BRADYKININ B2 RECEPTOR ANTAGONIST COMPOUNDS

Abstract

This document relates to a compound according to the general formula (1), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more compounds of this document; to a combination preparation containing at least one compound of this document and at least one other additional pharmaceutically active ingredient; and to the uses of said compound(s), including use as a medicament.

Description

NOVEL B2 BRADYKININ RECEPTOR ANTAGONISTS Field of invention This invention relates to a compound according to general formula 5 (I), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more compounds of the invention; to a combination preparation containing at least one compound of the invention and at least one other additional pharmaceutically active ingredient; and to the uses of said compound(s), including use as a medicament. Background of the invention BK is a peptide hormone involved in inflammatory processes by activating endothelial cells, which leads to vasodilation, increased vascular permeability, nitric oxide production, and arachidonic acid mobilization. BK also stimulates sensory nerve endings, causing burn-like dysesthesia. Therefore, classic parameters of inflammation (e.g., redness, heat, swelling, and pain) may all result from BK formation. BK is a short-lived component of the kallikrein-kinin system. Circulating BK concentration is maintained at a low level under normal physiological conditions and can increase rapidly in pathological situations through the enzymatic degradation of circulating glycoprotein precursors called kininogens.The two most potent enzymes in kininogen metabolism are the trypsin-like serine proteases, plasma kallikrein and tissue kallikrein. The 25 precursors of these enzymes are normally present in all cells. Pablo Schmukler - 30607243227 Digitally signed by PORTALTRAMITES - INPI Date: 2018.11.23 14:21:24 -03:00 Reason: Digitally Signed by the INPI Location: Buenos Aires, Argentina. The BK β2 receptor is constitutively expressed in most cell and tissue types and mediates most of the known effects of BK when it is produced in plasma or tissues. (Regoli, D. et al. Pharmacol. Rev. 1980, 32, 1-46). A significant number of in vivo studies have shown that agents that block the BK β2 receptor provide therapeutic advantages in pathologies such as asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease, and angioedema. Numerous peptide and non-peptide antagonists of the BK B2 receptor have been described in the previous technique. Quinoline derivatives that have BK2 receptor antagonist activity, for example, are disclosed in documents WO 2014 / 159637, WO 2010 / 031589, WO 2008 / 116620, WO 2006 / 40004, WO 03 / 103671, WO 03 / 87090, WO 00 / 23439, WO 00 / 50418, WO 99 / 64039, WO 97 / 41104, WO 97 / 28153, WO 97 / 07115, WO 96 / 13485, EP 0 795 547, EP 0 796 848, EP 0 867 432, and EP 1 213 289. However, these compounds exhibit numerous deficiencies that diminish their Usefulness as a drug, including low metabolic stability, low bioavailability, glutathione adduct formation and bioactivation (toxicity) as disclosed in WO 2014 / 159637. Given the shortcomings of the compounds in the previous technique and the serious ailments associated with a pathophysiological level of BK, both acute and chronic, there is a need for novel BK B2 receptor antagonists. Summary and description of the invention The present invention was made in view of the prior art and the needs described above, and the objective of the present invention is to provide novel BK B2 receptor antagonists according to the general formula (I), preferably BK B2 receptor antagonists having one or more improved properties, for example, improved pharmacokinetics and / or physicochemical properties, including bioavailability, solubility, metabolic stability, and LADME (liberation, absorption, distribution, metabolism, and excretion) properties.Other objectives of the present invention are to provide a pharmaceutical composition comprising at least one BK2 receptor antagonist as described herein; a combination preparation containing at least one compound of the invention and at least one other additional pharmaceutically active ingredient; and uses of one or more compounds of the invention, including use as a medicament. These objectives are achieved through the subject matter of the attached claims, which will become evident after reference to the following description and definitions. The present invention relates to: [1] a compound of general formula (I): TO AND F (I) or one of its salts, in which A represents a group: ra1 A 2A1^A3 A4 x A3 to A5 A1es N, or CH; A2es N, or C-RA2; A3es N, or C-RA3; A4 is NH, O or S; A5es N-RA5; RA1 represents a hydrogen atom or a methyl group; Each of RA2 and RA3, independently of each other, represents a hydrogen atom, halogen atom, OH, CN, NH2; alkyl (C1-C3), which may be substituted with one or more identical or different groups selected from a halogen atom, OH, =O, and NH2; alkoxy (C1-C3), which may be substituted with one or more identical or different groups selected from a halogen atom, OH, =O, and NH2; alkoxyalkyl (C2C5), which may be substituted with one or more identical or different groups selected from a halogen atom, OH, =O, and NH2; C(O)NRB1RB2; or NRB1R B2. ; RB1, each of RB2 and RA5, independently of each other, represents a hydrogen atom or an alkyl group (C1-C3), which may be substituted with one or more, identical or different, group(s), selected from a halogen atom, OH, =O, and NH2; R1 represents an alkyl (C1-C3) or alkoxyalkyl (C2-C5) group, said alkyl or alkoxyalkyl group may be substituted with one or more, identical or different, group(s) selected from a deuterium atom, halogen atom, OH, =O, and NH2; R2 represents a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, alkyl group (C1-C3), or haloalkyl group (C1-C3); E represents CRE1RE2RE3 or Hce; Hce represents a mono- or bicyclic, partially unsaturated or aromatic heterocycle, having from 3 to 10 C atoms and from 1 to 4 heteroatom(s) each, independently of each other, selected from N, O or S, said heterocycle is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, on each occasion independently, by a halogen atom, OH, G, NRC1RC2y / u =O; Each of RC1 and RC2, independently of each other, represents a hydrogen atom or an alkyl group (C1-C3); G represents an alkyl group (C1-C6), in which 1 to 7 H atoms may, on each occasion independently, be substituted with a halogen atom, ORG1, CN, NRG2RG3 or cycloalkyl (C3-C6), and / or in which a group CH2, or two non-adjacent CH2 groups, may be substituted with O, C(O), OC(O), C(O)O, C(O)NH, NH, S, SO, SO2 and / or by a CH=CH group; Each of RG1, RG2, and RG3, independently of each other, represents a hydrogen atom, alkyl (C1-C4) group, haloalkyl (C1-C4) group, hydroxyalkyl (C1-C4) group, heteroalkyl (C1-C4) group, or cycloalkyl (C3-C6) group; Each of RE1 and RE2, independently of each other, represents a hydrogen atom, halogen atom, or G; or RE1 and RE2 taken together form =O or Cyc; RE3 represents a hydrogen atom, halogen atom, G, OG or OH; and Cyc represents a 3- to 10-membered, saturated or partially unsaturated mono- or bicyclic cycloalkyl group or a 4- to 10-membered heterocycloalkyl group having 1 to 3 heteroatom(s) each, independently of each other, selected from N, O, or S, said cycloalkyl or heterocycloalkyl group being unsubstituted or may be monosubstituted, disubstituted, trisubstituted, or tetrasubstituted, each time independently, by a halogen atom, OH, G, NRC1RC2y / u =O. Compounds are normally described herein using conventional nomenclature or the definitions presented below. For compounds having asymmetric centers, it is understood that, unless otherwise specified, all optical isomers and mixtures thereof are included. Compounds with two or more asymmetric elements may also be presented as mixtures of diastereomers. Furthermore, compounds with carbon-carbon double bonds may occur in Z and E forms, all isomeric forms of the compounds being included in the present invention unless otherwise indicated. When a compound exists in several tautomeric forms, a cited compound is not limited to any specific tautomer but is instead intended to encompass all tautomeric forms. It will be evident that the compound of the invention may, but does not necessarily, be present in the form of a hydrate, solvate, or non-covalent complex.Furthermore, the various crystalline forms and polymorphs are within the scope of the present invention, as are prodrugs of the compound of the invention. It is further intended that the aforementioned compounds encompass compounds in which one or more atoms are substituted with an isotope, that is, an atom having the same atomic number but a different mass number. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11C, 13C, and 14C. Compounds according to the formulas provided herein, having one or more stereogenic centers, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be evident that the individual enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can be carried out, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column. The compound according to the invention is described herein using a general formula that includes variables such as, for example, A, A1-A5, E, R1-R3, RA1-RA5, RB1-RB2, RC1-RC2, RE1-RE3, and RG1-RG3 Unless otherwise specified, each variable included in such a formula is defined independently of any other variable, and any variable appearing more than once in a formula is defined independently in each instance. Thus, for example, if a group is shown to be substituted with 0-2 R*, the group may be unsubstituted, or substituted with 1 or 2 R* groups, where R* in each case is selected independently from the corresponding definition of R*. Also, combinations of substituents and / or variables are only permitted if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized, and tested for biological activity. As used in this document, wording that defines the limits of an interval of length such as, for example, “from 1 to 5” means any integer from 1 to 5, that is, 1, 2, 3, 4, and 5. In other words, any interval defined by two explicitly stated integers is understood to include and disclose any integer defining those limits and any integer contained within that interval. For example, the term C1-C3 refers to 1 to 3, that is, 1, 2, or 3 carbon atoms; and the term C1-C6 refers to 1 to 6, that is, 1, 2, 3, 4, 5, or 6 carbon atoms. Furthermore, the prefix (Cx.(y) as used herein means that the chain, ring or combination of chain and ring structures as a whole, indicated in direct association with the prefix, may consist of a minimum of xy and a maximum of y carbon atoms (i.e. x < y), wherein x and y represent whole numbers that define the limits of the chain length (number of carbon atoms) and / or the ring size (number of carbon atoms in the ring). A pharmacologically acceptable salt of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with human and animal tissues without excessive toxicity or carcinogenicity and, preferably, without irritation, allergic response, or other problems or complications. Such pharmaceutical salts include salts of mineral or organic acids from basic residues such as amines, as well as alkali or organic salts from acidic residues such as acids. Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethanedisulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is any integer from 0 to 4 (i.e., 0, 1, 2, 3 or 4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Those skilled in the art will recognize additional pharmacologically acceptable salts for the compounds provided herein.In general, a pharmacologically acceptable acid or base salt can be synthesized from a precursor compound containing a basic or acid moiety by any conventional chemical method. In short, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both. Generally, the use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is preferred. A substituent, as used herein, refers to a molecular moiety that is covalently bonded to an atom of a molecule of interest. For example, a ring substituent may be a moiety such as a halogen atom, an alkyl, haloalkyl, hydroxy, cyano, or amino group, or any other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a member of the ring. The term "substituted," as used herein, means that any one or more hydrogen atoms on the designated atom or group (e.g., alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heteroaryl) have been substituted with a selection of the indicated substituents, provided that the normal valency of the atom is not exceeded, the number of possible substitution