine or dobutamine;

[0715] • Vasopressin receptor antagonists, such as and preferably conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, pecavaptan, SR-121463, RWJ 676070 or BAY 86-8050, and compounds described in WO2010 / 105770, WO2011 / 104322 and WO 2016 / 071212;

[0716] • 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.

[0717] • Bronchodilators, such as and preferably β-adrenergic receptor agonists, such as and preferably salbutamol, isoproterenol, metaproterenol, terbutalin, formoterol, or salmeterol, or anticholinergic drugs, such as and preferably ipratropium bromide;

[0718] • Anti-inflammatory drugs, such as and preferably glucocorticoids, such as and preferably prednisolone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolone, budesonide, or fluticason, 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;

[0719] • Drugs that regulate the immune system, such as immunoglobulins;

[0720] • Drugs that inhibit signal transduction cascades, such as, and preferably, kinase inhibitors, such as, and preferably, tyrosine kinase and / or serine / threonine kinase inhibitors;

[0721] • 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, stromelysine, collagenase, gelatinase and agglutinase (preferably MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and inhibitors of metalloelastase (MMP-12) and neutrophil elastase (HNE), such as sivelestat or DX-890;

[0722] • Drugs that block the binding of serotonin to its receptors, such as, and preferably, 5-HT2b receptor antagonists;

[0723] • Organic nitrates and NO donors, such as and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, madolamine or SIN-1, and inhaled NO;

[0724] • A non-NO-dependent but heme-dependent stimulant of 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.

[0725] • A non-NO-dependent 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;

[0726] • Drugs that stimulate cGMP synthesis, such as sGC regulators, such as and preferably riociguat, cinaciguat, vericiguat or runcaciguat;

[0727] • Prostacyclin analogues, such as and preferably iloprost, beraprost, treprostinil, or epoprostenol;

[0728] • 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;

[0729] • 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, and sotagliflozin;

[0730] • Natriuretic peptides, such as and preferably atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, Nesiritid), natriuretic peptide type C (CNP), or urodilatin;

[0731] • Activators of cardiac myosin, such as and preferably omecamtiv mecarbil (CK-1827452);

[0732] • Calcium sensitizers, such as, and preferably, levosimendan;

[0733] • Drugs that affect cardiac energy metabolism, such as and preferably etomoxifen, dichloroacetate, ranolazine or trimetazidine, full or partial adenosine A1 receptor agonists, such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate;

[0734] • Medications that affect heart rate, such as, and preferably, ivabradin;

[0735] • Cyclooxygenase inhibitors, such as bromfenac and nepafenac;

[0736] • Inhibitors of the kallikrein-kinin system, such as safotibant and ecallantide;

[0737] • Inhibitors of the sphingosine 1-phosphate signaling pathway, such as sonepcizumab;

[0738] • Complement C5a receptor inhibitors, such as eculizumab;

[0739] • 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;

[0740] • Anticoagulants, such as heparin (UFH), low molecular weight heparin (LMW), such as tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675 / ORG42675;

[0741] • Direct thrombin inhibitors (DTIs), such as Pradaxa (dabigatran), ategatran (AZD-0837), DP-4088, SSR-182289A, aratroban, bivalirudin, tanogitran (BIBT-986 and prodrug BIBT-1011), and hirudin;

[0742] • Direct factor Xa inhibitors, such as rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinu, and fondaparinux;

[0743] • Inhibitors of coagulation factors XI and XIa, such as FXI ASO-LICA, fesomersen, BAY121-3790, MAA868, BMS986177, EP-7041, and AB-022;

[0744] • Substances that inhibit platelet aggregation (platelet aggregation inhibitors, serum cell aggregation inhibitors), such as acetylsalicylic acid (e.g., aspirin), P2Y12 antagonists, such as ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor, and enogrel, as well as PAR-1 antagonists, such as vorapaxar and PAR-4 antagonists;

[0745] • Platelet adhesion inhibitors, such as GPVI and / or GPIb antagonists, such as Revacept or caplacizumab;

[0746] • Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists), such as abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban, and fradifiban;

[0747] • Recombinant human activated protein C, such as thrombectomycin (Xigris) or recombinant thrombomodulin.

[0748] Antithrombotic agents are preferably understood to refer to compounds selected from platelet aggregation inhibitors, anticoagulants, or fibrinolytic substances.

[0749] 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.

[0750] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a thrombin inhibitor, such as and preferably ximelagatran, dabigatran, melagatran, bivalirudin, or clexane.

[0751] 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.

[0752] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a factor Xa inhibitor, such as and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, betrixaban, omexaban, fidexaban, razaxan, letaxaban, eribaxaban, fondaparinux sodium, heparin, PMD-3112, daressaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, and DPC.

[0753] 906, JTV 803, SSR-126512 or SSR-128428.

[0754] 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, fexomethena, or BAY.

[0755] 121-3790, MAA868, BMS986177, EP-7041 or AB-022.

[0756] 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.

[0757] 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.

[0758] The term "antihypertensive agent" is preferably understood to refer to compounds selected from calcium channel blockers, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors, and diuretics.

[0759] 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.

[0760] 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.

[0761] 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, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, and carazolol. alol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, latetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol, or bucindolol.

[0762] 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 embusatan, or a dual angiotensin II antagonist / neprilysin inhibitor, such as and preferably LCZ696 (valsartan / sacubitril).

[0763] 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, perinopril, or trandopril.

[0764] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an endothelin antagonist, such as and preferably bosentan, darusentan, ambrisentan or sitaxentan.

[0765] 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.

[0766] 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, finerenone, or eplerenone.

[0767] 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 piretanide; potassium-sparing diuretics, such as amiloride and triamterene; aldosterone antagonists, such as spironolactone, canilenate, and eplerenone; and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.

[0768] Lipid metabolism regulators are preferably understood to mean 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.

[0769] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a CETP inhibitor, such as and preferably dalcetrapib, anacetrapib, torcetrapib (CP-529414), JJT-705, or the CETP vaccine (Avant).

[0770] 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 axitirome (CGS26214).

[0771] 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.

[0772] 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.

[0773] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an ACAT inhibitor, such as and preferably avasimibe, melinamide, pactimibe, eflucimibe, or SMP-797.

[0774] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an MTP inhibitor, such as and preferably impitapide, BMS-201038, R-103757 or JTT-130.

[0775] 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.

[0776] 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.

[0777] 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, tiqueside, or pamaqueside.

[0778] 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.

[0779] 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, cholesta gel, or colestimide.

[0780] 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-

[0781] 8921, AK-105, BARI-1741, SC-435 or SC-635.

[0782] 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 gemcabene calcium (CI-1027) or niacin.

[0783] 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.

[0784] 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 vericiguat.

[0785] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an agent that affects glucose metabolism, such as and preferably insulin, sulfonylurea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors empagliflozin, dapagliflozin, canagliflozin, soragliflozin.

[0786] 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.

[0787] 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.

[0788] 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.

[0789] 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.

[0790] 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 bardoxolone.

[0791] 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.

[0792] 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.

[0793] 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, doxercalciferol, maxacalcitol, paricalcitol, cholecalciferol, or paracalcitol.

[0794] 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.

[0795] In a preferred embodiment of the invention, the compound of the invention is administered in combination with an immunosuppressant, such as, and preferably, cyclosporin.

[0796] In a preferred embodiment of the invention, the compound of the invention is used in combination with a phosphate binder, such as and preferably colestilan, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[0797] 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.

[0798] 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.

[0799] 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.

[0800] 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 rasburicase.

[0801] 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, daprodustat, molidustat, roxadustat, vadadustat, and desidustat.

[0802] 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.

[0803] 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, conivaptan, lixivaptan, mozavaptan, satavaptan, pecavaptan, or relcovaptan.

[0804] 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, lestaurtinib, pacritinib (SB1518), or TG101348.

[0805] In a preferred embodiment of the invention, the compound of the invention is administered in combination with a prostacyclin analogue for treating microthrombosis.

[0806] In a preferred embodiment of the invention, the compound of the invention is administered in combination with alkali therapy, such as, and preferably, sodium bicarbonate.

[0807] 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.

[0808] 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 tenapanor.

[0809] 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.

[0810] 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.

[0811] The present invention also provides a medicine comprising at least one compound of the present invention, usually together with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and its use for the above-mentioned purposes.

[0812] 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.

[0813] The compounds of the present invention can be administered in a manner suitable for these routes of administration.

[0814] Suitable oral administration forms are those that function according to the prior art, which rapidly and / or in an improved manner release the compounds of the invention, and contain the compounds of the invention in crystalline and / or amorphous and / or dissolved forms, such as tablets (uncoated or coated tablets, for example, having an anti-gastric juice or slow-dissolving or insoluble coating that controls the release of the compounds of the invention), tablets or films / capsules that rapidly disintegrate in the oral cavity, films / lyophilized forms or capsules (e.g., hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions.

[0815] 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.

[0816] 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 buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, transdermal therapy systems (e.g., patches), lotions, creams, foams, powders, implants or stents.

[0817] Oral or parenteral administration is preferred, especially oral and intravenous administration.

[0818] The compounds of the present invention can be converted into the described dosage form. This can be accomplished in a manner known per se, by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polysorbate oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxide), and flavoring and / or taste-enhancing agents.

[0819] Generally, it has been found that when administered parenterally, 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. When administered orally, the dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, and most preferably 0.1 to 10 mg / kg body weight.

[0820] However, it may be necessary to deviate from the prescribed amount 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 amount mentioned above may be sufficient, while in others, the upper limit mentioned must be exceeded. In cases involving large doses, it is recommended to divide these medications into several separate doses throughout the day.

[0821] The total amount of the active ingredient to be administered typically ranges from about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 50 mg / kg body weight per day, and more preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules range from once 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 the active ingredient and may be administered once or more or less daily. For injectable administration, including intravenous, intramuscular, subcutaneous, and parenteral injections, 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.

[0822] 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.

[0823] However, it may be necessary to deviate from the prescribed amount depending on factors such as body weight, route of administration, individual response to the active substance, type of formulation, and the time or interval at which the medication is administered. 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.

[0824] According to another embodiment, the compound of formula (I) of the present invention is administered orally once, twice, or three times daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once or twice daily. According to another embodiment, the compound of formula (I) of the present invention is administered orally once daily. For oral administration, rapid-release or modified-release formulations can be used.

[0825] Unless otherwise stated, 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.

[0826] Experimental Section

[0827] Experimental Section – General Section

[0828] NMR peaks are represented in the form they appear in the spectrum, without taking into account possible higher-order effects.

[0829] 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 in ppm is given, followed by the signal intensity in parentheses. The δ value-signal intensity pairs for different peaks are separated by commas. Therefore, the peak list is described in the following general form: δ1 (intensity 1), δ2 (intensity 2), ..., δi (intensity i), ..., δn (intensity).

[0830] The intensity of the spike signal is related to the signal height (in cm) in the printed NMR spectrum. This data can be correlated with the true proportion of the signal intensity when compared with other signals. In the case of a wide signal, more than one peak or signal center is displayed, along with their relative intensity compared to the strongest signal shown in the spectrum. 1 The H-NMR peak list is similar to the classic one. 1 1H-NMR readings, and therefore typically contain all the peaks listed in a classic NMR specification. Furthermore, similar to a classic 1H-NMR printout, the peak list can display the solvent signal, the signals from stereoisomers of the target compound (which is also the subject of this invention), and / or impurity peaks. The peaks of stereoisomers and / or impurities typically show lower intensities compared to the peaks of the target compound (e.g., purity > 90%). Such stereoisomers and / or impurities can be specific to a particular preparation method, and therefore their peaks can help identify the reproducibility of our preparation method based on a "by-product fingerprint." A person skilled in the art who calculates the peaks of the target compound using known methods (MestReC, ACD simulation, or expected values ​​estimated using experience) can optionally use additional intensity filters to separate the peaks of the target compound as needed. This operation is similar to that in conventional... 1 Peak selection is similar to that described in H-NMR descriptions. Detailed instructions for NMR data reports in peak list format 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). In the peak selection routine, as described in Research Disclosure Database Number 605005, the parameter "Minimum Height" can be adjusted between 1% and 4%. Setting the parameter "Minimum Height" <1% may be reasonable depending on the chemical structure and / or the concentration of the compound being measured.

[0831] Chemical names are generated using ACD / Labs' ACD / Name software. In some cases, the generally accepted name of the commercially available reagent is used instead of the name generated by ACD / Name.

[0832] Table 1 below lists the abbreviations used in this paragraph and the Examples section (unless otherwise explained in the text). Other abbreviations have their own meanings as commonly understood by those skilled in the art.

[0833] Table 1: Abbreviations

[0834] The following table lists the abbreviations used in this article.

[0835] BH3·THF Borane-Tetrahydrofuran

[0836] BINAP 2,2'-bis(diphenylphosphino)1,1'-binaphthyl

[0837] br broad peak ( 1 H-NMR signal)

[0838] CI chemical ionization

[0839] d double peak ( 1 H-NMR signal)

[0840] d day

[0841] DAD Diode Array Detector

[0842] dd Double peak

[0843] DMF N,N-dimethylformamide

[0844] DMSO (dimethyl sulfoxide)

[0845] ESI Electrospray (ES) Ionization

[0846] EtOAc (ethyl acetate)

[0847] h hours

[0848] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine 3-oxide hexafluorophosphate, CAS 148893-10-1

[0849] HPLC (High Performance Liquid Chromatography)

[0850] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0851] m multiplet ( 1 H-NMR signal)

[0852] M Moore

[0853] min minutes

[0854] MS mass spectrometry

[0855] MTBE (methyl tert-butyl ether)

[0856] Sodium borohydride (NaBH4), sodium tetrahydroborate

[0857] NaHCO3 (Sodium bicarbonate)

[0858] Na2SO4 Sodium sulfate

[0859] NMR spectroscopy: Chemical shifts (δ) are given in ppm. Unless otherwise specified, chemical shifts are corrected by setting the DMSO signal to 2.50 ppm.

[0860] PDA photodiode array

[0861] Pd2dba3 tris(dibenzylacetone)dipalladium(0), CAS 51364-51-3

[0862] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0), CAS 14221-01-3

[0863] quant.

[0864] rac racemic

[0865] R t Rt Retention time (measured by HPLC or UPLC), in minutes

[0866] RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate, CAS 1445085-77-7

[0867] s Single peak ( 1 H-NMR signal)

[0868] SFC Supercritical Fluid Chromatography

[0869] SQD Single Quadrupole Detector

[0870] t triple peak ( 1 H-NMR signal)

[0871] td triple peak ( 1 H-NMR signal)

[0872] TFA (trifluoroacetic acid)

[0873] THF Tetrahydrofuran

[0874] UPLC (Ultra-High Performance Liquid Chromatography)

[0875] X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, CAS 564483-18-7

[0876] 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.

[0877] The embodiments and test experiments described herein are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0878] 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.

[0879] Compounds and intermediates prepared according to the methods of this invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several methods may be available for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by stirring with a suitable solvent. In some cases, the compound may be purified by chromatography, particularly rapid column chromatography, for example using a pre-packed silica column, such as a Biotage SNAP column. or Combined with Biotage automated purification system ( or Isolera Purification can be achieved using a preparative HPLC system, employing, for example, a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, along with a suitable pre-packed reversed-phase column and an eluent (such as a gradient solution of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or ammonia).

[0880] 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.

[0881] 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.

[0882] This applies if the synthetic intermediate or working example or its salt is obtained by the preparation and / or purification methods described herein in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0883] HPLC and LC-MS methods:

[0884] Method 1 (LC-MS)

[0885] MS instrument model: SHIMADZU LCMS-2020, column: Kinetex EVO C18 30*2.1mm, 5μm, 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 and 254nm.

[0886] Method 2 (LC-MS)

[0887] HPLC instrument model: SHIMADZU LCMS-2020; column: Kinetex EVO C18 50*4.6mm, 5μm; 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, and 254nm.

[0888] Method 3 (LC-MS)

[0889] 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.

[0890] Method 4 (LC-MS)

[0891] Instrument MS: Thermo Scientific FT-MS; Instrument model 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: 50 °C; Flow rate: 0.90 mL / min; UV detection: 210 nm / optimal integration path 210-300 nm.

[0892] Method 5 (LC-MS)

[0893] 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: 50℃; Flow rate: 0.35ml / min; UV detection: 210nm.

[0894] Method 6 (LC-MS)

[0895] Instruments: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLCHSS 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: 50℃; Flow rate: 1, 20ml / min; UV detection: 205–305nm.

[0896] Method 7 (LC-MS)

[0897] 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: 50℃; Flow rate: 0.40ml / min; UV detection: 210nm.