sites is not exceeded, and the substitution results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity. When a substituent is oxo, i.e., =O, then two hydrogens of the atom are substituted. An oxo group that is a substituent on an aromatic carbon atom results in a conversion of -CH- to -C(=O)- and may lead to the loss of aromaticity. For example, a compound substituted with oxo is a pyridone. The terms monosubstituted, disubstituted, trisubstituted, or tetrasubstituted denote groups having one (mono), two (di), three (tri), or four substituents, provided that the substitution does not exceed the number of possible substitution sites and results in a stable compound. For example, a monosubstituted imidazoyl group can be an (imidazolidin-2-one)yl group, and a disubstituted isoxazolyl group can be a ((3,5-dimethyl)isoxazolyl group. As used herein, the terms comprising, including, containing, characterized by, and their grammatical equivalents are inclusive of open terms that do not exclude other elements or stages of additional methods that may have been mentioned. However, comprising, etc., should also be interpreted as including the more restrictive terms consisting essentially of and consisting of, respectively. As used herein, which consists of excluding any element, step, or ingredient not specified in the claims. When trade names are used herein, they are intended to independently include the formulation of the trade name product, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product. In general, unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains, and are consistent with general textbooks and dictionaries. The term alkyl or alkyl group represents a saturated hydrocarbon group with a linear or branched chain containing from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, or the number of carbon atoms indicated by the prefix. If an alkyl group is substituted, the substitution can occur independently of each other by monosubstitution, disubstitution, or trisubstitution of individual carbon atoms in the molecule; for example, 1, 2, 3, 4, 5, 6, or 7 hydrogen atom(s) can, on each occasion independently, be substituted by a selection of the indicated substituents. The above also applies if the alkyl group is part of a group, for example, haloalkyl, hydroxyalkyl, alkylamino, alkoxy, or alkoxyalkyl.Examples of an alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl, or n-octyl, and examples of a substituted alkyl group or a group where the alkyl is part of a group, include haloalkyl, for example a trifluoromethyl or difluoromethyl group; hydroxyalkyl, for example a hydroxymethyl or 2-hydroxyethyl group, and a methoxymethyl group. The term alkyl (C1-6) includes, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2CH(CH3)-, H3C-CH(CH3)-CH2, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3CCH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3CCH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, H3C-CH2CH(CH2CH3)-, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, (H3CH2C)CH(CH2CH2CH3)-, -C(CH3)2(CH2CH2CH3), -CH(CH3)CH(CH3)CH2CH3, and -CH(CH3)CH2CH(CH3)2. The term alkoxy or alkoxy group refers to a single alkyl group bonded to oxygen, that is, -O-alkyl. The term alkoxy(C1-C3) includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tere-butoxy, n-pentyloxy, tere-amyloxy, or n-hexyloxy, and consequently alkoxy(C1C3) includes methoxy, ethoxy, n-propoxy, or isopropoxy. The term alkoxyalkyl or alkoxyalkyl group refers to a single alkyl group bonded to one or more alkoxy groups, for example -alkyl-O-alkyl or alkyl-O-alkyl-O-alkyl. The term alkoxyalkyl (C2-C5) includes, for example, methoxymethyl, methoxyethoxymethyl, and 1-ethoxyethyl. The term haloalkyl or haloalkyl group refers to an alkyl group in which one, two, three, or more hydrogen atoms have been independently substituted by a halogen atom. The term (C-1-C3) haloalkyl includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, dibromomethyl, iodomethyl, (1- or 2-)haloethyl (e.g., (1- or 2-)fluoroethyl or (1- or 2-)chloroethyl), and (2- or 3-)halopropyl (e.g., (2- or 3-)fluoroethyl or (2- or 3-)chloroethyl). The term hydroxyalkyl or hydroxyalkyl group refers to an alkyl group in which one, two, three, or more hydrogen atoms have been independently replaced by a hydroxyl group (OH). The term hydroxyalkyl (C1-C4) includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl. As used herein, the term heteroalkyl or heteroalkyl group refers to an alkyl group, linear or branched as defined above, in which one or more, preferably 1, 2, 3, or 4, carbon atom(s) have been independently substituted by an atom of oxygen, nitrogen, selenium, silicon, or sulfur, preferably by an atom of oxygen, sulfur, or nitrogen, C(O), OC(O), C(O)O, C(O)NH, NH, SO, SO2, or by a CH=CH group, in which such heteroalkyl group may be substituted. For example, a (C1-C4) heteroalkyl group contains from 1 to 4, for example 1, 2, 3, or 4, carbon atoms and 1, 2, 3, or 4, preferably 1, 2, or 3, heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen).Examples of heteroalkyl groups include alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide, alkoxycarbonyloxy, alkylcarbamoyl, alkylamido, alkylcarbamoylalkyl, alkylamidoalkyl, alkylcarbamoyloxyalkyl, alkylureidoalkyl, alkoxy, alkoxyalkyl, or alkylthio. The term alkylthio or alkylthio group refers to an alkyl group in which one or more adjacent CH2 groups are substituted with sulfur, and in which the alkyl moiety of the alkyl group may be substituted.Specific examples of heteroalkyl groups include acyl, methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tere-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, isobutyrylaminomethyl, N-ethyl-N-methylcarbamoyl, N-methylcarbamoyl, cyano, nitrile, isonitrile, thiocyanate, isocyanate, isothiocyanate, and alkylnitrile. The term cycloalkyl or cycloalkyl group refers to a carbocyclic ring group comprising one or more rings (preferably one or two) and containing from 3 to 14 carbon atoms in the ring, preferably from 3 to 10 (more preferably 3, 4, 5, 6, or 7) carbon atoms in the ring. The cycloalkyl group may be substituted and may be attached as a substituent at any suitable position in the ring system. Examples of cycloalkyl include monocyclic hydrocarbon rings, bicyclic hydrocarbon rings, and spirocyclic hydrocarbons. In a bicyclic cycloalkyl group, two rings are linked together so that they share at least two carbon atoms. In a spirocyclic hydrocarbon, two or three rings are linked together by a common carbon atom (spiro atom).If a cycloalkyl group is substituted, the substitution can occur, independently of each other, by monosubstitution or disubstitution of individual carbon atoms in the ring of the molecule, and the cycloalkyl group as a whole can have 1, 2, 3 or 4 substituents from the indicated selection of substituents, i.e. 1, 2, 3 or 4 hydrogen atom(s) of the carbon atoms in the ring can, on each occasion independently, be substituted with a substituent selected from the indicated list of selected substituents, thus resulting in a monosubstituted, disubstituted, trisubstituted or tetrasubstituted cycloalkyl group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl), bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, and spiro[3.3]heptyl. If a cycloalkyl is partially unsaturated, the group contains one, two, or more double bonds, such as, for example, a cycloalkenyl group, including cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, bicyclo[2.2.1]heptadienyl, and spiro[4,5]decenyl. The term heterocycloalkyl or heterocycloalkyl group refers to a cycloalkyl group, saturated or partially unsaturated, as defined above, in which one or more, preferably 1, 2, or 3, carbon atom(s) of the ring have been independently substituted by an oxygen, nitrogen, or sulfur atom, preferably oxygen or nitrogen, or by NO, SO, or SO₂. The heterocycloalkyl may be substituted and may be attached as a substituent at any suitable position in the ring system. At least one carbon atom must be present between two oxygen atoms and between two sulfur atoms or between an oxygen atom and a sulfur atom. The ring as a whole must be chemically stable. A heterocycloalkyl group preferably has 1 or 2 rings containing from 3 to 10 (more preferably 3, 4, 5, 6, or 7, and most preferably 5, 6, or 7) ring atoms.Examples of heterocycloalkyl include: oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, trioxanyl, azepanyl, oxepanyl, tiepanyl, homopiperazinyl, urotropinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, and examples of substituted heterocycloalkyl include lactam, lactone, and cyclic imide ring systems. The terms aryl, Ar, or aryl group refer to an aromatic group containing one or more aromatic rings with 6 to 14 carbon atoms (O6-O14), preferably 6 to 10 (C6-Cw), and most preferably 6 carbon atoms. The aryl group may be substituted and can be attached as a substituent at any suitable position on the ring system. Examples of aryl groups include phenyl, naphthyl, biphenyl, indanyl, indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, and fluorenyl. The term heteroaryl or heteroaryl group refers to an aromatic group containing one or more aromatic rings containing from 5 to 14 atoms in the ring, preferably from 5 to 10 (more preferably 5 or 6) atoms in the ring, and containing one or more (preferably 1, 2, 3 or 4) atoms of oxygen, nitrogen, phosphorus or sulfur in the ring (preferably O, S or N); the heteroaryl may be substituted and may be attached as a substituent in any suitable position of the ring system. Examples of an unsubstituted heteroaryl group include 2-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzoimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidiyl, 2,3'-bifuryl, 3-pyrazolyl, and isoquinolinyl. The term heterocycle represents ring systems, including the heterocycloalkyl and heteroaryl ring systems defined earlier; for example, a partially unsaturated heterocycle is synonymous with a partially unsaturated heterocycloalkyl, and an aromatic heterocycle is synonymous with a heteroaryl. The heterocycle may be substituted and can have a substituent attached at any suitable position on the ring system.Examples of a partially unsaturated or aromatic heterocycle include oxetenyl, thietenyl, azetinyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl, 2,5-dihydro-1H-pyrrolyl, furanyl, thiophenyl, pyrrolyl, benzo[b]furanyl, benzo[b]thiophenyl, indolyl, benzo[c]pyrrolyl, benzo[a]pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, dihydropyridinyl, oxazinyl, pyridinyl, dihydropyranyl, azepinyl, tetrahydropyranyl, dihydrothiopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, and pteridinyl. The general term ring, as used herein unless otherwise defined, includes the cyclic groups defined above in this document, for example a cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, and heterocycle. The term halogen or halogen atom as used herein means fluorine, chlorine, bromine, or iodine. The term heteroatom as used herein preferably represents an atom of oxygen, nitrogen or sulfur, more preferably an atom of oxygen or nitrogen. The term 8-benzyloxyquinoline, as used herein, refers to compounds of general formula (I) provided herein, as well as salts and preferably pharmaceutically acceptable salts thereof. It shall be evident that such compounds may be further substituted as indicated. The present invention preferably relates to one or more of the following: [2] the compound or salt according to [1] above, wherein A represents: [3] the compound or salt according to [1] or [2], wherein A represents: [4] the compound or salt according to any one of [1] to [3], wherein A represents: [5] the compound or salt according to any one of [1] to [4], wherein R1 represents an alkyl (C1-C2) or alkoxyalkyl (C2-C4) group, said alkyl or alkoxyalkyl group may be substituted with one or more, identical or different, group(s) selected from a deuterium atom, halogen atom, and OH; [6] the compound or salt according to any one of [1] to [5], wherein R1 represents a methyl, ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl group, which may be substituted with one or more, identical or different, group(s) selected from a deuterium atom, halogen atom, and OH; [7] the compound or salt according to any one of [1] to [6], wherein R1 represents CH3, C2H5, CD3, C2D5, CH2OH, CH2F, CHF2, CF3, CH2CH2OH, CH2CH2F, CH2CF3, CH2OCH3, CH2OCHF2, or CH2OCF3; [8] the compound or salt according to any one of [1] to [7], wherein R1 represents CH3, C2H5, CD3, or CH2OH; [9] the compound or salt according to any one of [1] to [8], wherein 3 represents a hydrogen atom or a methyl group;