[0898] Method 8 (LC-MS)

[0899] System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters, HSST3, 2.1 x 50 mm, C18 1.8 μm; Eluent A: 1 L water + 0.01% formic acid; Eluent B: 1 L acetonitrile + 0.01% formic acid; Gradient: 0.0 min 2% B → 0.5 min 2% B → 7.5 min 95% B → 10.0 min 95% B; Oven: 50 °C; Flow rate: 1.00 ml / min; UV detection: 210 nm

[0900] Method 9 (Preparative HPLC)

[0901] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30 mm, UV detection 200-400nm, room temperature, on-column injection (complete injection); Elution buffer A: water; Elution buffer B: acetonitrile; Elution buffer C: 2% formic acid aqueous solution; Elution buffer D: acetonitrile / water (80% / 20%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Elution buffer A 55 ml / min, Elution buffer B 15 ml / min; 2 to 10 minutes: Elution buffer A from 55 ml / min to 31 ml / min, Elution buffer B from 15 ml / min to 39 ml / min; 10 to 12 minutes: Elution buffer A 0 ml / min, Elution buffer B 70 ml / min; Elution buffers C and D maintained a constant flow rate of 5 ml / min throughout the run.

[0902] Method 10 (Preparative HPLC)

[0903] Instrumentation: Waters Prep LC / MS system; Column: XBridge C18 5μm 100x30mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Elution buffer A: Water; Elution buffer B: Acetonitrile; Elution buffer C: 2% ammonia solution; Elution buffer D: Acetonitrile / water (80% / 20% vol); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Elution buffer A 55 ml / min, Elution buffer B 15 ml / min; 2 to 10 minutes: Elution buffer A from 55 ml / min to 31 ml / min, Elution buffer B from 15 ml / min to 39 ml / min; 10 to 12 minutes: Elution buffer A 0 ml / min, Elution buffer B 70 ml / min; Elution buffers C and D maintained a constant flow rate of 5 ml / min throughout the run.

[0904] Method 11 (Preparative HPLC)

[0905] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30 mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Elution buffer: Water; Elution buffer B: Acetonitrile; Elution buffer C: 2% formic acid aqueous solution; Elution buffer D: Acetonitrile / water (80% / 20% vol); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Elution buffer A 47 ml / min, Elution buffer B 23 ml / min; 2 to 10 minutes: Elution buffer A from 7 ml / min to 23 ml / min, Elution buffer B from 23 ml / min to 47 ml / min; 10 to 12 minutes: Elution buffer A 0 ml / min, Elution buffer B 70 ml / min; Elution buffers C and D maintained a constant flow rate of 5 ml / min throughout the run.

[0906] Method 12 (Preparative HPLC)

[0907] Instrumentation: Waters Prep LC / MS system; Column: Phenomenex Kinetex C18 5μm 100x30 mm; UV detection 200-400nm; Room temperature; On-column injection (complete injection); Elution buffer A: Water; Elution buffer B: Acetonitrile; Elution buffer C: 2% formic acid aqueous solution; Elution buffer D: Acetonitrile / water (80% / 20%); Flow rate: 80 ml / min; Gradient curve: 0 to 2 minutes: Elution buffer A 23 ml / min, Elution buffer B 47 ml / min; 2 to 10 minutes: Elution buffer A from 23 ml / min to 0 ml / min, Elution buffer B from 47 ml / min to 70 ml / min; 10 to 12 minutes: Elution buffer A 0 ml / min, Elution buffer B 70 ml / min; Elution buffers C and D maintained a constant flow rate of 5 ml / min throughout the run.

[0908] Method 13 (Preparative HPLC)

[0909] Instrument: Waters Prep LC / MS system 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; 2 to 10 minutes: eluent A 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.

[0910] microwave The microwave reactor used is Initiator with 60 robots + Microwave system.

[0911] 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, they can be obtained in the form of salts, such as trifluoroacetate salts, formate salts, or ammonium salts. Such salts can be converted into the corresponding free bases or acids by those skilled in the art using various known methods.

[0912] 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, additional terms such as “hydrochloride,” “trifluoroacetate,” “sodium salt,” or “x HCl,” “xCF3COOH,” “x Na…” are used in names and structural formulas. + In the case of this type of salt, it should not be understood in a stoichiometric sense, but rather in a descriptive sense regarding the salt-forming components present.

[0913] This applies if the synthetic intermediate or working example or its salt is obtained by the preparation and / or purification methods described herein in the form of a solvate, such as a hydrate, with an unknown stoichiometric composition (if they are of a defined type).

[0914] Enantiomer 1 It is the first enantiomer eluted from the column, for example when preparative separation is performed under separation conditions (see Example 4A).

[0915] Enantiomer 2 It is the second enantiomer eluted from the column, for example when preparative separation is performed under separation conditions (see Example 4A).

[0916] diastereomer mixture 1 A compound is defined as having an enantiomer 1 as its starting material and reacting with a structural unit containing at least one chiral center, the configuration of which is not defined.

[0917] diastereomer mixture 2 A compound is defined as having an enantiomer 2 as its starting material and reacting with a structural unit containing at least one chiral center, the configuration of which is not defined.

[0918] diastereomer 1 and diastereomer 2 Two compounds generated by the chiral separation of the above diastereomer mixture 1 are defined.

[0919] diastereomer 3 and diastereomer 4 Two compounds generated by the chiral separation of the above diastereomer mixture 2 are defined.

[0920] Stereoisomer 1 A compound is defined whose starting material is defined as enantiomer 1, which reacts with a structural unit containing at least one chiral center, and whose configuration is defined.

[0921] Stereoisomer 2 A compound is defined whose starting material is defined as enantiomer 2, and reacts with a structural unit containing at least one chiral center, and whose configuration is defined.

[0922] Experimental Section - Starting Materials and Intermediates

[0923] Example 1A

[0924] 3-{2-[(benzyloxy)carbonyl]hydrazinoyl}piperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[0925]

[0926] 250 g (1.51 mol) of benzyl hydrazide carboxylate [CAS No. 5331-43-1] was added to a solution of 3-oxopiperidinyl-1-carboxylate [CAS No. 989-36-7] (300 g, 1.51 mol) in tetrahydrofuran (1.50 L) and methanol (300 mL) at 25 °C. 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 until the pH reached approximately 6. The mixture was extracted with EtOAc (300 mL × 2) and concentrated under vacuum. The residue was dissolved in MTBE (300 mL) and petroleum ether (300 mL) was added. The mixture was filtered and the precipitate was washed with petroleum ether (100 mL) to give the title compound as a white solid (400 g, 1.14 mol, 76.0% yield).

[0927] LC-MS: (Method 1) R t =0.832min,MS(M-100+1)=250.4.

[0928] Example 2A

[0929] 3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester acetate adduct (racemate)

[0930]

[0931] In H2 (15 Psi), acetic acid (415 g, 6.91 mol, 395 mL) and Pd / C (120 g, 20% purity) were added to a solution of 3-{2-[(benzyloxy)carbonyl]hydrazinoyl}piperidine-1-carboxylic acid tert-butyl ester (prepared similarly to Example 1A, 1.20 kg, 3.43 mol) in ethanol (11.0 L). 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 a solution of the title compound in ethanol (945 g, acetate) as a black liquid. The filtrate was ready for use in the next step without further purification.

[0932] 1H-NMR (400MHz, CDCl3) δ [ppm]: 7.52 (s, 5H), 3.59 (d, J = 6.0Hz, 12H), 3.30-3.24 (m,2H),2.75-2.71(m,2H),1.38-1.34(m,1H),1.20-1.18(m,1H),1.10(s,9H).

[0933] LC-MS: (Method 1) R t =0.263min,MS(M-HOAc-56+1)=160.2

[0934] Example 3A

[0935] 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (racemic mixture)

[0936]

[0937] 3-Hydroxypiperidine-1-carboxylic acid tert-butyl acetic acid (Example 2A, 945 g, 3.43 mol) in ethanol (20 L) was treated with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (907 g, 3.78 mol). The resulting mixture was stirred at 25 °C for 16 h, diluted with a saturated sodium bicarbonate solution (2.0 L), and concentrated to ~5.0 L. The resulting mixture was diluted with water (5.0 L) and extracted with ethyl acetate (5.0 L). The organic phase was washed with a saturated sodium chloride solution (5.0 L) and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate, 10:1) to give 548 g (41% yield) of the title compound.

[0938] 1 H-NMR(400MHz, CDCl3)δ[ppm]:7.90(s,1H),4.33-3.09(m,5H),3.26-3.12(m,1H),2.89-2.61(m ,1H),2.35-2.05(m,2H),1.98-1.78(m,1H),1.71-1.51(m,1H),1.50-1.37(m,9H),1.32(m,3H).

[0939] Example 4A

[0940] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (racemic mixture)

[0941]

[0942] 3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (Example 3A, 548 g, 1.40 mol) was treated with a solution of hydrogen chloride in dioxane (4 M, 2.38 L), stirred at 25 °C for 2 h, and evaporated. The residue was redissolved in 1.0 L of water and extracted with MTBE (500 mL × 1). The aqueous phase was separated and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (1.0 L × 2), and the combined organic layers were washed with saturated sodium chloride solution (1 L), dried over sodium sulfate, and evaporated to give 325 g (80% yield) of the title compound.

[0943] LC-MS: (Method 1) Rt = 0.955 min, MS(M+1) = 292.1

[0944] Two enantiomers were separated by SFC [325g, column: Phenomenex-Cellulose-2 (250mm*50mm, 10μm); eluent: CO2 / (methanol + 0.1% ammonia); 75:25, 4.5min; 1400min] to obtain 103.0g of enantiomer 1 (Example 5A) and 110.1g of enantiomer 2 (Example 6A).

[0945] Example 5A

[0946] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0947]

[0948] For separation conditions, see Example 4A.

[0949] Analytical SFC: R t =1.345min, ee=99% [Column cellulose 2-3:50×4.6mm; Eluent: CO2 / [methanol + 0.5% diethylamine]: 95:5 to 60:40; Flow rate: 3.0ml / min; Temperature: 35℃; UV detection: 220nm, back pressure 100 bar].

[0950] LCMS (Method 2), R t =0.906min, MS(M+1) =292.1.

[0951] 1H-NMR(400MHz, CDCl3)δ[ppm]:7.89(s,1H),4.50-4.47(m,1H),4.31-4.25(m,2H),3.24-3.05(m,4H) ,2.70-2.67(m,1H),2.10-2.02(m,2H),1.92-1.79(m,1H),1.74-1.56(m,1H),1.31(t,J=7.2Hz,3H).

[0952] Example 6A

[0953] 1-(piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[0954]

[0955] For separation conditions, see Example 4A.

[0956] Analytical SFC: R t =1.071 min, ee=99% [Column cellulose 2-3: 50×4.6 mm; Eluent: CO2 / [methanol + 0.5% diethylamine]: 95:5 to 60:40; Flow rate: 3.0 ml / min; Temperature: 35℃; UV detection: 220 nm, back pressure 100 bar].

[0957] LCMS (Method 2), R t =0.906min, MS(M+1) =292.1.

[0958] 1 H-NMR(400MHz, CDCl3)δ[ppm]:7.91(s,1H),4.58-4.41(m,1H),4.35-4.23(m,2H),3.70-3.56(m,1H),3.31-3.12(m,2H) ,3.11-3.02(m,1H),2.75-2.62(m,1H),2.15-2.02(m,2H),1.92-1.79(m,1H),1.74-1.56(m,1H),1.33(t,J=7.2Hz,3H).

[0959] Example 7A

[0960] 2-Bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene

[0961]

[0962] 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.

[0963] LC-MS (Method 4): R t =2.48min; MS(ESIneg):m / z=324[MH] -

[0964] 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).

[0965] Example 8A

[0966] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0967]

[0968] Under argon atmosphere, a solution of ethyl 1-[piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 5A, enantiomer 1, 75.0 g, 257 mmol) and 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared similarly to Example 7A, 84.4 g, 257 mmol) in 1,4-dioxane (1.11) was treated with Pd2dba3 (23.6 g, 25.7 mmol), rac-BINAP (32.1 g, 51.5 mmol), and cesium carbonate (252 g, 772 mmol). The resulting mixture was stirred at 100 °C for 3 days and cooled to room temperature. The reaction mixture was diluted with an aqueous solution of sodium chloride (10%) and ethyl acetate, filtered through diatomaceous earth, and washed with ethyl acetate. The aqueous phase of the filtrate was separated and extracted with ethyl acetate. The combined organic layers were washed with an aqueous sodium chloride solution (10%), dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 119 g (71% yield) of the title compound.

[0969] LC-MS (Method 4): R t =2.81min; MS(ESIpos):m / z=538[M+H] +

[0970] Example 9A

[0971] 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0972]

[0973] A solution of 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 8A, enantiomer 1, 119 g, 221 mmol) in dichloromethane (1.8 L) was treated with trifluoroacetic acid (170 mL, 2.2 mol) and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was carefully quenched with an aqueous solution of sodium bicarbonate (10%) until pH = 8. The phases were separated. The organic layer was evaporated and the residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 85 g (90% purity, 92% yield) of the title compound.

[0974] LC-MS (Method 4): R t =2.47min; MS(ESIpos):m / z=418[M+H] +

[0975] Example 10A

[0976] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[0977]

[0978] Under argon atmosphere, a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 9A, enantiomer 1, 85.0 g, 90% purity, 184 mmol) in dichloromethane (520 ml) was cooled to -50 °C and treated with triethylamine (77 ml, 550 mmol). Trifluoromethanesulfonic anhydride (43 ml, 260 mmol) was added dropwise to the reaction mixture, and the resulting solution was stirred at -50 °C for 1 hour. The reaction mixture was diluted with dichloromethane (520 ml) and ice-cooled water (590 ml). The aqueous layer was extracted with dichloromethane (520 ml). The combined organic layers were washed once with ice-cooled water (590 ml), dried over sodium sulfate, and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / petroleum ether gradient) to give 94 g (93% yield) of the title compound.

[0979] LC-MS (Method 4): R t =2.79min; MS(ESIpos):m / z=550[M+H] +

[0980] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.259(7.63),1.271(16.00),1.282(7.94),1.771(0.45),1.7 79(0.80),1.786(0.61),1.793(0.61),1.800(0.94),1.807(0.61),1.821(0.45),1.932(1.22) ,1.955(0.96),2.099(0.77),2.106(0.73),2.120(1.04),2.126(1.33),2.138(1.91),2.820(0.73),2.825(0.87),2.841(1.56),2.845(1.61),2.861(0.93),2.865(0.82),3.140(1.18),3.1 59(1.09),3.186(1.39),3.204(2.87),3.222(1.78),3.318(1.51),3.324(1.60),3.336(1.08),3.342(1.04),4.247(2.31),4.259(7.26),4.270(7.27),4.282(2.41),4.669(0.70),4.679(0 .84), 4.686(1.34), 4.694(0.96), 4.704(0.72), 4.711(0.42), 7.286(2.29), 7.290(2.44), 7.300(2.89), 7.304(3.11), 7.415(5.01), 7.430(4.13), 7.457(5.11), 7.461(5.05), 8.123(6.61).

[0981] Example 11A

[0982] 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (enantiomer 1)

[0983]

[0984] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 10A, enantiomer 1, 92.1 g, 167 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine-1-carboxylate tert-butyl ester (78.0 g, 201 mmol) in toluene (840 ml) and ethanol (840 ml) was treated with an aqueous sodium carbonate solution (250 ml, 2.0 M, 500 mmol) and Pd(PPh3)4 (9.68 g, 8.37 mmol), and the resulting mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, and evaporated. The residue was purified by rapid chromatography (silica gel, petroleum ether / ethyl acetate gradient) to give 94 g (85% yield) of the title compound.

[0985] LC-MS (Method 4): R t =3.19min; MS(ESIpos):m / z=662[M+H] +

[0986] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.66),0.008(0.84),1.038(0.55),1.088(0.76),1.232(1.60),1.250(3.49),1.268 (1.69),1.419(0.77),1.431(16.00),1.989(0.77),2.957(0.43),3.127(0.91),3.140(1.32),3.152(1.09),3.457(0.99),3.4 70(1.25),3.481(0.88),4.211(0.45),4.228(1.43),4.246(1.38),4.264(0.43),6.985(1.10),7.007(1.20),7.068(0.79),7.073(1.06),7.089(0.49),7.109(0.80),7.114(0.69),7.146(1.34),7.166(0.65),7.433(1.33),7.455(1.19),8.062(1.56).

[0987] Example 12A

[0988] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (enantiomer 1)

[0989]

[0990] A solution of 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Example 11A, enantiomer 1, 93.0 g, 140 mmol) in dichloromethane (290 mL) was treated with a solution of hydrogen chloride in dioxane (350 mL, 4.0 M, 1.4 mol) and stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was co-evaporated with MTBE to give 95 g (quantitative) of the title compound, which was used in the next step without further purification.