[10] the compound or salt according to any one of [1] to [9], wherein R2 represents a hydrogen atom;

[11] the compound or salt according to any one of [1] to [9], wherein R2 represents a deuterium atom;

[12] the compound or salt according to any one of [1] to

[11] , wherein E is CRE1RE2RE3 and each of RE1, RE2, and RE3 is defined as in [1];

[13] the compound or salt according to any one of [1] to

[12] , in RE1 represents a hydrogen atom, fluorine atom, methyl or ethyl atom;

[14] the compound or salt according to any one of [1] to

[13] , in the RE2 represents a hydrogen atom, fluorine atom, alkyl group (O1-Cs), preferably a (C1-C3) alkyl group, in which 1 to 4 H atoms may, on each occasion independently, be substituted with a fluorine atom, OH, =O, or NRC1RC2; alkoxy group (C1-C6), preferably a (C1-C3) alkoxy group, in which 1 to 4 H atoms may, on each occasion independently, be substituted with a fluorine atom, OH, =O, NRC1RC2 or cyclopropyl; or alkoxyalkyl group (C2-C6), preferably a (C2-C5) or (C2-C4) alkoxyalkyl group, in which 1 to 5 H atoms may, on each occasion independently, be substituted with a fluorine atom, OH, =O, NRC1RC2 or cyclopropyl; and each of RC1 and RC2 is defined as in [1];

[15] the compound or salt according to any one of [1] to

[14] , in RE3 represents a hydrogen atom, fluorine atom, OH, alkyl group (C1Cs), preferably an alkyl group (C1-C3), wherein 1 to 5 H atoms may, on each occasion independently, be substituted with a fluorine atom, OH, =O, or NRC1RC2; alkoxy group (C1-C6), wherein 1 to 5 H atoms may, on each occasion independently, be substituted with a fluorine atom, OH, =O, NRC1RC2 or cyclopropyl; an alkoxyalkyl (C2-C6) group, preferably an alkoxyalkyl (C2-C5) or (C2-C4) group, wherein 1 to 5 H atoms may, on each occasion independently, be substituted with a fluorine, OH, =O, NRC1RC2 or cyclopropyl atom; and each of RC1 and RC2 is defined as in [1];

[16] the compound or salt according to

[12] , wherein RE1 and RE2 are taken together to form =O or Cyc, wherein Cyc is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxethanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,3-dioxolanyl, morpholinyl, azetidinylpyrrolidinyl, piperidinyl, piperazinyl, (imidazolidin-2-on)yl and (oxazolidin-2-on)yl, and is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, each time independently, by a halogen atom, OH, G, NRC1RC2 and / or =O;

[17] the compound or salt according to

[16] , wherein the Cyc is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, on each occasion independently, by a fluorine, OH, (C1-C3) alkyl, (C1-C3) alkoxy, NRC1RC2y / u =O atom; and each of RC1y RC2 is defined as in [1];

[18] the compound or salt according to

[16] or

[17] , wherein Cyc is an oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (imidazolidin-2-on)yl or (oxazolidin-2-on)yl, which is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, in each instance independently, by a fluorine, OH, (C1-C3) alkyl and / or (C1-C3) alkoxy atom;

[19] the compound or salt according to any one of

[16] to

[18] , in RE3 represents a hydrogen atom, fluorine atom, OH or an alkyl group (C1-C3);

[20] the compound or salt according to any one of [1] to

[11] , wherein E represents Hce;

[21] the compound or salt according to

[20] , wherein Hce represents a monocyclic, partially unsaturated or aromatic heterocycle having 3 to 5 C atoms and 1 to 3 N atom(s); 3 to 5 C atoms, 1-2 N atom(s) and 1 O atom; or 3 to 5 C atoms, 1-2 N atom(s) and 1 S atom; said heterocycle is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, in each instance independently, by a halogen, OH, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy and / or =O atom;

[22] the compound or salt according to

[20] or

[21] , wherein E is selected from: N~N N'N NO F3C CF3O'N ONF CF3O'N N'N CF3 NO

[23] the compound or salt according to any one of [1] to

[15] , and of

[20] to

[22] , wherein E represents a group: OH yx^-O h F F F; J

[24] the compound or salt according to any one of [1] to

[23] , wherein the compound is selected from the group: EITHER Cl F F EITHER NH D D3C Cl NH NH / =N D / =N F F Cl F NH O FvF OF F N. > N F F F NH NH F F F F / tn N. > N F ^N N. > N ^N N. > N F DO NHF F DO NHF / =N Compounds that include suitable combinations of preferred embodiments, namely [2] to

[23] , of the compound according to general formula (I) or a salt thereof, are especially preferred; for example, a compound or salt thereof that includes a combination of [1], [3], [6], and [9] as disclosed herein. In other words, the present invention specifically covers all possible combinations of [1] to

[23] as indicated above, resulting in a stable compound. The 8-benzyloxyquinoline BK receptor antagonist B2 antagonist according to any one of [1] to

[24] provided herein exhibits high activity on the human BK receptor B2, e.g. an inhibition constant IC50 (semimax inhibitory concentration) for BK-induced inhibition of BK receptor B2 activity of 1 micromolar (μM) or less, e.g. from 251 nanomolar (nM) to 1 μM; preferably an IC50 of 250 nM or less, e.g. from 51 nM to 250 nM; more preferably an IC50 of 50 nM or less; even more preferably an IC50 of approximately 10 nM or less, or 1 nM or less in the assay mentioned below.8-benzyloxyquinoline antagonists of the BK B2 receptor according to any one of [1] to