[0991] LC-MS (Method 4): R t =1.97min; MS(ESIpos):m / z=562[M+H] +

[0992] Example 13A

[0993] [4-[4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl]phenyl]boronic acid

[0994]

[0995] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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, and then the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was washed with water, dried, concentrated, and passed through a preparative HPLC (RP18 column, eluent:

[0996] Purification was performed using acetonitrile / water + 0.1% formic acid gradient to give 384 mg (88% purity, 45% yield) of the title compound.

[0997] LC-MS (Method 3): R t =0.60min; MS(ESIpos):m / z=311[M+H] +

[0998] Example 14A

[0999] 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1000]

[1001] Under argon atmosphere, a solution of 2-bromo-4-chloro-1-[(4-methoxyphenyl)methoxy]benzene (prepared similarly to Example 7A, 5.00 g, 15.3 mmol) and ethyl 1-[piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 6A, enantiomer 2, 4.45 g, 15.3 mmol) in 1,4-dioxane (50 ml) was treated with Pd2dba3 (1.40 g, 1.53 mmol), rac-BINAP (1.90 g, 3.05 mmol), and (14.9 g, 45.8 mmol). The resulting mixture was stirred overnight at 100 °C and cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 3.38 g (86% purity, 35% yield) of the title compound.

[1002] LC-MS (Method 4): R t =2.82min; MS(ESIpos):m / z=538[M+H] +

[1003] Example 15A

[1004] 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1005]

[1006] A solution of 1-[1-{5-chloro-2-[(4-methoxyphenyl)methoxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 14A, enantiomer 2, 3.38 g, 86% purity, 5.40 mmol) in dichloromethane (40 mL) was treated with trifluoroacetic acid (4.8 mL, 63.0 mmol), and the resulting mixture was stirred overnight at room temperature and evaporated. The residue was dissolved in ethyl acetate, diluted, and carefully quenched with an aqueous solution of sodium bicarbonate (10%) until pH = 8. The phases were separated. The organic layer was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate) to give 2.6 g (quantitative) of the title compound.

[1007] LC-MS (Method 4): R t =2.46min; MS(ESIpos):m / z=418[M+H] +

[1008] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.176(0.44),1.261(6.08),1.272(12.40),1.284(6.07 ),1.398(16.00),1.805(0.57),1.818(0.52),1.826(0.78),1.833(0.49),1.846(0.42),1 .875(1.16),1.897(0.62),1.986(0.77),2.062(0.67),2.070(0.60),2.083(0.90),2.089(1.21),2.101(1.54),2.628(0.69),2.643(1.23),2.647(1.25),2.662(0.64),2.947(1.1 1), 2.965(2.10), 2.982(1.17), 3.312(1.00), 3.331(0.94), 3.594(1.12), 3.613(1.04), 4.247(1.87), 4.258(5.78), 4.270(5.74), 4.282(1.87), 4.698(0.76), 4.707(0.92), 4.71 5(1.28),4.722(1.00),4.732(0.78),4.936(0.43),6.770(3.45),6.784(4.67),6.855(2.01),6.859(2.61),6.869(1.22),6.873(2.28),6.882(4.25),6.887(2.97),8.109(5.86).

[1009] Example 16A

[1010] 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1011]

[1012] Triethylamine (7.0 ml, 50 mmol) was added to a solution of ethyl 1-[1-(5-chloro-2-hydroxyphenyl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 15A, enantiomer 2, 7.00 g, 16.8 mmol) in dichloromethane (140 ml) under argon atmosphere. The mixture was cooled to -20 °C and trifluoromethanesulfonic anhydride (4.0 ml, 23 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reactants were diluted with ethyl acetate, and the organic phase was washed with an aqueous solution of sodium bicarbonate (10%) and water. The phases were separated. The organic layer was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate) to give 9.4 g (97% yield) of the title compound.

[1013] LC-MS (Method 3): R t =1.44min; MS(ESIpos):m / z=550[M+H] +

[1014] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.258(7.75),1.270(16.00),1.282(7.76),1.777(0.68),1.784(0.50),1.791(0.49),1.7 99(0.78),1.806(0.47),1.932(1.05),1.954(0.78),2.098(0.68),2.105(0.62),2.119(0.86),2.125(1.06),2.137(1.55) ,2.820(0.65),2.824(0.76),2.840(1.36),2.844(1.37),2.860(0.78),2.864(0.68),3.139(1.01),3.158(0.88),3.185(1.21),3.203(2.56),3.221(1.56),3.317(1.14),3.324(1.26),3.335(0.91),3.342(0.87),3.666(0.43),3.670(0.45),3.6 76(0.61),3.688(0.47),3.692(0.56),3.695(1.11),3.701(0.61),3.721(0.62),3.726(0.68),3.747(0.83),4.246(2.25),4.258(7.12),4.270(7.16),4.281(2.27),4.668(0.60),4.678(0.69),4.686(1.14),4.693(0.78),4.703(0.58),7.285(2 .31),7.289(2.40),7.299(2.89),7.304(3.08),7.341(1.25),7.368(1.36),7.415(4.98),7.430(3.96),7.456(5.11),7.460(5.57),7.474(1.14),7.782(1.03),7.789(0.90),7.792(1.01),7.802(0.84),7.805(0.97),7.808(1.03),8.123(6.32).

[1015] Example 17A

[1016] 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (enantiomer 2)

[1017]

[1018] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 16A, prepared enantiomer 2, 118 mg, 215 μmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine-carboxylic acid tert-butyl ester (100 mg, 258 μmol) in toluene / ethanol (1:1) (3.0 mL) was treated with an aqueous sodium carbonate solution (320 μl, 2N, 640 μmol) and Pd(PPh3)4 (12.4 mg, 10.7 μmol), and the resulting mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, acidified with formic acid, filtered through an EXtrelut NT 3 column, and washed with ethyl acetate. The filtrate was concentrated to obtain 260 mg (75% purity, quantitative) of the title compound, which can be used without further purification.

[1019] LC-MS (Method 4): R t =3.19min; MS(ESIpos):m / z=662[M+H] +

[1020] Example 18A

[1021] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 2)

[1022]

[1023] Trifluoroacetic acid (460 μl, 5.9 mmol) was added to a solution of 4-(4'-chloro-2'-{3-[4-(ethoxycarbonyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]piperidin-1-yl}[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Example 17A, enantiomer 2, 260 mg, 75% purity, 296 μmol) in dichloromethane (4.4 mL). The reaction mixture was stirred overnight at room temperature, then the reaction mixture was evaporated, and the residue was co-evaporated three times with acetonitrile to give 400 mg (75% purity, quantitative) of the title compound, which was used in the next step without further purification.

[1024] LC-MS (Method 4): R t=1.93min; MS(ESIpos):m / z=562[M+H] +

[1025] Example 19A

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

[1027]

[1028] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, enantiomer 1, 500 mg, 909 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (314 mg, 1.09 mmol) in toluene / ethanol (1:1) (10 mL) was treated with an aqueous solution of sodium carbonate (910 μl, 2N, 1.8 mmol) and Pd(PPh3)4 (52.5 mg, 45.5 μmol), and the resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) and then further purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 552 mg (53% yield) of the title compound.

[1029] LC-MS (Method 4): R t =1.88min; MS(ESIpos):m / z=562[M+H] +

[1030] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.236(7.50),1.254(16.00),1.272(7.71),1.539(0.72),1.570( 0.84),1.744(1.16),1.776(0.88),1.887(0.81),1.896(0.76),1.917(0.88),1.948(0.44),2.000 (1.17), 2.023(0.69), 2.366(0.41), 2.580(0.97), 2.609(1.51), 2.634(0.86), 2.670(0.45), 2.710(0.46), 2.888(4.60), 2.900(6.62), 2.912(5.88), 2.932(1.61), 2.959(2.55), 2.985(1.65), 3.0 64(1.64),3.094(1.74),3.112(6.24),3.126(7.13),3.137(5.32),3.220(2.74),3.248(2.88),4.215(2.35),4.232(7.15),4.250(6.97),4.268(2.22),4.358(0.74),4.385(1.25),4.412(0.69),6 .954(5.56),6.976(6.02),7.064(4.03),7.068(5.30),7.086(2.20),7.091(1.36),7.106(3.85),7.111(3.33),7.142(6.63),7.163(3.21),7.422(6.64),7.444(6.11),8.066(5.87),8.238(3.91).

[1031] Example 20A

[1032] 1-{1-[4-chloro-4'-(4-methylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1033]

[1034] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared as enantiomer 1, 500 mg, 909 μmol) and [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (400 mg, 1.82 mmol) in a toluene / ethanol mixture (1:1) (10 mL) was treated with an aqueous solution of sodium carbonate (1.4 mL, 2.0 M, 2.7 mmol) and Pd(PPh3)4 (52.5 mg, 45.5 μmol) and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times 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 470 mg (89% yield) of the title compound.

[1035] LC-MS (Method 4): R t =1.97min; MS(ESIpos):m / z=576[M+H] +

[1036] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.239(5.58),1.251(11.50),1.263(5.65),1.394(2.94),1.550(0 .62),1.571(0.68),1.751(0.85),1.773(0.69),1.885(0.68),1.892(0.63),1.906(0.69),1.912(0. 64), 1.987(0.86), 1.998(0.82), 2.014(0.58), 2.211(1.04), 2.226(16.00), 2.444(4.17), 2.452(5.61), 2.460(4.19), 2.593(0.63), 2.609(1.21), 2.612(1.24), 2.629(0.62), 2.929(0.99), 2.947(1.8 9), 2.965(1.09), 3.071(0.90), 3.091(0.84), 3.155(3.93), 3.164(5.08), 3.172(3.81), 3.208(0.97), 3.221(0.82), 4.220(1.62), 4.232(4.88), 4.244(4.75), 4.255(1.49), 4.355(0.54), 4.373(0.92) ),4.391(0.51),6.958(4.43),6.973(4.61),7.061(3.22),7.064(3.84),7.086(1.71),7.089(1.27),7.099(2.56),7.103(2.26),7.140(4.53),7.153(2.69),7.416(5.07),7.430(4.59),8.058(5.44).

[1037] Example 21A

[1038] 1-{1-[4-chloro-4'-(4-ethylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1039]

[1040] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 80.0 mg, 145 μmol) and 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (50.6 mg, 160 μmol) in toluene (710 μl) and ethanol (710 μl) was treated with aqueous sodium carbonate solution (220 μl, 2.0 M, 440 μmol) and Pd(PPh3)4 (8.41 mg, 7.27 μmol) and stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, acidified with formic acid, and filtered through an EXtrelut NT 3 column. The column was washed with ethyl acetate and the filtrate was evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 31.0 mg (36% yield) of the title compound.

[1041] LC-MS (Method 4): R t =2.12min; MS(ESIpos):m / z=590[M+H] +

[1042] Example 22A

[1043] 1-Propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine

[1044]

[1045] 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 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, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. The mixture was purified by silica gel chromatography (dichloromethane / methanol 100 / 1, then isocratic dichloromethane / methanol 50 / 1). 186 mg of the target compound was obtained (53% of the theoretical value).

[1046] LC-MS (Method 6): Rt =0.97min; MS(ESIpos):m / z=331[M+H] +

[1047] 1 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).

[1048] Example 23A

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

[1050]

[1051] Under argon atmosphere, ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 10A, enantiomer 1, 100 mg, 182 μmol) and 1-propyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (prepared similarly to Example 22A, 72.1 mg, 218 μmol) were dissolved in toluene / ethanol (1.0 / 1.0 mL). Tetra(triphenylphosphine)palladium(0) (10.5 mg, 9.09 μmol) and 2M sodium carbonate solution (273 μl, 546 μmol) were added and stirred at 100 °C for 2 hours. The reaction mixture was filtered through diatomaceous earth. The filtrate was acidified with 1M hydrochloric acid. The aqueous reaction solution was extracted with ethyl acetate. The phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phase was then dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in acetonitrile and a few drops of water and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with 0.1% TFA added). 92 mg of the target compound was obtained (83% of the theoretical value).

[1052] LC-MS (Method 4): R t =2.13min; MS(ESIpos):m / z=604[M+H] +

[1053] Example 24A

[1054] 3-[4-(4-bromophenyl)piperazin-1-yl]propionitrile

[1055]

[1056] 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 87 mg (16% yield) of the title compound.

[1057] LC-MS (Method 4): R t =1.10min; MS(ESIpos):m / z=294[M+H] +

[1058] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:2.516(0.46),2.564(14.44),2.601(5.52),2.612(14.75),2.623(9.73),2.691(9.92),2.702(15. 57),2.714(5.72),3.118(14.05),3.126(16.00),3.135(13.12),3.167(0.44),3.175(0.43),6.879(1.53),6.884(14.43),6.888(4. 58), 6.896(5.16), 6.899(14.98), 6.905(1.43), 7.032(0.43), 7.044(0.44), 7.318(1.69), 7.324(15.75), 7.327(4.66), 7.335(4.90), 7.339(14.32), 7.344(1.24), 7.352(0.45), 7.366(0.47), 7.521(0.73), 7.532(0.56), 7.574(0.96), 7.591(0.92), 7.605(0.60).

[1059] Example 25A

[1060] 3-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl}

[1061] Propylon

[1062]

[1063] Under argon atmosphere, a solution of 3-[4-(4-bromophenyl)piperazin-1-yl]propionitrile (prepared similarly to Example 24A, 579 mg, 1.97 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-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), Xphos (56.3 mg, 118 μmol), and potassium acetate (579 mg, 5.90 mmol). The reaction mixture 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), followed by preparative HPLC (RP18 column, eluent: acetonitrile / water, gradient) to give 321 mg (48% yield) of the title compound.

[1064] LC-MS (Method 4): R t =1.37min; MS(ESIpos):m / z=342[M+H] +

[1065] 1 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).

[1066] Example 26A

[1067] 1-[1-{4-chloro-4'-[4-(2-cyanoethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1068]

[1069] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared as enantiomer 1, 90.0 mg, 164 μmol) and 3-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl}propionitrile (Example 25A, 67.0 mg, 196 μmol) in toluene / ethanol (1:1, 2.4 ml) was treated with Pd(PPh3)4 (9.46 mg, 8.18 μmol) and sodium carbonate solution (250 μl, 2N, 490 μmol). The reactants were stirred at 100 °C for 3 hours, then concentrated, and the residue was dissolved in dichloromethane and purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 62.0 mg (62% yield) of the title compound.

[1070] LC-MS (Method 4): R t =2.51min; MS(ESIpos):m / z=615[M+H] +

[1071] Example 27A

[1072] 1-[1-{4-chloro-4'-[4-(propyl-2-yl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester formic acid adduct (enantiomer 1)

[1073]

[1074] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 10A, enantiomer 1, 100 mg, 97% purity, 176 μmol) and 1-(propyl-2-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (69.7 mg, 211 μmol) were dissolved in toluene / ethanol (0.98 / 0.98 mL) under argon atmosphere. Tetra(triphenylphosphine)palladium(0) (10.2 mg, 8.79 μmol) and 2M sodium carbonate solution (264 μl, 528 μmol) were added and stirred at 100 °C for 2 hours. The reaction mixture was filtered through a microporous filter, washed with ethanol, and the filtrate was evaporated. The residue was dissolved in acetonitrile / formic acid / water and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with addition of 0.1% formic acid). 113 mg of the target compound was obtained (quantitative).

[1075] LC-MS (Method 3): R t =1.05min; MS(ESIpos):m / z=604[M-HCOOH+H] +

[1076] Example 28A

[1077] 1-(cyclopropylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1078]

[1079] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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. Cyclopropylformaldehyde (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, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. 519 mg of the target compound was given (98% of theoretical value, 85% purity).

[1080] LC-MS (Method 4): R t =1.18min; MS(ESIpos):m / z=343[M+H] +

[1081] 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).

[1082] Example 29A

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

[1084]

[1085] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared enantiomer 1, 150 mg, 273 μmol) and 1-(cyclopropylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 28A, 112 mg, 85% purity, 278 μmol) were dissolved in toluene / ethanol (1.5 / 1.5 mL) under argon atmosphere. Tetra(triphenylphosphine)palladium(0) (15.8 mg, 13.6 μmol) and 2M sodium carbonate solution (410 μl, 820 μmol) were added and stirred at 100 °C for 2 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic phase was then dried over sodium sulfate, filtered, and evaporated. The residue was dissolved in acetonitrile and a few drops of water and purified by preparative HPLC (RP18 column, acetonitrile / water gradient with addition of 0.1% TFA). 191 mg of the target compound was obtained as a TFA adduct (81% of the theoretical value).

[1086] LC-MS (Method 4): R t =2.09min; MS(ESIpos):m / z=616[M+H] +

[1087] Example 30A

[1088] [(1S,2S)-2-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl}methyl ketone

[1089]

[1090] 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, extracted with ethyl acetate, and 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.

[1091] LC-MS (Method 4): R t =1.92min; MS(ESIpos):m / z=375[M+H] +

[1092] 1 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).

[1093] Example 31A

[1094] 1-{[(1S,2S)-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1095]

[1096] 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 30A, 759 mg, 2.03 mmol) in THF (18 mL) was treated dropwise with a solution of the BH3·THF complex (41 mL, 1 M, 41 mmol), and the resulting mixture was stirred at room temperature for 30 min. The reaction was carefully quenched with methanol and concentrated. The residue was dissolved in ethyl acetate and purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 250 mg (31% yield) of the title compound.

[1097] LC-MS (Method 4): R t =1.23min; MS(ESIpos):m / z=361[M+H] +

[1098] 1H-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).

[1099] Example 32A

[1100] 1-{1-[4-chloro-4'-(4-{[(1S,2S)-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1101]

[1102] Under argon atmosphere, solutions of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (Example 16A, enantiomer 2, 178 mg, 324 μmol) and 1-{[(1S,2S)-2-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 31A, 140 mg, 389 μmol) in toluene / ethanol (1:1, 4.7 ml) were treated with Pd(PPh3)4 (18.7 mg, 16.2 μmol) and sodium carbonate solution (490 μl, 2N, 970 μmol). The reactants were stirred at 100 °C for 3 hours, then diluted with water, extracted three times with dichloromethane, and concentrated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 76.0 mg (36% yield) of the title compound.

[1103] LC-MS (Method 4): R t =1.96min; MS(ESIpos):m / z=634[M+H] +

[1104] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.543(0.63),0.551(1.26),0.567(0.72),0.582(0.68),0.590(1.25),0.601(0.74),0.811(0.58),0.822(1.11),0.831(1.14),0.839(1.72),0.848(1.24),0.858(1.22),0.868(0.64),1.024(1.14),1.037(1.25),1.241(7.88),1.253(16.00),1.265(7.89),1.557(1.07),1.578(1.20),1.757(1.52),1.778(1.24),1.880(0.46),1.893(1.19),1.914(1.22),1.935(0.56),2.004(1.48),2.021(1.08),2.383(1.91),2.396(1.68),2.404(1.92),2.417(1.87),2.568(1.96),2.576(3.03),2.585(3.37),2.594(2.70),2.620(3.52),2.630(3.77),2.638(5.68),2.649(3.63),2.660(2.17),2.670(1.60),2.938(1.59),2.955(3.09),2.973(1.78),3.077(1.68),3.097(1.57),3.192(7.69),3.215(2.74),3.234(2.08),3.568(0.66),4.222(2.41),4.234(7.15),4.246(6.98),4.257(2.24),4.364(0.93),4.382(1.63),4.400(0.87),4.730(0.75),4.735(1.33),4.740(1.31),4.846(1.37),4.850(1.28),4.855(0.77),5.747(1.15),6.968(6.64),6.982(6.88),7.066(5.75),7.088(2.53),7.101(3.77),7.144(6.17),7.158(3.82),7.420(7.44),7.435(6.81),8.056(8.13),8.140(0.89).

[1105] Example 33A

[1106] (1-Fluorocyclopropyl){4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl} methyl ketone

[1107]

[1108] A solution of 1-fluorocyclopropane-1-carboxylic acid (99.3 mg, 954 μmol) in DMF (4.2 mL) was treated with HATU (330 mg, 867 μmol), N,N-diisopropylethylamine (300 μl, 1.7 mmol), and finally 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (250 mg, 867 μmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 279 mg (82% yield) of the title compound.

[1109] LC-MS (Method 4): R t =2.17min; MS(ESIpos):m / z=375[M+H] +

[1110] Example 34A

[1111] 1-[(1-fluorocyclopropyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1112]

[1113] Under argon atmosphere, a solution of (1-fluorocyclopropyl){4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (Example 33A, 279 mg, 745 μmol) in THF (1.5 mL) was treated dropwise with a solution of the BH3·THF complex (7.5 mL, 1.0 M, 7.5 mmol), and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 146 mg (88% purity, 48% yield) of the title compound.

[1114] LC-MS (Method 4): R t =1.28min; MS(ESIpos):m / z=361[M+H] +

[1115] Example 35A

[1116] 1-[1-(4-chloro-4'-{4-[(1-fluorocyclopropyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1117]

[1118] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared as enantiomer 1, 100 mg, 182 μmol) and 1-[(1-fluorocyclopropyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 34A, 89.0 mg, 88% purity, 218 μmol) in toluene (1.0 ml) and ethanol (1.0 ml) was treated with an aqueous sodium carbonate solution (270 μl, 2.0 M, 550 μmol) and Pd(PPh3)4 (10.5 mg, 9.09 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 (amino-phase silica gel, cyclohexane / ethyl acetate gradient) to give 109 mg (89% purity, 84% yield) of the title compound.

[1119] LC-MS (Method 4): R t =2.12min; MS(ESIpos):m / z=634[M+H] +

[1120] Example 36A

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

[1122]

[1123] 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. Then 2-methylpropionaldehyde (440 μl, 4.9 mmol) was added and the mixture was stirred for 10 min. Sodium triacetoxyborohydride (772 mg, 3.64 mmol) was then added and the mixture was stirred at 55 °C for 4 h. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. 342 mg of the target compound was given (79% of theoretical value, 97% purity).

[1124] LC-MS (Method 4): R t =1.23min; MS(ESIpos):m / z=345[M+H] +

[1125] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:0.058(0.55),0.927(4.09),0.938(4.13),1.316(16.00),2.121(0.98),2.133(0.89),2.492(0.99),2.5 08(0.99),2.559(2.25),2.599(2.62),3.241(1.07),3.249(1.38),3 .257(0.98),6.935(1.05),6.949(1.07),7.552(1.15),7.566(1.07).

[1126] Example 37A

[1127] 1-[4-(4-bromophenyl)piperazin-1-yl]-2-fluoro-2-methylprop-1-one

[1128]

[1129] A solution of 2-fluoro-2-methylpropionic acid (121 mg, 1.14 mmol) in DMF (5.0 mL) was treated with HATU (394 mg, 1.04 mmol), N,N-diisopropylethylamine (360 μl, 2.1 mmol), and finally l-(4-bromophenyl)piperazine (250 mg, 1.04 mmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 331 mg (96% yield) of the title compound.

[1130] LC-MS (Method 4): R t =2.05min; MS(ESIpos):m / z=329[M+H] +

[1131] Example 38A

[1132] 1-(4-bromophenyl)-4-(2-fluoro-2-methylpropyl)piperazine

[1133]

[1134] Under argon atmosphere, a solution of 1-[4-(4-bromophenyl)piperazin-1-yl]-2-fluoro-2-methylprop-1-one (Example 37A, 331 mg, 1.01 mmol) in THF (2.0 mL) was treated dropwise with a solution of the BH3·THF complex (10 mL, 1.0 M, 10 mmol), and the resulting mixture was stirred overnight at room temperature. Another BH3·THF complex (3 mL, 1.0 M, 3 mmol) was added, and the resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was carefully quenched with methanol and evaporated. The residue was redissolved in ethyl acetate, and the solid was filtered off. The filtrate was evaporated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 374 mg (65% purity, 77% yield) of the title compound.

[1135] LC-MS (Method 4): R t =1.25min; MS(ESIpos):m / z=315[M+H] +

[1136] Example 39A

[1137] 1-(2-fluoro-2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1138]

[1139] Under argon atmosphere, a solution of 1-(4-bromophenyl)-4-(2-fluoro-2-methylpropyl)piperazine (Example 38A, 260 mg, 65% purity, 536 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxacyclopentaborane (204 mg, 804 μmol), Pd(dppf)Cl2 (21.9 mg, 26.8 μmol), and potassium acetate (158 mg, 1.61 mmol) in cyclopentylmethyl ether (1.7 mL) was stirred overnight at 110 °C. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 149 mg (89% purity, 68% yield) of the title compound.

[1140] LC-MS (Method 4): R t =1.49min; MS(ESIpos):m / z=363[M+H] +

[1141] Example 40A

[1142] 1-[1-{4-chloro-4'-[4-(2-fluoro-2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1143]

[1144] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared as enantiomer 1, 83.9 mg, 153 μmol) and 1-(2-fluoro-2-methylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 39A, 74.5 mg, 89% purity, 183 μmol) in a toluene / ethanol mixture (1:1) (1.9 ml) was treated with an aqueous sodium carbonate solution (230 μl, 2.0 M, 460 μmol) and Pd(PPh3)4 (8.81 mg, 7.63 μmol) and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and filtered through an EXtrelut NT 3 column. The column was washed with ethyl acetate and the filtrate was evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 37.0 mg (85% purity, 32% yield) of the title compound.

[1145] LC-MS (Method 4): R t =2.68min; MS(ESIpos):m / z=636[M+H] +

[1146] Example 41A

[1147] 2,2-Difluoro-1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]piperazin-1-yl}prop-1-one

[1148]

[1149] 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) and stirred for 10 min at room temperature. Then, 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (350 mg, 1.21 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed three times with water. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 287 mg (62% yield) of the title compound.

[1150] LC-MS (Method 4): R t =2.25min; MS(ESIpos):m / z=381[M+H] +

[1151] 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).

[1152] Example 42A

[1153] 1-(2,2-Difluoropropyl)-4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1154]

[1155] Under argon atmosphere, a solution of 2,2-difluoro-1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazin-1-yl}prop-1-one (Example 41A, 286 mg, 752 μmol) in THF (1.4 mL) was treated dropwise with a solution of the BH3·THF complex (7.5 mL, 1 M, 7.5 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, a second portion of the BH3·THF complex (7.5 mL, 1 M, 7.5 mmol) was added, and the reaction mixture was stirred for another 1 hour. The reaction was carefully quenched with methanol and concentrated. The residue was dissolved in ethyl acetate and purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 212 mg (77% yield) of the title compound.

[1156] LC-MS (Method 4): R t =2.19min; MS(ESIpos):m / z=367[M+H] +

[1157] 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).

[1158] Example 43A

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

[1160]

[1161] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 87.6 mg, 159 μmol) and 1-(2,2-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 42A, 70.0 mg, 191 μmol) in toluene / ethanol (1:1, x ml) was treated with Pd(PPh3)4 and an aqueous solution of sodium carbonate (240 μl, 2.0 M, 480 μmol), and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate, gradient) to give 98.7 mg (97% yield) of the title compound.

[1162] LC-MS (Method 4): R t =3.05min; MS(ESIpos):m / z=640[M+H] +

[1163] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:1.235(1.90),1.253(3.74),1.270(1.80),1.398(16.00),1.612(1.14),1.660(2.20),1.707 (0.98),2.675(1.16),2.687(1.46),2.699(1.21),2.748(0.58),2.783(1.13),2.818(0.53),2.954(0.49),3.162(1.17),3.1 75(1.44),3.187(1.11),4.213(0.50),4.231(1.58),4.249(1.54),4.266(0.47),6.959(1.24),6.981(1.32),7.062(0.89),7.067(1.16),7.085(0.50),7.105(0.83),7.110(0.70),7.144(1.45),7.164(0.72),7.417(1.47),7.439(1.31),8.063(1.29).

[1164] Example 44A

[1165] 4-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[1166]

[1167] Under argon atmosphere, a solution of 2-bromo-4-chloro-1-iodobenzene (1.22 g, 3.84 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine-1-carboxylic acid tert-butyl ester (1.49 g, 3.84 mmol) in toluene / ethanol (1:1, 30 mL) was treated with Pd(PPh3)4 (444 mg, 384 μmol) and an aqueous sodium carbonate solution (5.8 mL, 2.0 M, 12 mmol). The reaction mixture was stirred at 110 °C for 3 h, followed by stirring at 90 °C overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.66 g (55% purity, 85% yield) of the title compound, which was ready for use without further purification.

[1168] LC-MS (Method 4): R t =2.82min; MS(ESIpos):m / z=451[M+H] +

[1169] Example 45A

[1170] 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine hydrochloride

[1171]

[1172] A solution of 4-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine-1-carboxylic acid tert-butyl ester (prepared similarly to Example 44A, 2.89 g, 65% purity, 4.15 mmol) in dichloromethane (23 mL) was treated with a solution of hydrogen chloride in dioxane (10 mL, 4 M, 42 mmol) and stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was stirred in diethyl ether. The solid was collected by filtration to give 1.74 g (89% purity, 96% yield) of the title compound, which was used in the next step without further purification.

[1173] LC-MS (Method 4): R t =1.48min; MS(ESIpos):m / z=351[M+H] +

[1174] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.069(2.10),1.266(16.00),3.361(0.41),3.439(6.29),3.452 (8.01),3.568(1.82),4.326(2.46),5.756(0.56),6.954(1.23),6.975(1.29),7.055(3.93),7.0 76(4.53),7.294(4.70),7.315(3.95),7.362(2.61),7.382(3.36),7.502(2.01),7.507(2.02),7.522(1.60),7.527(1.62),7.543(1.37),7.564(1.21),7.835(2.69),7.839(2.58),9.225(1.46).

[1175] Example 46A

[1176] 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)-4-(2,2-difluoroethyl)piperazine

[1177]

[1178] Under argon atmosphere, a solution of 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)piperazine hydrochloride (Example 45A, 1.68 g, 89% purity, 3.85 mmol) in N,N-dimethylformamide (19 mL) was treated with N,N-diisopropylethylamine (4.0 mL, 23 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (2.47 g, 11.5 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, concentrated, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 700 mg (44% yield) of the title compound.

[1179] LC-MS (Method 4): R t =2.49min; MS(ESIpos):m / z=415[M+H] +

[1180] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.230(0.75),2.072(1.48),2.637(0.43),2.673(11.78),2.681(16.00),2.689(11.82),2.768(3.11),2. 775(3.17),2.794(6.21),2.801(6.05),2.820(3.05),2.827(2.79),3 .198(12.36),3.206(15.47),3.214(10.99),6.093(0.84),6.100(1.5 9), 6.107(0.81), 6.185(1.70), 6.193(3.26), 6.200(1.61), 6.278(0.82), 6.286(1.55), 6.292(0.76), 6.992(10.27), 7.006(11.00), 7.245(11.91), 7.259(10.16), 7.354(6.80), 7.367(8.11), 7.486(5.14), 7.489(4.50), 7.500(4.18), 7.503(3.69), 7.816(8.73), 7.819(7.50).

[1181] Example 47A

[1182] 1-[1-{4-chloro-4'-[4-(2,2-difluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1183]

[1184] Under argon atmosphere, a solution of 1-(2'-bromo-4'-chloro[1,1'-biphenyl]-4-yl)-4-(2,2-difluoroethyl)piperazine (Example 46A, 100 mg, 241 μmol) and ethyl 1-(3-piperidinyl)-5-(trifluoromethyl)pyrazole-4-carboxylate (similar to Example 5A, prepared enantiomer 1, 70.7 mg, 241 μmol) in toluene (2.0 mL) was treated with RuPhos Pd G3 (40.2 mg, 48.0 μmol) and cesium carbonate (196 mg, 601 μmol). The reaction mixture was stirred at 100 °C for 40 hours, then cooled, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated and purified by preparative HPLC (Method 12) to give 35.0 mg (60% purity, 14% yield) of the title compound, which was ready for use without further purification.

[1185] LC-MS (Method 4): R t =2.95min; MS(ESIpos):m / z=626[M+H] +

[1186] Example 48A

[1187] 1-[1-{4-chloro-4'-[4-(2,2-difluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1188]

[1189] Under argon atmosphere, a solution of 1-[1-[5-chloro-2-(4-piperazin-1-ylphenyl)phenyl]-3-piperidinyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid (Example 18A, enantiomer 2,400 mg, 75% purity, 445 μmol) in N,N-dimethylformamide (2.2 mL) was treated with N,N-diisopropylethylamine (460 μl, 2.7 mmol) and 2,2-difluoroethyl trifluoromethanesulfonic acid (286 mg, 1.33 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 82.5 mg (30% yield) of the title compound.

[1190] LC-MS (Method 4): R t =2.93min; MS(ESIpos):m / z=626[M+H] +

[1191] Example 49A

[1192] 3,3-Difluoropropyl 4-methylbenzene-1-sulfonic acid

[1193]

[1194] 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 added, and the reaction 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, dried over sodium sulfate, and evaporated to give 202 mg (quantitative) of the title compound, which was used in the next step without further purification.

[1195] 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).

[1196] Example 50A

[1197] 1-(3,3-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1198]

[1199] 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, 66 mmol) was treated with 3,3-difluoropropyl 4-methylbenzene-1-sulfonic acid (Example 49A, 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 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.