[24] may exhibit high activity on the human BK B2 receptor, but also on BK B2 receptors of other non-human species, e.g. rat, mouse, gerbil, guinea pig, rabbit, dog, cat, pig, or macaque. The activity, and more specifically the bioactivity, of the compounds according to the present invention can be evaluated using suitable assays known to those skilled in the art, for example, in vitro or in vivo assays. For example, the inhibitory effect (expressed as an IC50 value) of a compound of the invention on the activity of the B2 receptor can be determined by an intracellular calcium mobilization assay, such as the assay provided in Example 12, which is, therefore, an implementation of a conventional in vitro assay mediated by the B2 receptor. A particularly preferred compound or salt according to any one of [1] to

[24] exhibits an IC50 of 50 nM or less in a conventional in vitro assay of the B2 receptor of BK; for example, the assay provided in Example 12. The therapeutic use of a compound of general formula (I), a pharmaceutically acceptable salt, solvate, or hydrate; and also a pharmaceutical formulation or composition containing the same, are within the scope of the present invention. The present invention also relates to the use of a compound of general formula (I) as an active ingredient in the preparation or manufacture of a medicament. A pharmaceutical composition according to the present invention comprises at least one compound of formula (I) or a pharmacologically acceptable salt thereof, preferably a compound according to any one of [1] to

[24] or a salt thereof, and optionally at least one, i.e., one or more, carrier, excipient, and / or adjuvant. In particular, a pharmaceutical composition of the invention may comprise one or more compound(s) according to the invention, for example, a compound according to any one of [1] to

[24] , and optionally at least one carrier, excipient, and / or adjuvant.The pharmaceutical composition may additionally comprise, for example, one or more of water, buffers (for example, neutral saline or phosphate-buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (for example, glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and / or preservatives. Furthermore, one or more additional active ingredients may be included (although this is not required) in the pharmaceutical composition provided herein. For example, one or more compounds of the invention may be advantageously included in a combination preparation containing at least one additional active pharmaceutical ingredient. The additional or supplementary active pharmaceutical ingredient is preferably an active agent or pharmaceutical ingredient that is useful in the prevention or treatment of one or more ailments responsive to modulation of the B2 receptor of BK, including an ailment selected from the group comprising a skin disorder; eye disease; ear disease; disease of the mouth, throat, and respiratory tract; gastrointestinal disease; liver, gallbladder, and pancreatic disease; urinary tract and kidney disease;Disease of the male and female reproductive organs; disease of the hormonal system; metabolic disease; cardiovascular disease; blood disease; lymphatic disease; disorder of the central nervous system; disorder of the brain; disease of the musculoskeletal system; allergic disorder; pain; infectious disease; inflammatory disorder; injury; immune disorder; cancer; hereditary disease;and edema. For example, at least one pharmaceutically acceptable compound or salt of the invention may be advantageously included in a combination preparation that includes an antibiotic, antifungal, or antiviral agent, an antihistamine, a non-steroidal anti-inflammatory drug, a disease-modifying antirheumatic drug, a cytostatic drug, a drug with smooth muscle activity modulating activity, an antibody, or mixtures thereof as an additional or supplementary active or pharmaceutically active ingredient. The pharmaceutical composition of the invention can be formulated for any suitable route of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal, or parenteral administration. The term "parenteral" as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.Among other additional embodiments, the compositions provided herein may be formulated in lyophilized form. The formulation for topical administration may be preferred for certain conditions (e.g., in the treatment of skin conditions such as burns or pruritus). In summary, the pharmaceutical composition may, for example, be formulated as a spray, cream, gel, pill, capsule, syrup, solution, transdermal patch, or a pharmaceutical agent delivery device. For the prevention and / or treatment of diseases mediated by BK or its analogues, the dosage of the biologically active compound according to the invention can vary widely and can be adjusted to individual requirements. The active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred dosages range from approximately 0.1 mg to approximately 140 mg per kilogram of body weight per day (from approximately 0.5 mg to approximately 7 g per patient per day). The daily dose can be administered as a single dose or in multiple doses. The amount of active ingredient that can be combined with carrier materials to produce an individual pharmaceutical formulation will vary depending on the host being treated and the specific mode of administration.Unit dosage forms will generally contain from approximately 1 mg to approximately 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend on several factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, timing of administration, route of administration, and rate of excretion, drug combination (i.e., other drugs to be used to treat the patient), and the severity of the specific disease to be treated. The 8-benzyloxyquinolines provided herein can also be used as BK B2 receptor antagonists in various applications, both in vitro and in vivo. The BK B2 receptor antagonists according to the present invention can be used to inhibit the binding of BK B2 receptor ligands (e.g., BK) to the BK B2 receptor in vitro or in vivo. This use includes, for example, a method for inhibiting the binding of BK to the BK B2 receptor in vitro or in vivo, wherein the method comprises contacting the BK B2 receptor with at least one compound or salt according to the invention, e.g., according to any one of [1] to

[39] , under conditions and in a quantity sufficient to detectably inhibit the binding of BK or any other substance to the BK B2 receptor.The BK B2 receptor antagonists provided herein are preferably administered to a patient (e.g., a human) orally or topically, and are present within at least one of the patient's body fluids or tissues while modulating BK B2 receptor activity. BK2 receptor antagonists according to any one of [1] to