[1200] LC-MS (Method 4): R t =1.20min; MS(ESIpos):m / z=367[M+H] +

[1201] Example 51A

[1202] 1-[1-{4-chloro-4'-[4-(3,3-difluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1203]

[1204] Under argon atmosphere, solutions of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared as enantiomer 1, 94.5 mg, 172 μmol) and 1-(3,3-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 50A; 75.5 mg, 206 μmol) in toluene (960 μl) and ethanol (960 μl) were treated with aqueous sodium carbonate 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. Add 1-(3,3-difluoropropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 51A; 75.5 mg, 206 μmol), an aqueous sodium carbonate solution (260 μl, 2.0 M, 520 μmol), and Pd(PPh3)4 (9.93 mg, 8.59 μmol), and stir the resulting mixture at 100 °C for 2 hours. Cool the reaction mixture to room temperature, filter through diatomaceous earth and wash with ethyl acetate. Evaporate the filtrate and purify the residue by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 50.9 mg (46% yield) of the title compound.

[1205] LC-MS (Method 4): R t =2.16min; MS(ESIpos):m / z=640[M+H] +

[1206] Example 52A

[1207] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (enantiomer 1)

[1208]

[1209] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared as enantiomer 1, 290 mg, 516 μmol) in a THF / methanol mixture (10:1) (11 mL) was treated with an aqueous lithium hydroxide solution (5.2 mL, 1.0 M, 5.2 mmol) and stirred at room temperature for 2.5 h. The reaction mixture was acidified with an aqueous hydrogen chloride solution (2N) and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 316 mg (73% yield) of the title compound.

[1210] LC-MS (Method 4): R t =1.62min; MS(ESIpos):m / z=534[M+H] +

[1211] Example 53A

[1212] 1-(1-{4-chloro-4'-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][biphenyl]-2-yl}piperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid 2,2,2-trifluoroethyl ester (enantiomer 1)

[1213]

[1214] Under argon atmosphere, a solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 52A, enantiomer 1, 100 mg, 187 μmol) in DMF (1.7 mL) was treated with N,N-diisopropylethylamine (100 μl, 580 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (81 μl, 560 μmol). The resulting mixture was stirred at room temperature for 2 hours, acidified with formic acid, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 88 mg (67% yield) of the title compound.

[1215] LC-MS (Method 4): R t =3.01min; MS(ESIpos):m / z=698[M+H] +

[1216] Example 54A

[1217] 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1218]

[1219] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (prepared similarly to Example 16A, 150 mg, 273 μmol) in a toluene / ethanol mixture (1:1) (4 ml) was treated with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (94.3 mg, 327 μmol), an aqueous solution of sodium bicarbonate (270 μl, 2.0 M, 550 μmol), and Pd(PPh3)4 (15.8 mg, 13.6 μmol). The resulting suspension was stirred at 95 °C for 2 hours and then evaporated. The residue was purified by rapid chromatography (amino-phase silica gel, cyclohexane / ethyl acetate gradient) to give 140 mg (77% purity, 70% yield) of the title compound.

[1220] LC-MS (Method 4): R t =1.83min; MS(ESIpos):m / z=562[M+H] +

[1221] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.072(16.00),1.243(0.85),1.255(1.77),1.267(0.86),1. 990(0.47),2.828(0.59),2.836(0.73),2.845(0.64),3.066(0.69),3.075(0.78),3.083(0.6 0), 3.323(0.68), 3.926(0.89), 4.236(0.72), 4.248(0.69), 6.942(0.61), 6.957(0.63), 7.060(0.46), 7.063(0.55), 7.142(0.66), 7.156(0.41), 7.416(0.71), 7.430(0.65), 8.063(0.79).

[1222] Example 55A

[1223] 1-[1-{4-chloro-4'-[4-(2,2,2-trifluoroethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1224]

[1225] Under argon atmosphere, a solution of ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 54A, enantiomer 2, 140 mg, 77% purity, 249 μmol) in DMF was treated with N,N-diisopropylethylamine (130 μl, 750 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (110 μl, 750 μmol). The resulting mixture was stirred at room temperature for 3 hours. 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 70.0 mg (44% yield) of the title compound.

[1226] LC-MS (Method 4): R t =3.09min; MS(ESIpos):m / z=644[M+H] +

[1227] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(1.97),0.008(2.11),1.234(2.43),1.252(4.96),1.270(2.41),1.398(16.00),1.988(0.44),2.366(0 .44),2.608(0.51),2.710(0.46),2.757(1.56),2.769(2.16),2.780(1. 74),2.957(0.71),2.983(0.41),3.169(1.72),3.181(2.13),3.193(1.7 0), 3.211(0.99), 3.236(1.77), 3.262(1.40), 3.288(0.80), 4.214(0.69), 4.231(2.18), 4.249(2.11), 4.267(0.64), 6.965(1.74), 6.987(1.91), 7.064(1.24), 7.069(1.63), 7.086(0.69), 7.106(1.15), 7.111(0.99), 7.144(2.00), 7.164(0.99), 7.421(2.07), 7.443(1.86), 8.064(1.77).

[1228] Example 56A

[1229] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-(3,3,3-trifluoropropyl)piperazine

[1230]

[1231] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (300 mg, 1.04 mmol) in THF (6.4 mL) was treated with 3,3,3-trifluoropropanal (481 mg, 4.16 mmol) and sodium triacetoxyborohydride (662 mg, 3.12 mmol) and stirred at 55 °C for 4 h. The reaction mixture was quenched 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.

[1232] LC-MS (Method 4): R t =1.54min; MS(ESIpos):m / z=385[M+H] +

[1233] Example 57A

[1234] 1-[1-{4-chloro-4'-[4-(3,3,3-trifluoropropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1235]

[1236] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 100 mg, 182 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-(3,3,3-trifluoropropyl)piperazine (Example 56A, 115 mg, 73% purity, 218 μmol) in a toluene / ethanol mixture (1:1) (2 ml) was treated with an aqueous sodium carbonate solution (270 μl, 2.0 M, 550 μmol) and Pd(PPh3)4 (10.5 mg, 9.09 μmol) and stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, acidified with formic acid, and filtered through an EXtrelut NT 3 column. The column was washed with ethyl acetate and the filtrate was evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water) to give 73.0 mg (59% yield) of the title compound.

[1237] LC-MS (Method 4): R t =2.64min; MS(ESIpos):m / z=658[M+H] +

[1238] Example 58A

[1239] 1-(2,2-Dimethylpropyl)-4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1240]

[1241] 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, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated. 366 mg of the target compound was given (96% of the theoretical value).

[1242] LC-MS (Method 4): R t =1.38min; MS(ESIpos):m / z=359[M+H] +

[1243] 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).

[1244] Example 59A

[1245] 1-[1-{4-chloro-4'-[4-(2,2-dimethylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid (enantiomer 1)

[1246]

[1247] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared enantiomer 1, 50.0 mg, 90.9 μmol) and 1-(2,2-dimethylpropyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 58A, 35.8 mg, 100 μmol) were dissolved in toluene / ethanol (0.5 / 0.5 mL) under argon atmosphere. Tetra(triphenylphosphine)palladium(0) (5.25 mg, 4.55 μmol) and 2M sodium carbonate solution (136 μl, 273 μmol) were added and stirred at 100 °C for 2.5 h. The reaction mixture was filtered through a microporous 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 addition of 0.1% TFA). 45 mg of the target compound was obtained (63% of the theoretical value, 95% purity).

[1248] LC-MS (Method 4): R t =2.27min; MS(ESIpos):m / z=632[M-TFA+H] +

[1249] Example 60A

[1250] 1-(cyclobutylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1251]

[1252] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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. Cyclobutane formaldehyde (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, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated 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 target compound was given (91% of the theoretical value).

[1253] LC-MS (Method 4): Rt =1.37min; MS(ESIpos):m / z=357[M+H] +

[1254] 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).

[1255] Example 61A

[1256] 1-[1-{4-chloro-4'-[4-(cyclobutylmethyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid (enantiomer 1)

[1257]

[1258] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared as enantiomer 1, 50.0 mg, 90.9 μmol) and 1-(cyclobutylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 60A, 35.6 mg, 100 μmol) were dissolved in toluene / ethanol (0.50 / 0.50 mL) under argon atmosphere. Tetra(triphenylphosphine)palladium(0) (5.25 mg, 4.55 μmol) and 2M sodium carbonate solution (136 μl, 273 μmol) were added and stirred at 100 °C for 2 h. The reaction mixture was filtered through a microporous 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 added). 43 mg of the target compound was obtained (64% of the theoretical value).

[1259] LC-MS (Method 4): R t=2.10min; MS(ESIpos):m / z=630[M-TFA+H] +

[1260] Example 62A

[1261] 1-[(3,3-difluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1262]

[1263] A solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (700 mg, 2.43 mmol) in N,N-dimethylformamide (30 mL) was treated with potassium carbonate (1.01 g, 7.29 mmol) and 3-(bromomethyl)-1,1-difluorocyclobutane (674 mg, 3.64 mmol). The reaction mixture was stirred overnight at 80 °C, then diluted with water and extracted with dichloromethane. The organic phase was washed with water, concentrated, and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 325 mg (34% yield) of the title compound.

[1264] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.259(16.00),2.661(0.40),3.210(0.96),3.219(1.31),3.227(1.0 7),3.499(0.83),4.086(1.05),4.097(1.13),6.909(1.06),6.923(1.06),7.512(1.21),7.526(1.10).

[1265] Example 63A

[1266] 1-[1-(4-chloro-4'-{4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1267]

[1268] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 70.0 mg, 127 μmol) and 1-[(3,3-difluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (similar to Example 62A, 59.9 mg, 153 μmol) in toluene / ethanol (1:1, 1.8 ml) was treated with Pd(PPh3)4 (7.36 mg, 6.37 μmol) and an aqueous sodium carbonate solution (190 μl, 2.0 M, 380 μmol), and the reaction mixture 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 34.0 mg (38% yield) of the title compound.

[1269] LC-MS (Method 3): R t =1.12min; MS(ESIpos):m / z=666[M+H] +

[1270] Example 64A

[1271] 1-[1-(4-chloro-4'-{4-[(3,3-difluorocyclobutyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1272]

[1273] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 16A, prepared enantiomer 2, 80.0 mg, 145 μmol) and 1-[(3,3-difluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 13A, 61.5 mg, 88% purity, 175 μmol) in toluene / ethanol (1:1, 2.0 ml) was treated with Pd(PPh3)4 (8.41 mg, 7.27 μmol) and an aqueous sodium carbonate solution (220 μl, 2.0 M, 440 μmol), and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was filtered through diatomaceous earth, concentrated, and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 52.7 mg (54% yield) of the title compound.

[1274] LC-MS (Method 4): R t =2.17min; MS(ESIpos):m / z=666[M+H] +

[1275] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.243(7.72),1.254(16.00),1.266(7.89),1.549(0.80), 1.570(0.85),1.753(1.11),1.776(0.93),1.893(0.87),1.899(0.80),1.914(0.92),1.934 (0.44), 2.001(1.10), 2.017(0.76), 2.272(0.92), 2.383(0.89), 2.423(0.66), 2.598(1.08), 2.614(1.82), 2.634(1.00), 2.652(0.82), 2.686(1.27), 2.939(1.25), 2.956(2.44), 2.9 74(1.46),3.072(1.29),3.090(1.23),3.155(2.78),3.214(1.48),3.227(1.36),4.223(2.30),4.235(7.05),4.246(6.81),4.258(2.13),4.359(0.71),4.377(1.21),4.394(0.67),6 .958(3.06),6.972(3.14),7.064(3.82),7.067(4.60),7.086(2.25),7.089(1.63),7.100(3.29),7.103(2.89),7.142(5.99),7.155(3.63),7.418(4.34),7.432(4.00),8.053(6.94).

[1276] Example 65A

[1277] 1-[(3-fluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1278]

[1279] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (687 mg, 2.38 mmol) was dissolved in 29 mL of DMF. Potassium carbonate (659 mg, 4.77 mmol) and 1-(bromomethyl)-3-fluorocyclobutane (438 mg, 2.62 mmol) were added, and the mixture was stirred overnight at 60 °C. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The residue was purified on silica gel (cyclohexane / ethyl acetate gradient: ethyl acetate 10%–35%). 348 mg of the target compound was given (39% of the theoretical value).

[1280] LC-MS (Method 3): R t =0.69min; MS(ESIpos):m / z=375[M+H] +

[1281] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.257(16.00),2.362(1.07),2.375(1.31),2.450(1.01),2.458(1.33),2.4 66(1.09),3.172(1.02),3.180(1.24),3.188(0.99),6.868(1.02),6.883(1.04),7.490(1.12),7.504(1.02).

[1282] Example 66A

[1283] 1-[1-[5-chloro-2-[4-[4-[(3-fluorocyclobutyl)methyl]piperazin-1-yl]phenyl]phenyl]-3-piperidinyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid ethyl ester trifluoroacetic acid adduct (enantiomer 1)

[1284]

[1285] Ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (similar to Example 10A, prepared enantiomer 1, 150 mg, 267 μmol) and 1-[(3-fluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 65A, 110 mg, 294 μmol) were dissolved in toluene / ethanol (1.50 / 1.50 mL) under argon atmosphere. Tetra(triphenylphosphine)palladium(0) (15.4 mg, 13.4 μmol) and 2M sodium carbonate solution (400 μl, 800 μmol) were added and stirred at 100 °C for 2.5 h. The reaction mixture was filtered through a microporous 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 addition of 0.1% TFA). 130 mg of the target compound was obtained (64% of the theoretical value).

[1286] LC-MS (Method 7): R t =1.02min; MS(ESIpos):m / z=648[M-TFA+H] +

[1287] Example 67A

[1288] [4-(4-bromophenyl)piperazin-1-yl](1-fluorocyclobutyl)methyl ketone

[1289]

[1290] 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. 1-(4-bromophenyl)piperazine (500 mg, 2.07 mmol) was added and the reaction 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, concentrated, and 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.

[1291] LC-MS (Method 4): R t =2.15min; MS(ESIpos):m / z=341[M+H] +

[1292] 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).

[1293] Example 68A

[1294] 1-(4-bromophenyl)-4-[(1-fluorocyclobutyl)methyl]piperazine

[1295]

[1296] Under argon atmosphere, a solution of [4-(4-bromophenyl)piperazin-1-yl](1-fluorocyclobutyl) methyl ketone (Example 67A, 440 mg, 1.29 mmol) in THF (8.9 mL) was treated dropwise with a solution of the BH3·THF complex (26 mL, 1 M, 26 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction was carefully quenched with methanol and concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 300 mg (71% yield) of the title compound.

[1297] LC-MS (Method 4): R t =1.18min; MS(ESIpos):m / z=327[M+H] +

[1298] 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),7.321(6.99),7.334(6.82).

[1299] Example 69A

[1300] 1-[(1-fluorocyclobutyl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine

[1301]

[1302] Under argon atmosphere, a solution of 1-(4-bromophenyl)-4-[(1-fluorocyclobutyl)methyl]piperazine (Example 68A, 100 mg, 306 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxane (116 mg, 458 μmol), Pd(dppf)Cl2 (8.39 mg, 9.17 μmol), and potassium acetate (90.0 mg, 917 μmol) in 1,4-dioxane (2.8 mL) was stirred overnight at 105 °C. The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) followed by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 95.0 mg (83% yield) of the title compound.

[1303] LC-MS (Method 4): R t =1.42min; MS(ESIpos):m / z=375[M+H] +

[1304] Example 70A

[1305] 1-[1-(4-chloro-4'-{4-[(1-fluorocyclobutyl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1306]

[1307] Under argon atmosphere, a solution of ethyl 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 16A, enantiomer 2, 150 mg, 273 μmol) and (4-{4-[(1-fluorocyclobutyl)methyl]piperazin-1-yl}phenyl)boronic acid (Example 69A, 95.6 mg, 327 μmol) in toluene / ethanol (1:1, 4.0 ml) was treated with an aqueous solution of Pd(PPh3)4 (15.8 mg, 13.6 μmol) and sodium carbonate (410 μl, 2.0 M, 820 μmol) and the reaction mixture 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 59.0 mg (33% yield) of the title compound.

[1308] LC-MS (Method 4): Rt =2.37min;MS(ESIpos):m / z=648[M+H] +

[1309] 1 H-NMR(400MHz,DMSO-d6)δ[ppm]:0.853(0.63),0.883(0.84),0.900(0.82),1.152(0.94),1.169(1.01),1.234(10.30),1.252(16.00),1.270(7.17),1.483(0.58),1.504(1.23),1.526(1.41),1.548(1.16),1.576(1.02),1.750(1.78),1.778(1.57),1.883(0.80),1.910(0.88),1.999(1.26),2.072(1.85),2.140(0.97),2.164(2.01),2.191(3.34),2.208(4.31),2.230(2.74),2.328(1.09),2.366(1.40),2.581(1.05),2.627(10.69),2.641(5.86),2.670(1.30),2.693(5.01),2.710(1.39),2.926(1.09),2.952(2.11),2.979(1.29),3.067(1.21),3.097(1.14),3.155(5.05),3.167(6.36),3.179(4.71),3.213(1.54),3.239(1.47),4.212(1.97),4.230(6.14),4.248(5.92),4.266(1.88),4.380(1.12),5.753(3.31),6.928(0.78),6.952(4.98),6.974(5.30),7.060(3.78),7.065(4.70),7.083(1.97),7.104(3.26),7.109(2.75),7.142(5.56),7.163(2.76),7.413(5.87),7.435(5.25),8.063(5.35),8.143(0.41).