[24] , the pharmaceutical composition, or the combination preparation according to the present invention are useful as a medicament. In particular, the BK2 receptor antagonists, the pharmaceutical composition, or the combination preparation according to the present invention are useful in the treatment and / or prophylaxis of a disease or ailment that is responsive to modulation of the BK2 receptor.The ailment or disorder that is sensitive to modulation of the B2 receptor of BK may be a skin disorder; eye disease; ear disease; disease of the mouth, throat, and respiratory tract; gastrointestinal disease; liver, gallbladder, and pancreatic disease; urinary tract and kidney disease; disease of the male and female reproductive organs; disease of the hormonal system; metabolic disease; cardiovascular disease; blood disease; lymphatic disease; disorder of the central nervous system; brain disorder; disease of the musculoskeletal system; allergic disorder; pain; infectious disease; inflammatory disorder; injury; immune disorder; cancer; hereditary disease; edema; or capillary leak syndrome(s).The diseases and ailments indicated above that are sensitive to modulation of the BK B2 receptor are further specified below. Skin disorders: In this application, the term “skin disorders” includes, but is not limited to, disorders such as skin aging, skin efflorescence including pressure ulcers, bedsores, irritated, sensitive and diasthetic skin, erythema, rash, skin edema, psoriasis, eczema, lichens, skin infections induced by bacteria, viruses, fungi and parasites including boils, abscesses, phlegmons, erysipelas, folliculitis and impetigo, lice, scabies and herpes simplex, acne, exanthema, dermatitis including atopic dermatitis, allergic contact dermatitis (Scholzen, TE; Luger, TA Exp Dermatol. 2004; 13 Suppl 4:22-6), neurodermatitis, radiation damage, sunburn, pruritus, itching, urticaria (EP document) 0622361; Frigas, E.; Park, M. Immunol. Allergy Clin. North Am. 2006, 26, 739-51; Luquin, E.; Kaplan, A.P.; Ferrer, M. Clin. Exp. Allergy 2005, 35, 456-60; Kaplan, A.P.; Greaves, MWJ Am. Acad.Dermatol. 2005, 53, 373-88; quiz 389-92), psoriasis, mycosis, tissue ulceration, epidermolysis bullosa, wounds including abnormal wound healing, burns (Nwariaku, FE; Sikes, PJ; Lightfoot, E.; Mileski, WJ; Baxter, C. Burns 1996, 22, 324-7; Neely, AN; Imwalle, AR; Holder, IA Burns 1996,. 22, 520-3), frostbite, skin inflammation and edema caused by poisons, alopecia, dandruff, calluses, warts and panaris. Eye diseases: In this application, the term “eye diseases” includes, but is not limited to, inflammatory disorders such as scleritis, conjunctivitis, chemosis, iritis, iridocyclitis, uveitis, chorioretinitis, as well as disorders such as retinochoroidal circulatory disorders, bacterial infections of the eye, nonspecific conjunctivitis and eye irritations, retinopathy of prematurity, proliferative vitroretinopathy, macular degeneration (including age-related macular degeneration, including both wet and dry forms), diseases of the cornea including corneal graft rejection, corneal injury, corneal scarring, corneal ulceration, corneal clouding, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, ocular hypertension, ocular vessel damage, angiogenesis, ocular fibrosis (e.g., fibrosis of the anterior subcapsule, opacities of the posterior subcapsule,posterior capsule opacities, corneal clouding after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitroretinopathy (PVR), bacterial eye infections including hordeolum and ptilosis. Ear diseases: In this application, the expression “ear diseases” includes, but is not limited to, disorders such as Meniere's disease, inflammation of the middle ear, inflammation of the external auditory canal, and acute hearing loss. Diseases of the mouth, throat and respiratory tract: In the present application, the expression “diseases of the mouth, throat and respiratory tract” includes, but is not limited to, disorders such as inflammation of the oral mucosa and gums, including aphthous ulcers and stomatitis, periodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, the common cold, tonsillitis, rhinitis, including seasonal allergic rhinitis or chronic allergic rhinitis, rhinorrhea, sinusitis of any type, etiology or pathogenesis, or sinusitis that is a selected element of the group consisting of purulent or non-purulent sinusitis, acute and chronic sinusitis, and ethmoid, frontal, maxillary, sphenoid sinusitis, expectoration, pneumoconiosis of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, siderosis, silicosis, tabacosis and, in particular, byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, pulmonary eosinophilic infiltrates,chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other lung diseases, treatment related to fibrotic lung disease, for example, radiation-related, methotrexate, chemotherapy, amiodarone or nitrofurantoin, sarcoidosis, acute respiratory stress syndrome (ARDS), bronchoconstriction, asthma of any type (Akbary, AM; Wirth, KJ; Scholkens, BA Immunopharmacology 1996, 33, 238-42; document WO 00 / 75107 A2), etiology, or pathogenesis, or asthma that is a selected element from the group of atopic asthma, non-atopic asthma, allergic and non-allergic asthma, extrinsic asthma produced by environmental factors, intrinsic asthma produced by pathophysiological disturbances, bronchial asthma, IgE-mediated asthma, essential asthma and essential asthma of unknown or non-evident cause, asthma true asthma, emphysemic asthma, exercise-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infections,Incipient asthma, wheezing syndrome in infants, bronchial hyperreactivity, chronic obstructive pulmonary disease (COPD), COPD characterized by progressive irreversible airway obstruction, acute respiratory distress syndrome (ARDS), and