[1310] Example 71A

[1311] (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

[1312]

[1313] A solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (248 mg, 1.91 mmol) in N,N-dimethylformamide (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. 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl]piperazine (500 mg, 1.73 mmol) was added and the reaction 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, concentrated, and 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.

[1314] LC-MS (Method 4): R t =2.12min; MS(ESIpos):m / z=401[M+H] +

[1315] 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).

[1316] Example 72A

[1317] 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

[1318]

[1319] Under argon atmosphere, a solution of [4-(4-bromophenyl)piperazin-1-yl](1-fluorocyclobutyl) ketone (Example 71A, 440 mg, 1.29 mmol) in THF (6.0 mL) was treated dropwise with a solution of the BH3·THF complex (17 mL, 1 M, 17 mmol), and the resulting mixture was stirred at room temperature for 30 min. The reaction was carefully quenched with methanol and concentrated. 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.

[1320] LC-MS (Method 4): R t =2.41min; MS(ESIpos):m / z=387[M+H] +

[1321] 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).

[1322] Example 73A

[1323] 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-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1324]

[1325] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 190 mg, 346 μmol) and 1-[(3-fluorobicyclo[1.1.1]pent-1-yl)methyl]-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 72A, 160 mg, 415 μmol) in toluene / ethanol (1:1, 5.1 ml) was treated with Pd(PPh3)4 (20.0 mg, 17.3 μmol) and an aqueous sodium carbonate solution (520 μl, 2 M, 1.0 mmol), and the reaction mixture 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 100 mg (44% yield) of the title compound.

[1326] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.234(1.35),1.243(4.18),1.255(7.84),1.26 7(4.12),1.547(0.63),1.568(0.69),1.749(0.85),1.772(0.74),1.897(0.68), 1.910 (0.71), 2.014 (16.00), 2.018 (16.00), 2.561 (5.12), 2.589 (0.83), 2.611 (1.26), 2.629 (0.68), 2.670 (6.03), 2.940 (0.81), 2.958 (1.58), 2.975 (0.92), 3.0 69(0.95),3.087(0.89),3.161(5.07),3.215(1.17),3.229(1.17),4.224(1.20),4.235(3.51),4.247(3.50),4.259(1.25),4.363(0.51),4.379(0.90),4.397(0 .51),6.945(3.32),6.959(3.48),7.063(3.04),7.084(1.35),7.097(1.91),7.141(2.88),7.154(1.86),7.411(3.68),7.426(3.46),8.053(3.83),8.133(0.83).

[1327] Example 74A

[1328] [2-trans-fluorocyclopropyl]{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazin-1-yl} methyl ketone (racemic mixture)

[1329]

[1330] 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 reaction 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, concentrated, and 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.

[1331] LC-MS (Method 4): R t =2.04min; MS(ESIpos):m / z=375[M+H] +

[1332] 1 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).

[1333] Example 75A

[1334] 1-{[2-trans-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (racemic mixture)

[1335]

[1336] Under 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 74A, 696 mg, 1.86 mmol) in THF (17 mL) was treated dropwise with a BH3·THF complex solution (37 mL, 1 M, 37 mmol), and the resulting mixture was stirred at room temperature for 30 min. The reaction was carefully quenched with methanol and concentrated. 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.

[1337] LC-MS (Method 4): R t =2.29min; MS(ESIpos):m / z=361[M+H] +

[1338] 1 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).

[1339] Example 76A

[1340] 1-{1-[4-chloro-4'-(4-{[2-trans-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 1)

[1341]

[1342] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared as enantiomer 1, 120 mg, 218 μmol) and 1-{[2-trans-fluorocyclopropyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]piperazine (Example 75A, racemic, 94.3 mg, 262 μmol) in toluene / ethanol (1:1, 3.2 ml) was treated with Pd(PPh3)4 (12.6 mg, 10.9 μmol) and an aqueous sodium carbonate solution (330 μl, 2 M, 650 μmol), and the reaction mixture 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 60 mg (42% yield) of the title compound.

[1343] LC-MS (Method 4): R t =1.99min; MS(ESIpos):m / z=634[M+H] +

[1344] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.523(1.19),0.534(1.27),0.541(1.25),0.552(1.14),0.562(0.43),1.018(0.48),1.030(0.50),1.036(0.61),1.041(0.55),1.048(0.53),1.052(0.57),1.066(0.51),1.071(0.67),1.077(0.54),1.084(0.51),1.088(0.46),1.243(7.74),1.254(16.00),1.266(7.74),1.357(0.43),1.377(0.51),1.388(0.60),1.400(0.51),1.554(0.75),1.576(0.77),1.756(0.99),1.778(0.80),1.893(0.78),1.899(0.72),1.913(0.79),2.004(0.95),2.021(0.74),2.128(0.71),2.134(0.70),2.141(0.74),2.149(1.18),2.156(0.90),2.162(0.88),2.169(0.84),2.272(0.89),2.277(0.90),2.282(0.87),2.288(0.77),2.293(0.72),2.299(0.64),2.304(0.63),2.423(0.41),2.563(1.81),2.572(2.46),2.581(2.22),2.593(2.68),2.598(2.49),2.615(2.13),2.634(0.78),2.652(0.46),2.939(1.18),2.957(2.19),2.975(1.32),3.078(1.06),3.096(1.00),3.178(3.84),3.186(6.70),3.195(3.79),3.215(1.43),3.230(1.22),4.223(2.16),4.235(6.44),4.247(6.23),4.259(1.94),4.363(0.64),4.382(1.05),4.399(0.62),4.498(0.99),4.508(0.92),4.606(0.97),4.616(0.96),5.747(2.68),6.966(5.35),6.980(5.65),7.063(4.00),7.067(4.87), 7.088(2.37), 7.091(1.72), 7.101(3.41), 7.105(2.93), 7.144(6.03), 7.158(3.64), 7.420(6.35), 7.435(5.82), 8.057(6.64), 8.138(1.37).

[1345] Example 77A

[1346] 1-[-1-(4-chloro-4'-{4-[2-trans-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 1)

[1347]

[1348] A solution of 2-trans-fluorocyclopropane-1-carboxylic acid (18.3 mg, 176 μmol) in DMF (1.6 mL) was treated with HATU (91.3 mg, 240 μmol) and N,N-diisopropylethylamine (84 μl, 480 μmol) and stirred at room temperature for 10 min. Then, ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 19A, enantiomer 1, 90.0 mg, 160 μmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 72.0 mg (69% yield) of the title compound.

[1349] LC-MS (Method 4): R t =2.79min; MS(ESIpos):m / z=648[M+H] +

[1350] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.151(0.72),1.162(1.99),1.172(2.53),1.182(2.51),1.193(1.87),1.204(0.82),1.241(8.09),1.253(16.00),1.265(8.14),1.382(0.79),1.392(0.93),1.399(1.25),1.404(0.89),1.419(0.99),1.429(0.92),1.435(1.25),1.441(0.91),1.446(0.89),1.545(1.31),1.565(1.50),1.748(1.78),1.769(1.46),1.888(0.59),1.901(1.42),1.922(1.50),1.942(0.74),2.004(1.80),2.383(0.56),2.423(0.56),2.592(1.38),2.611(2.79),2.629(2.16),2.650(1.30),2.660(1.81),2.678(1.13),2.690(0.99),2.958(1.82),2.975(3.51),2.992(2.08),3.065(1.91),3.085(1.82),3.163(2.00),3.226(2.94),3.245(3.38),3.256(2.92),3.260(2.95),3.315(0.89),3.320(1.66),3.613(3.15),3.849(3.83),4.223(2.69),4.235(7.80),4.247(7.75),4.258(2.58),4.372(1.08),4.390(1.88),4.764(1.38),4.872(1.34),7.010(8.00),7.024(8.47),7.074(7.00),7.095(3.06),7.109(4.38),7.112(3.95),7.156(7.51),7.169(4.87),7.448(8.95),7.463(8.28),8.060(9.80).

[1351] Two diastereomers were separated by preparative chiral HPLC [Sample preparation: 71 mg dissolved in 4.7 mL of an ethanol / acetonitrile / diethylamine mixture (4:4:1); injection volume: 50 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, 28 mg of diastereomer 1 eluted first (Example 79A) and 36 mg of diastereomer 2 eluted later were obtained (Example 80A).

[1352] Example 78A

[1353] 1-[1-(4-chloro-4'-{4-[2-trans-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 1)

[1354] For separation conditions, see Example 77A.

[1355] Analytical chiral HPLC:R t =4.354 min, ee=100% [Column: Daicel Chiralpak OX-3 3μm, 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].

[1356] LC-MS (Method 3): R t =1.45min; MS(ESIpos):m / z=648[M+H] +

[1357] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.91),0.146(0.87),1.101(0.46),1.119(0.41),1.140(2.39),1.151(1.71),1.158(4.89),1.167(2.17),1.176(2.61),1.183(2.15),1.199(1.56),1.215(0.67),1.233(7.73),1.250(16.00),1.268(7.74),1.366(0.52),1.374(0.54),1.381(0.64),1.389(0.83),1.400(0.64),1.408(0.62),1.421(0.66),1.429(0.58),1.437(0.66),1.447(0.83),1.456(0.67),1.463(0.58),1.471(0.54),1.534(0.71),1.567(0.80),1.740(1.13),1.773(0.82),1.901(0.75),1.923(0.86),1.953(0.43),2.004(1.11),2.328(0.46),2.367(0.65),2.578(0.94),2.606(1.42),2.630(1.27),2.670(1.42),2.698(0.68),2.710(0.84),2.919(0.92),2.946(1.37),2.973(2.20),2.999(1.30),3.060(1.18),3.088(1.09),3.159(2.21),3.228(2.07),3.246(2.88),3.611(2.73),3.851(3.00),4.212(2.17),4.230(6.68),4.248(6.58),4.265(2.00),4.364(0.66),4.391(1.11),4.735(0.86),4.904(0.88),7.009(5.28),7.031(5.80),7.070(3.94),7.075(5.01),7.092(2.20),7.097(1.31),7.113(3.60),7.118(3.06),7.154(6.13),7.174(3.10),7.448(6.33),7.470(5.68),8.070(6.89).

[1358] Example 79A

[1359] 1-[1-(4-chloro-4'-{4-[2-trans-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 2)

[1360] For separation conditions, see Example 77A.

[1361] Analytical chiral HPLC:R t =4.793 min, ee=98.9% [Column: Daicel Chiralpak OX-3 3μm, 50x 4.6mm; Eluent: n-heptane / ethanol 90:10 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 23℃; UV detection: 220 nm].

[1362] LC-MS (Method 3): R t =1.45min; MS(ESIpos):m / z=648[M+H] +

[1363] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(1.15),0.146(1.14),1.101(0.44),1.118(0.45),1.139(2.23),1.157(4.41),1.168(2.19),1.176(2.37),1.184(2.12),1.200(1.60),1.216(0.67),1.234(7.91),1.252(16.00),1.270(7.82),1.365(0.57),1.373(0.58),1.380(0.67),1.391(0.88),1.399(0.65),1.408(0.63),1.420(0.69),1.428(0.62),1.436(0.68),1.446(0.88),1.455(0.66),1.462(0.60),1.470(0.55),1.536(0.78),1.566(0.88),1.740(1.19),1.775(0.90),1.891(0.84),1.922(0.92),1.951(0.45),2.003(1.20),2.328(0.67),2.366(1.01),2.576(0.98),2.603(1.48),2.631(1.28),2.674(1.60),2.690(0.69),2.703(0.69),2.710(1.13),2.920(0.79),2.944(1.46),2.971(2.28),2.998(1.40),3.059(1.24),3.088(1.17),3.155(1.55),3.226(2.16),3.244(2.95),3.615(2.32),3.852(2.81),4.213(2.24),4.231(6.92),4.249(6.78),4.266(2.10),4.362(0.69),4.390(1.21),4.737(0.92),4.900(0.87),7.009(5.65),7.031(6.09),7.070(4.08),7.075(5.22),7.093(2.30),7.097(1.40),7.113(3.77),7.118(3.16),7.154(6.39),7.174(3.22),7.448(6.72),7.469(5.90),8.069(6.68).

[1364] Example 80A

[1365] 1-{1-[4-chloro-4'-(4-{[2-trans-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 1)

[1366]

[1367] Under argon atmosphere, a solution of ethyl 1-[1-(4-chloro-4'-{4-[2-trans-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 78A, diastereomer 1, 28.0 mg, 43.2 μmol) in THF (1.0 mL) was treated dropwise with a solution of the BH3·THF complex (860 μl, 1.0 M, 860 μmol), and the resulting mixture was stirred overnight at 35 °C. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 16.0 mg (58% yield) of the title compound.

[1368] LC-MS (Method 7): R t =1.01min; MS(ESIpos):m / z=634[M+H] +

[1369] Example 81A

[1370] 1-{1-[4-chloro-4'-(4-{[2-trans-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 2)

[1371]

[1372] Under argon atmosphere, a solution of ethyl 1-[1-(4-chloro-4'-{4-[2-trans-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 79A, diastereomer 2, 28.0 mg, 43.2 μmol) in THF (1.0 mL) was treated dropwise with a solution of the BH3·THF complex (860 μl, 1.0 M, 860 μmol), and the resulting mixture was stirred overnight at 35 °C. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 18.0 mg (66% yield) of the title compound.

[1373] LC-MS (Method 6): R t =1.44min; MS(ESIpos):m / z=634[M+H] +

[1374] Example 82A

[1375] 1-[1-(4-chloro-4'-{4-[(1S,2S)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 1)

[1376]

[1377] A solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (22.4 mg, 215 μmol) in DMF (2.0 mL) was treated with HATU (112 mg, 294 μmol) and N,N-diisopropylethylamine (100 μl, 590 μmol) and stirred at room temperature for 10 min. Then, ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 19A, enantiomer 1, 110 mg, 196 μmol) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 82.0 mg (65% yield) of the title compound.

[1378] LC-MS (Method 4): R t =2.73min; MS(ESIpos):m / z=648[M+H] +

[1379] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.005(0.50),1.016(0.99),1.021(0.67),1.027(1.11),1.032(1.08),1.037(1.05),1.042(1.15),1.052(0.94),1.063(0.53),1.236(8.27),1.247(16.00),1.259(7.89),1.512(0.64),1.518(0.75),1.524(1.32),1.529(1.21),1.536(1.00),1.541(1.07),1.551(1.16),1.563(1.68),1.568(1.81),1.574(1.11),1.579(0.82),1.749(1.18),1.772(1.02),1.899(0.91),1.919(0.96),1.940(0.47),1.999(1.18),2.068(1.41),2.184(0.56),2.195(1.43),2.207(1.50),2.211(1.53),2.222(1.32),2.234(0.52),2.422(0.45),2.597(0.87),2.612(1.83),2.632(0.88),2.651(0.45),2.949(1.36),2.966(2.55),2.984(1.50),3.068(1.67),3.086(2.06),3.142(1.02),3.213(2.00),3.230(1.55),3.331(0.97),3.598(0.87),3.703(0.90),3.822(1.68),4.218(2.25),4.229(6.70),4.241(6.56),4.253(2.13),4.363(0.77),4.381(1.24),4.399(0.69),4.868(0.62),4.873(0.67),4.878(1.01),4.884(0.96),4.889(0.65),4.894(0.57),4.979(0.56),4.990(0.95),4.995(0.94),5.000(0.66),5.005(0.58),5.744(9.67),7.009(5.95),7.024(6.28),7.071(4.44),7.075(5.33),7.094(2.50),7.098(1.82),7.108(3.48),7.111(3.03),7.154(5.97), 7.168(3.84), 7.445(6.89), 7.460(6.31), 8.055(7.13).

[1380] Example 83A

[1381] 1-{1-[4-chloro-4'-(4-{[(1S,2S)-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 1)

[1382]

[1383] Under argon atmosphere, a solution of ethyl 1-[1-(4-chloro-4'-{4-[(1S,2S)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 82A; stereoisomer 1, 61.0 mg, 94.1 μmol) in THF (2.0 mL) was treated dropwise with a solution of the BH3·THF complex (1.9 mL, 1.0 M, 1.9 mmol), and the resulting mixture was stirred overnight at 35 °C. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 18.0 mg (28% yield) of the title compound.

[1384] LC-MS (Method 7): R t =1.00min; MS(ESIpos):m / z=634[M+H] +

[1385] Example 84A

[1386] 1-[1-(4-chloro-4'-{4-[(1R,2R)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 1)

[1387]

[1388] A solution of (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (22.4 mg, 215 μmol) in DMF (2.0 mL) was treated with HATU (112 mg, 294 μmol) and N,N-diisopropylethylamine (100 μl, 590 μmol) and stirred at room temperature for 10 min. Then, ethyl 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 19A, enantiomer 1, 110 mg, 196 μmol) was added, and the resulting mixture was stirred at room temperature for 2 h and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 83.0 mg (65% yield) of the title compound.

[1389] LC-MS (Method 4): R t =2.73min; MS(ESIpos):m / z=648[M+H] +

[1390] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.007(0.50),1.018(1.04),1.023(0.73),1.028(1.16),1.033(1.13),1.038(1.10),1.043(1.20),1.049(0.74),1.054(1.05),1.063(0.53),1.157(0.44),1.168(0.50),1.239(8.29),1.251(16.00),1.263(7.80),1.514(0.77),1.520(0.89),1.525(1.34),1.531(1.33),1.537(1.25),1.543(1.51),1.552(1.11),1.557(1.32),1.564(2.16),1.569(1.68),1.575(0.96),1.581(0.85),1.747(1.33),1.769(1.08),1.888(0.40),1.903(1.02),1.922(1.09),1.943(0.55),2.003(1.34),2.020(0.94),2.069(0.97),2.186(0.60),2.198(1.46),2.210(1.63),2.213(1.65),2.225(1.38),2.236(0.53),2.591(0.93),2.611(1.96),2.627(0.96),2.952(1.44),2.969(2.76),2.987(1.58),3.065(1.96),3.081(2.23),3.144(1.07),3.222(2.38),3.237(1.90),3.306(1.57),3.597(1.00),3.711(0.99),3.822(2.74),4.221(2.27),4.233(6.86),4.244(6.74),4.256(2.20),4.366(0.84),4.385(1.41),4.402(0.80),4.868(0.60),4.878(1.05),4.884(1.06),4.894(0.58),4.979(0.56),4.989(1.08),4.994(1.03),5.005(0.62),5.745(12.44),7.010(6.21),7.025(6.54),7.071(4.56),7.074(5.45),7.094(2.51),7.098(1.81),7.108(3.53),7.111(3.16), 7.154(6.01), 7.168(3.78), 7.446(7.04), 7.460(6.49), 8.058(7.48).

[1391] Example 85A

[1392] 1-{1-[4-chloro-4'-(4-{[(1R,2R)-2-fluorocyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (stereoisomer 1)

[1393]

[1394] Under argon atmosphere, a solution of ethyl 1-[1-(4-chloro-4'-{4-[(1R,2R)-2-fluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Example 84A, stereoisomer 1, 65.0 mg, 100 μmol) in THF (4.0 mL) was treated dropwise with a solution of the BH3·THF complex (2.0 mL, 1.0 M, 2.0 mmol), and the resulting mixture was stirred at room temperature for 5 hours. A solution of the BH3·THF complex (1.0 mL, 1.0 M, 1.0 mmol) was added, and the resulting mixture was stirred overnight at room temperature and then stirred at 50 °C for 2 hours. The reaction mixture was carefully quenched with methanol and evaporated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 7.00 mg (11% yield) of the title compound.

[1395] LC-MS (Method 3): R t =1.07min; MS(ESIpos):m / z=634[M+H] +

[1396] Example 86A

[1397] 1-[1-{4-chloro-4'-[4-(spiro[2,2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid methyl ester (enantiomer 1)

[1398]

[1399] At 0 °C, a solution of 1-[1-{4-chloro-4'-[4-(spiro[2.2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 53, enantiomer 1, 33.0 mg, 52.5 μmol) in methanol (260 μl) was treated dropwise with thionyl chloride (34 μl, 460 μmol). The resulting mixture was stirred at 0 °C for 20 minutes and then stirred overnight at room temperature. The reaction mixture was evaporated to give 31.0 mg (92% yield) of the title compound, which was used in the next step without further purification.

[1400] LC-MS (Method 7): R t =1.48min; MS(ESIpos):m / z=642[M+H] +

[1401] Example 87A

[1402] 1-[1-(4-chloro-4'-{4-[(spiro[2,2]pent-1-yl)methyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid methyl ester (enantiomer 1)

[1403]

[1404] Under argon atmosphere, a solution of methyl 1-[1-{4-chloro-4'-[4-(spiro[2,2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 86A, enantiomer 1, 31.0 mg, 48.3 μmol) in THF (2.7 mL) was treated dropwise with a solution of the BH3·THF complex (970 μl, 1.0 M, 970 μmol), 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 evaporated and the residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 10.0 mg (33% yield) of the title compound.

[1405] LC-MS (Method 8): R t =6.94min; MS(ESIpos):m / z=628[M+H] +

[1406] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.704(1.38),0.710(1.20),0.719(1.71),0.727(2.62),0.734(1.48),0. 783(1.95),0.789(2.16),0.797(2.24),0.802(2.24),0.823(1.59),0.835(1.40),1.124(1.29),1.235(0.6 8), 1.540(1.21), 1.561(1.44), 1.733(1.51), 1.746(1.72), 1.770(1.00), 1.904(0.83), 1.925(0.89), 2.002(1.10), 2.594(1.24), 2.612(1.89), 2.632(1.04), 2.651(0.55), 2.747(0.85), 2.768(1.09), 2.781(0.99) ),2.898(1.17),2.906(0.91),2.920(0.95),2.953(1.57),2.970(4.00),3.075(3.30),3.217(1.26),3.233(1.08),3.402(1.83),3.410(2.02),3.417(2.24),3.423(2.19),3.453(2.00),3.460(2.09),3.473(1.48) ,3.775(16.00),4.368(0.69),4.386(1.14),6.995(4.33),7.010(4.45),7.073(3.35),7.076(3.86),7.096(1.91),7.109(2.62),7.113(2.27),7.153(4.13),7.167(2.66),7.449(4.68),7.463(4.35),8.075(5.09).

[1407] Example 88A

[1408] 1-[1-{4-chloro-4'-[4-(spiro[2,2]pentane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1409]

[1410] Spiro[2,2]pentane-1-carboxylic acid (18.3 mg, 163 μmol) in dichloromethane (960 μl) was treated with HATU (61.9 mg, 163 μmol) and N,N-diisopropylethylamine (100 μl, 590 μmol) and stirred at room temperature for 10 min. Then, 1-[1-[5-chloro-2-(4-piperazin-1-ylphenyl)phenyl]-3-piperidinyl]-5-(trifluoromethyl)pyrazole-4-carboxylic acid ethyl ester hydrochloride (Example 19A, enantiomer 1, 100 mg, 148 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, and 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 86.2 mg (89% yield) of the title compound.

[1411] LC-MS (Method 4): R t =2.88min; MS(ESIpos):m / z=656[M+H] +

[1412] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.097(0.44),0.683(2.00),0.791(2.40),0.799(2.98),0.806(1.65 ),0.840(1.97),0.923(2.16),0.930(2.15),0.938(2.00),1.199(2.40),1.204(2.88),1.211(2.89), 1.216(2.71), 1.239(8.60), 1.251(16.00), 1.263(7.99), 1.420(3.66), 1.567(1.24), 1.753(1.80), 1.776(1.48), 1.894(1.33), 1.915(1.41), 2.000(1.93), 2.355(2.48), 2.362(2.79), 2.374(2.58), 2.4 21(1.50),2.620(2.20),2.640(1.12),2.651(1.12),2.940(1.64),2.957(3.18),2.974(1.88),3.067(2.95),3.206(2.77),3.221(2.29),3.253(2.01),3.299(5.04),3.545(1.06),3.673(3.12),4.221(2 .42),4.232(7.42),4.245(7.20),4.256(2.47),4.369(1.69),6.988(7.83),7.003(8.52),7.075(6.96),7.092(3.03),7.106(4.35),7.149(7.17),7.162(4.36),7.438(8.57),7.452(7.97),8.054(8.77).

[1413] Example 89A

[1414] [4-(4-bromophenyl)piperazin-1-yl][2-cis-(trifluoromethyl)cyclopropyl] methyl ketone (racemic mixture)

[1415]

[1416] 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, extracted with ethyl acetate, and 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.

[1417] LC-MS (Method 4): R t =2.09min; MS(ESIpos):m / z=377[M+H] +

[1418] 1 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).

[1419] Example 90A

[1420] 1-(4-Bromophenyl)-4-{[2-cis-(trifluoromethyl)cyclopropyl]methyl}piperazine (racemic mixture)

[1421]

[1422] Under argon atmosphere, a solution of [4-(4-bromophenyl)piperazin-1-yl]-2-cis-(trifluoromethyl)cyclopropyl]methyl ketone (Example 89A, 461 mg, 1.22 mmol) in THF (2.4 mL) was treated dropwise with a solution of the BH3·THF complex (12 mL, 1 M, 12 mmol), and the resulting mixture was stirred overnight at room temperature. A second portion of the BH3·THF complex (6.1 mL, 1 M, 6.1 mmol) was added, and the reaction mixture was stirred again at room temperature for 4 hours. A third portion of the BH3·THF complex (6.1 mL, 1 M, 6.1 mmol) was added, and the reaction mixture was stirred again at room temperature for 24 hours. The reaction was carefully quenched with methanol and concentrated. 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.

[1423] LC-MS (Method 4): R t =1.25min; MS(ESIpos):m / z=363[M+H] +

[1424] 1 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).

[1425] Example 91A

[1426] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[2-cis-(trifluoromethyl)cyclopropyl]methyl}piperazine (racemic mixture)

[1427]

[1428] Under argon atmosphere, a solution of 1-(4-bromophenyl)-4-[[2-cis-(trifluoromethyl)cyclopropyl]methyl]piperazine (similar to the preparation in Example 90A, 193 mg, 531 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxacyclopentaborane (202 mg, 797 μmol), Pd2dba3 (14.6 mg, 15.9 μmol), XPhos (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 without further purification.

[1429] LC-MS (Method 4): R t =1.45min; MS(ESIpos):m / z=411[M+H] +

[1430] 1 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).

[1431] Example 92A

[1432] 1-{1-[4-chloro-4'-(4-{[2-cis-(trifluoromethyl)cyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 1)

[1433]

[1434] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 70.0 mg, 127 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-[[2-cis-(trifluoromethyl)cyclopropyl]methyl]piperazine (Example 91A, 83.6 mg, 75% purity, 153 μmol) in toluene / ethanol (1:1, 1.8 ml) was treated with Pd(PPh3)4 (7.36 mg, 6.37 μmol) and an aqueous sodium carbonate solution (190 μl, 2 M, 380 μmol), and the reaction mixture 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 27.7 mg (32% yield) of the title compound.

[1435] LC-MS (Method 4): R t =2.14min; MS(ESIpos):m / z=684[M+H] +

[1436] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.60),0.146(0.64),0.761(0.63),0.981(0.69),1.234(7.3 9),1.252(16.00),1.270(7.60),1.339(0.57),1.545(0.61),1.577(0.70),1.753(1.47),1.784(0.97 ), 1.883(0.70), 1.915(0.74), 1.997(0.98), 2.023(0.61), 2.328(1.02), 2.333(0.91), 2.366(1.13), 2.406(0.57), 2.592(3.13), 2.614(2.92), 2.645(1.10), 2.666(0.67), 2.670(0.78), 2.675(0.61), 2.7 10(0.96),2.928(0.95),2.954(1.85),2.981(1.15),3.072(1.12),3.098(1.04),3.181(3.10),3.230(1.24),4.212(2.10),4.230(6.61),4.248(6.35),4.266(1.92),4.350(0.55),4.377(0.98),4.403(0 0.53), 6.974(2.20), 6.995(2.37), 7.066(3.10), 7.071(3.92), 7.087(1.86), 7.092(1.11), 7.107(3.11), 7.112(2.67), 7.143(6.00), 7.164(2.91), 7.423(3.14), 7.444(2.88), 8.064(5.25), 8.133(0.48).

[1437] Example 93A

[1438] 1-{1-[4-chloro-4'-(4-{[2-cis-(trifluoromethyl)cyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 2)

[1439]

[1440] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 16A, prepared enantiomer 2, 70.0 mg, 127 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-[[2-cis-(trifluoromethyl)cyclopropyl]methyl]piperazine (Example 91A, 83.6 mg, 75% purity, 153 μmol) in toluene / ethanol (1:1, 1.8 ml) was treated with Pd(PPh3)4 (7.36 mg, 6.37 μmol) and an aqueous sodium carbonate solution (190 μl, 2 M, 380 μmol), and the reaction mixture 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 32.7 mg (38% yield) of the title compound.

[1441] LC-MS (Method 4): R t =2.14min; MS(ESIpos):m / z=684[M+H] +

[1442] 1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.149(0.62),0.146(0.61),0.758(0.63),0.986(0.69),1.234(7.3 7),1.252(16.00),1.270(7.59),1.341(0.56),1.546(0.61),1.578(0.72),1.752(1.48),1.785(0.98 ), 1.885(0.69), 1.914(0.75), 1.998(0.97), 2.023(0.64), 2.327(1.04), 2.332(0.92), 2.366(1.05), 2.402(0.57), 2.592(3.18), 2.614(2.92), 2.645(1.10), 2.665(0.70), 2.670(0.84), 2.674(0.64), 2.7 10(0.93),2.928(0.95),2.955(1.86),2.981(1.14),3.071(1.08),3.099(1.05),3.181(3.09),3.230(1.29),4.212(2.09),4.230(6.61),4.248(6.38),4.265(1.95),4.350(0.57),4.377(0.96),4.403(0 0.54), 6.974(2.12), 6.995(2.31), 7.066(3.05), 7.071(3.91), 7.087(1.90), 7.092(1.12), 7.107(3.10), 7.112(2.68), 7.143(6.07), 7.163(2.92), 7.423(3.08), 7.444(2.82), 8.063(5.58), 8.132(0.45).

[1443] Example 94A

[1444] [4-(4-bromophenyl)piperazin-1-yl][1-(trifluoromethyl)cyclopropyl]methyl ketone

[1445]

[1446] A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (703 mg, 4.56 mmol) in N,N-dimethylformamide (20 mL) was treated with HATU (1.58 g, 4.15 mmol) and N,N-diisopropylethylamine (1.4 mL, 8.3 mmol) and stirred at room temperature for 10 min. 1-(4-bromophenyl)piperazine (1.00 g, 4.15 mmol) was added and the reaction 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 brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 284 mg (18% yield) of the title compound.

[1447] LC-MS (Method 6): R t =1.39min; MS(ESIpos):m / z=377[M+H] +

[1448] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:1.176(0.53),1.215(2.06),1.225(9.44),1.234(3.41),1.261(0.54),1.281(0.88) ,1.307(5.68),1.315(11.35),1.319(10.04),1.328(3.65),1.400(3.52),1.987(0.93),3.149(9.71),3.157(13.51) ,3.166(10.11),3.256(0.54),3.264(0.71),3.317(0.42),3.686(6.57),6.912(1.47),6.918(14.16),6.921(4.64),6.933(15.00),6.938(1.39),7.355(1.60),7.361(16.00),7.365(4.77),7.373(4.82),7.376(14.72),7.382(1.25).

[1449] Example 95A

[1450] 1-(4-bromophenyl)-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine

[1451]

[1452] Under argon atmosphere, a solution of [4-(4-bromophenyl)piperazin-1-yl][1-(trifluoromethyl)cyclopropyl] methyl ketone (Example 94A, 282 mg, 733 μmol) in THF (1.4 mL) was treated dropwise with a solution of the BH3·THF complex (7.3 mL, 1 M, 7.3 mmol), and the resulting mixture was stirred overnight at room temperature. A second portion of the BH3·THF complex (7.3 mL, 1 M, 7.3 mmol) was added, and the reaction mixture was stirred again at room temperature for 24 hours. The reaction was carefully quenched with methanol and concentrated. The residue was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 139 mg (73% purity, 38% yield) of the title compound, which was used without further purification.

[1453] LC-MS (Method 3): R t =0.77min; MS(ESIpos):m / z=363[M+H] +

[1454] 1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.752(10.75),0.944(0.46),0.970(4.65),0.978(13.12), 0.981(12.99),0.989(3.89),1.228(0.90),1.309(0.61),1.318(1.07),1.330(0.42),2.422 (0.64), 2.562(1.40), 2.581(0.84), 2.650(0.59), 2.773(0.94), 2.790(1.75), 2.810(0.88), 3.000(1.25), 3.022(1.11), 3.103(13.69), 3.112(16.00), 3.120(12.89), 3.140(0.96), 3.1 49(1.24),3.579(1.67),3.601(1.54),3.698(0.57),6.810(0.64),6.817(0.55),6.865(1.40),6.870(14.23),6.886(15.26),6.891(4.23),6.906(2.93),6.925(1.15),6.939(1.08),6 .956(0.82),6.969(0.92),7.209(0.84),7.221(1.22),7.233(1.02),7.245(0.52),7.315(1.43),7.320(15.67),7.332(4.76),7.335(14.57),7.351(2.93),7.366(2.73),8.176(0.70).

[1455] Example 96A

[1456] 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine

[1457]

[1458] Under argon atmosphere, a solution of 1-(4-bromophenyl)-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine (Example 95A, 137 mg, 73% purity, 275 μmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxacyclopentaborane (105 mg, 413 μmol), Pd2dba3 (7.56 mg, 8.26 μmol), X-Phos (7.88 mg, 16.5 μmol), and potassium acetate (81.1 mg, 826 μmol) in cyclopentylmethyl ether (2.7 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 242 mg (39% purity, 84% yield) of the title compound, which was used without further purification.

[1459] LC-MS (Method 4): R t =1.94min; MS(ESIpos):m / z=411[M+H] +

[1460] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:0.980(0.50),0.983(0.48),1.071(0.47 ),1.159(8.83),1.168(16.00),1.259(3.13),2.035(0.88),7.887(0.63).

[1461] Example 97A

[1462] 1-{1-[4-chloro-4'-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1463]

[1464] Under argon atmosphere, a solution of 1-[1-{5-chloro-2-[(trifluoromethanesulfonyl)oxy]phenyl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (similar to Example 10A, prepared enantiomer 1, 80.0 mg, 145 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-4-{[1-(trifluoromethyl)cyclopropyl]methyl}piperazine (similar to Example 96A, 82.1 mg, 86% purity, 160 μmol) in toluene / ethanol (1:1, 2.0 ml) was treated with Pd(PPh3)4 (8.41 mg, 7.27 μmol) and an aqueous sodium carbonate solution (220 μl, 2.0 M, 440 μmol), and the reaction mixture 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 29.4 mg (29% yield) of the title compound.

[1465] LC-MS (Method 4): R t =3.09min; MS(ESIpos):m / z=684[M+H] +

[1466] Example 98A

[1467] 1-[1-(4-chloro-4'-{4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1468]

[1469] A solution of ethyl 1-[1-[5-chloro-2-(4-piperazin-1-ylphenyl)phenyl]-3-piperidinyl]-5-(trifluoromethyl)pyrazole-4-carboxylate (Example 19A, enantiomer 1, 100 mg, 178 μmol) in N,N-dimethylformamide (1.8 mL) was treated with potassium carbonate (73.8 mg, 534 μmol) and 1-bromo-2-(trifluoromethoxy)ethane (31 μl, 270 μmol). The reaction mixture was stirred overnight at room temperature and then diluted with water. The mixture was extracted with dichloromethane, and the organic phase was filtered through a Chromabond column and concentrated. The residue was concentrated by preparative HPLC (RP18 column, eluent: acetonitrile / water + 0.1% formic acid gradient) to give 31.0 mg (25% yield) of the title compound.

[1470] LC-MS (Method 4): R t=2.59min; MS(ESIpos):m / z=675[M+H] +

[1471] 1 H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.021(0.52),1.240(8.40),1.252(16.00),1.264(8.05),1.553(1. 06),1.575(1.16),1.757(1.42),1.779(1.19),1.892(1.14),1.913(1.21),1.933(0.61),2.001(1.51 ),2.383(0.49),2.422(0.59),2.600(7.40),2.608(9.46),2.616(8.88),2.636(1.28),2.651(0.55),2.692(3.38),2.701(6.44),2.710(3.46),2.938(1.50),2.956(2.96),2.973(1.74),3.075(1.58),3.0 93(1.44),3.169(6.59),3.178(8.46),3.185(6.42),3.212(1.88),3.226(1.58),3.314(1.15),4.198(4.28),4.207(8.11),4.216(4.41),4.221(2.86),4.233(7.26),4.245(7.06),4.257(2.33),4.360(0 .86),4.377(1.53),6.964(6.36),6.979(6.67),7.063(4.69),7.067(5.65),7.087(2.46),7.090(1.96),7.100(3.61),7.103(3.25),7.144(6.05),7.157(3.77),7.418(7.19),7.432(6.69),8.053(7.93).

[1472] Example 99A

[1473] 1-{1-[4'-(4-acetylpiperazin-1-yl)-4-chloro[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1474]

[1475] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared as enantiomer 1, 50.0 mg, 83.5 μmol) in dichloromethane (1.0 mL) was treated with potassium carbonate (23.1 mg, 167 μmol) and acetyl chloride (8.9 μl, 130 μmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous sodium hydroxide solution (1 N) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 52.0 mg (quantitative) of the title compound.

[1476] LC-MS (Method 4): R t =2.68min; MS(ESIpos):m / z=604[M+H] +

[1477] Example 100A

[1478] 1-{1-[4-chloro-4'-(4-propionylpiperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1479]

[1480] A solution of 1-{(-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 50.0 mg, 83.5 μmol) in dichloromethane (1.0 mL) was treated with potassium carbonate (23.1 mg, 167 μmol) and propionyl chloride (11 μl, 130 μmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 53.0 mg (94% yield) of the title compound.

[1481] LC-MS (Method 4): R t =2.78min; MS(ESIpos):m / z=618[M+H] +

[1482] Example 101A

[1483] 1-[1-{4-chloro-4'-[4-(2-methylpropionyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1484]

[1485] A solution of 2-methylpropionic acid (16 μl, 170 μmol) in dichloromethane (1.5 mL) was treated with HATU (57.8 mg, 152 μmol) and N,N-diisopropylethylamine (53 μl, 300 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 91.0 mg, 152 μmol) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 67.0 mg (70% yield) of the title compound.

[1486] LC-MS (Method 4): R t =2.85min; MS(ESIpos):m / z=632[M+H] +

[1487] Example 102A

[1488] 1-[1-{4-chloro-4'-[4-(2-fluoro-2-methylpropionyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1489]

[1490] A solution of 2-fluoro-2-methylpropionic acid (17.7 mg, 167 μmol) in DMF (730 μl) was treated with HATU (57.8 mg, 152 μmol) and N,N-diisopropylethylamine (53 μl, 300 μmol), followed by the addition of l-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared as enantiomer 1, 91.0 mg, 152 μmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, dichloromethane / methanol gradient) to give 41 mg (41% yield) of the title compound.

[1491] LC-MS (Method 4): R t =2.94min; MS(ESIpos):m / z=650[M+H] +

[1492] Example 103A

[1493] 1-{1-[4'-(4-butyrylpiperazin-1-yl)-4-chloro[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1494]

[1495] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared as enantiomer 1, 50.0 mg, 83.5 μmol) in dichloromethane (1.0 mL) was treated with potassium carbonate (23.1 mg, 167 μmol) and butyryl chloride (13 μl, 130 μmol) and stirred at room temperature for 30 min. The reaction mixture was 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 51.0 mg (92% purity, 89% yield) of the title compound.

[1496] LC-MS (Method 4): R t =2.85min; MS(ESIpos):m / z=632[M+H] +

[1497] Example 104A

[1498] 1-[1-{4-chloro-4'-[4-(3-methoxypropionyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1499]

[1500] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 60.0 mg, 100 μmol) in dichloromethane (1.2 mL) was treated with potassium carbonate (27.7 mg, 201 μmol) and 3-methoxypropionyl chloride (18.4 mg, 150 μmol) and stirred at room temperature for 2 hours. An additional 3-methoxypropionyl chloride (18.4 mg, 150 μmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 63.3 mg (90% yield) of the title compound.

[1501] LC-MS (Method 4): R t =2.72min; MS(ESIpos):m / z=648[M+H] +

[1502] Example 105A

[1503] 1-[1-{4-chloro-4'-[4-(cyclopropanecarbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1504]

[1505] A solution of cyclopropanecarboxylic acid (13 μl, 170 μmol) in DMF (1.5 mL) was treated with HATU (57.8 mg, 152 μmol) and N,N-diisopropylethylamine (53 μl, 300 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 91.0 mg, 152 μmol) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 104 mg (80% purity, 87% yield) of the title compound.

[1506] LC-MS (Method 4): R t =2.80min; MS(ESIpos):m / z=630[M+H] +

[1507] Example 106A

[1508] 1-[1-{4-chloro-4'-[4-(1-fluorocyclopropane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1509]

[1510] A solution of 1-fluorocyclopropane-1-carboxylic acid (17.4 mg, 167 μmol) in DMF (730 μl) was treated with HATU (57.8 mg, 152 μmol) and N,N-diisopropylethylamine (53 μl, 300 μmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 91.0 mg, 152 μmol) was added. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by rapid chromatography (silica gel, cyclohexane / ethyl acetate gradient) to give 24 mg (24% yield) of the title compound.

[1511] LC-MS (Method 4): R t =2.90min; MS(ESIpos):m / z=648[M+H] +

[1512] Example 107A

[1513] 1-[1-{4-chloro-4'-[4-(2-fluorocyclopropane-1-carbonyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (enantiomer 1)

[1514]

[1515] A solution of 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared enantiomer 1, 60.0 mg, 100 μmol) in dichloromethane (1.2 mL) was treated with potassium carbonate (27.7 mg, 201 μmol) and 2-fluorocyclopropane-1-formyl chloride (18.4 mg, 150 μmol) and stirred at room temperature for 1 hour. An additional 2-fluorocyclopropane-1-formyl chloride (18.4 mg, 150 μmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated to give 55.0 mg (85% yield) of the title compound.

[1516] LC-MS (Method 4): R t =2.72min; MS(ESIpos):m / z=648[M+H] +

[1517] Example 108A

[1518] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diasterois mixture 1)

[1519]

[1520] A solution of 2,2-difluorocyclopropane-1-carboxylic acid (56.1 mg, 459 μmol) in DMF (2.0 mL) was treated with HATU (159 mg, 418 μmol) and N,N-diisopropylethylamine (290 μl, 1.7 mmol). Then, 1-{1-[4-chloro-4'-(piperazin-1-yl)[1,1'-biphenyl]-2-yl]piperidin-3-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (similar to Example 12A, prepared as enantiomer 1, 250 mg, 418 μmol) was added, and the resulting mixture was stirred overnight at room temperature. Add 2,2-difluorocyclopropane-1-carboxylic acid (28 mg, 230 μmol), HATU (80 mg, 209 μmol), and N,N-diisopropylethylamine (145 μl, 0.85 mmol), and stir the resulting mixture at room temperature for 4 hours. The reaction mixture was purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient) to give 191 mg (69% yield) of the title compound.

[1521] LC-MS (Method 4): R t =2.80min; MS(ESIpos):m / z=666[M+H] +

[1522] Two diastereomers were separated by preparative chiral HPLC [Sample preparation: 190 mg dissolved in 3 ml methanol + 3 ml acetonitrile + 5 ml tetrahydrofuran; injection volume: 150 μl; column: Daicel Chiralcel OX-H 5 μm, 250 x 20 mm; eluent: n-heptane / ethanol 70:30; flow rate: 17 ml / min; temperature: 40 °C; UV detection: 210 nm]. After separation, 65 mg of diastereomer 1 eluted first (Example 109A) and 66 mg of diastereomer 2 eluted later were obtained (Example 110A).

[1523] Example 109A

[1524] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 1)

[1525] For separation conditions, see Example 108A.

[1526] Analytical chiral HPLC:R t =2.066 min, ee=100% [Column: Daicel Chiralpak OX-3 3μm, 50 x 4.6 mm; Eluent: n-heptane / ethanol 70:30 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 23℃; UV detection: 220 nm].

[1527] LC-MS (Method 4): R t =2.81min; MS(ESIpos):m / z=666[M+H] +

[1528] Example 110A

[1529] 1-[1-(4-chloro-4'-{4-[2,2-difluorocyclopropane-1-carbonyl]piperazin-1-yl}[1,1'-biphenyl]-2-yl)piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (diastereomer 2)

[1530] For separation conditions, see Example 108A.

[1531] Analytical chiral HPLC:R t =3.386 min, ee=100% [Column: Daicel Chiralpak OX-3 3 μm, 50 x 4.6 mm; Eluent: n-heptane / ethanol 70:30 + 0.2% diethylamine; Flow rate: 1.0 ml / min; Temperature: 23℃; UV detection: 220 nm].

[1532] LC-MS (Method 4): R t =2.80mi...

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, C1-C4 alkyl, or halogen. R 5 Groups representing the following formulas Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic group; where m is 0-4 R 6 represent C1-C6-alkyl groups, which are substituted by one or more substituents independently selected from the following: Methoxy, trifluoromethoxy, nitrile, amide C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents. C3-C6-cycloalkyl, C3-C6-cycloalkyl-methyl, optionally substituted with 1 to 5 fluorine substituents or one trifluoromethyl group, C1-C6-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents, C3-C6-cycloalkyl-carbonyl, optionally substituted with 1 to 3 fluorine substituents, or (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy, trifluoromethoxy, or C3-C6- Cycloalkyl substitution, (C3-C6)-cycloalkoxy-carbonyl, Mono-(C1-C4)-alkylaminocarbonyl, (C1-C4)-alkylsulfonyl, or Oxycyclic butyl, Spiro[2.2]pentyl-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl, R 7 Represents C1-C4-alkylcarbonyl and C3-C6-cycloalkyl-carbonyl. R 8 Represents a C2-C4 alkyl group, or a C2-C4 haloalkyl group substituted with 1 to 6 fluorine substituents, where X1 represents nitrogen, carbon, or CF. X2 represents nitrogen or carbon.

2. The compound according to claim 1, or a salt thereof, characterized in that... R 1 Represents hydrogen and fluorine R 2 Represents hydrogen and fluorine R 3 Represents chloro or trifluoromethyl. R 4 Represents hydrogen or methyl R 5 Groups representing the following formulas Where # represents the point connected to the 6-ring system of the aromatic or hybrid aromatic tribes; where m is 0. R 6 represent C1-C4-alkyl, optionally substituted by one or more substituents independently selected from the following: methoxy, trifluoromethoxy, nitrile, amide, C2-C6-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents, or C3-C6-cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group, C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents, C3-C6-cycloalkyl-carbonyl, (C1-C6)-alkoxy-carbonyl, optionally substituted with methoxy or C3-C4-cycloalkyl, (C3-C6)-cycloalkoxy-carbonyl, Mono-methylaminocarbonyl, Methylsulfonyl, R 7 C1-C3-alkyl carbonyl group, optionally substituted with a cyclopropyl group. R 8 Represents C2-C4-haloalkyl groups, which are substituted with 1 to 3 fluorine substituents. X1 represents nitrogen or carbon. X2 represents nitrogen or carbon.

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 Where # represents the point connecting to the 6-ring system of the Aromatic or Hybrid Aromatic tribes. R 6 represent C1-C4 alkyl groups, which are substituted with trifluoromethoxy or nitrile groups. C2-C3-haloalkyl groups, which are substituted with 1 to 5 fluorine substituents. C3-C4 cycloalkyl-methyl, optionally substituted with one or two fluorine substituents or one trifluoromethyl group, C1-C3-alkyl carbonyl group, optionally substituted with 1 to 3 fluorine substituents, (C1-C3)-alkoxy-carbonyl, cyclopropoxy-carbonyl R 7 Represents a C1-C3 alkyl carbonyl group, which may optionally be substituted with a cyclopropyl group. X1 represents carbon. X2 represents carbon.

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 the first step [B], the compound of formula (III) is made Where R 1 R 2 and R 3 As defined in any one of claims 1-3, Compounds of formula (IV) Where R 4 R 5 And X1 and X2 as defined in any one of claims 1-3, And R 9 Represents hydrogen, methyl, or two Rs 9 4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane is formed via adjacent oxygen atoms. The reaction, in the presence of a palladium source, a suitable ligand, and a base, yields a compound of formula (II). Where R 1 R 2 R 3 R 4 R 5 X1 and X2 are defined as in any one of claims 1-3 and In the second step [A], Reacting the compound of formula (II) with a base yields the compound of formula (I). Where R 1 R 2 R 3 R 4 R 5 And X1 and X2 optionally convert the compound of formula (I) into the corresponding salt in a suitable solvent in the presence of a suitable acid, as defined in any one of claims 1-3.

5. Use of the compound or salt thereof according to any one of claims 1 to 3 in the preparation of a medicament for treating and / or preventing diseases.

6. Use of the compound or salt thereof 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) and diabetic kidney disease (DKD), pulmonary hypertension (PH), systemic sclerosis (SSc), sickle cell disease (SCD), neurodegenerative diseases and dementia, and diabetic foot ulcer (DFU).

7. The use according to claim 6, wherein the heart failure is selected from HFrEF, HFmrEF and HFpEF.

8. A pharmaceutical product comprising a combination of the compound or a salt thereof as described in any one of claims 1 to 3 with an inert, non-toxic, pharmaceutically suitable excipient.

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