worsening of airway hyperreactivity following other drug treatments, dyspnea, hyperoxic alveolar injury, pulmonary emphysema, pleurisy, tuberculosis, exposure to high altitude, i.e., acute mountain sickness and preferably high altitude pulmonary edema (HAPE), persistent cough, bronchial hyporeactivity. Gastrointestinal diseases: In the present application, the term “gastrointestinal diseases” includes, but is not limited to, disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcers, ileus, irritable bowel syndrome, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastropathy and colopathy, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding due to portal hypertension, collateral circulation or hyperemia, rapid gastric emptying syndrome following gastrectomy, digestive problems, diarrhea, hemorrhoids, dracunculiasis, abdominal colic and colic of parts of the gastrointestinal system. Liver, gallbladder and pancreatic diseases (Cugno, M.; Salerno, F.; Nussberger, J.; Bottasso, B.; Lorenzano, E.; Agostoni, A. Clin. Sci. (Lond) 2001, 101, 651-7; document WO 01 / 56995 A1; document EP 0797997 B1; Wirth, KJ; Bickel, M.; Hropot, M.; Gunzler, V.; Heitsch, H.; Ruppert, D.; Scholkens, BA Eur. J. Pharmacol. 1997, 337, 45-53): In the present application, the expression “liver and gallbladder diseases” includes, but is not limited to, disorders such as hepatitis, cirrhosis of the liver, hepatic fibrosis (e.g., due to viral infections (HBV / HCV), toxins (alcohol), hepatic lipidosis, biliary stasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatogenic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic. Diseases of the urinary tract and kidney: In this application, the expression “diseases of the urinary tract and kidney” includes, but is not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis (Campbell, DJ Clin. Exp. Pharmacol. Physiol. 2001, 28, 1060-5; Meini, S.; Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, D.; Maggi, CA; Lecci, A. Eur. J. Pharmacol. 2000, 388, 177-82; Zuraw, BL; Sugimoto, S.; Parsons, CL; Hugli, T.; Lotz, M.; Koziol, JJ Urol. 1994, 152, 874-8; Rosamilia, A.; Clements, JA; Dwyer, PL; Kende, M.; Campbell, DJJ Urol. 1999, 162, 129-34), irritable bladder, overactive bladder (document WO 2007003411 A2), incontinence including, but not limited to, stress, urge and reflex incontinence, benign prostatic hyperplasia (Srinivasan, D.; Kosaka, AH; Daniels, DV; Ford, AP; Bhattacharya, A. Eur J Pharmacol.2004, 504(3):155-67), chronic kidney disease, urethritis, inflammatory kidney diseases including glomerulonephritis, glomerular kidney disease, interstitial nephritis, pyelonephritis, diuresis, proteinuria, natriuresis, calciuresis, water balance disorders, electrolyte balance disorders, acid-base balance disorders and renal colic, renal fibrosis, chronic renal allograft dysfunction, contrast-induced nephropathy. Diseases of the male and female reproductive organs: In the present application, the expression “diseases of the male and female reproductive organs” includes, but is not limited to, impaired sperm motility, male infertility, orchitis, prostatitis, enlarged prostate, mastitis, pelvic inflammatory disease, vaginal infections and pain, adnexitis, colpitis, soft ulcer, syphilis, gonorrhea, and ovarian hyperstimulation syndrome (Ujioka, T.; Matsuura, K.; Tanaka, N.; Okamura, H. Hum Reprod. 1998 Nov;13(11):3009-15.). Hormonal system diseases: In this application, the expression “hormonal system diseases” includes, but is not limited to, menstrual disorders and pain, climacteric disturbances, vomiting, premature uterine contractions, premature birth, endometriosis, endometritis, fibroids, preeclampsia. Metabolic diseases: In this application, the term “metabolic diseases” includes, but is not limited to, disorders such as diabetes, including non-insulin-dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema (Speicher, MA; Danis, RP; Criswell, M.; Pratt, L. Expert Opin. Emerg. Drugs 2003, 8, 239-50; Gao, BB; Clermont, A.; Rook, S.; Fonda, SJ; Srinivasan, VJ; Wojtkowski, M.; Fujimoto, JG; Avery, RL; Arrigg, PG; Bursell, SE; Aiello, LP; Feener, EP Nat. Med. 2007, 13, 181-8; Tranos, PG; Wickremasinghe, SS; Stangos, NT; Topouzis, F.; Tsinopoulos, I.; Pavesio, CE Surv. Oftalmol 2004, 49, 470-90), diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulceration, diseases of protein and purine metabolism such as gout and lipometabolism disorder, hypoglycemia. Cardiovascular diseases: In the present application, the expression “cardiovascular diseases” encompasses, but is not limited to, disorders including vascular permeability, vasodilation, peripheral circulation disorders, arterial circulation disorders including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm, hypertension and hypotension associated with sepsis, restenosis following percutaneous transluminal coronary angioplasty, atherosclerosis including rupture of sclerotic plaque (Fernando, AN; Fernando, LP; Fukuda, Y.; Kaplan, AP Am J Physiol Heart Circ Physiol.2005 Jul;289(1):H251-7) hemangioma, angiofibroma, venous disorders such as thrombosis, varicosities, phlebitis, thrombophlebitis, phlebothrombosis, heart disease, congestive heart failure, coronary heart disease, carcinoid syndrome, angina pectoris, cardiac dysrhythmias, inflammatory diseases of the heart including endocarditis, pericarditis and constrictive pericarditis, myocarditis, myocardial infarction, post-myocardial infarction syndrome, left ventricular dilation, post-ischemic reperfusion injury, shock and collapse, including septic, allergic, post-traumatic and hemodynamic shock, amniotic fluid embolism (Robillard, J.; Gauvin, F.; Molinaro, G.; Leduc, L.; Adam, A.; Rivard, GE Am J Obstet Gynecol. 2005 Oct;193(4):1508-12.), systemic inflammatory response syndrome (SIRS) including SIRS produced by cardiopulmonary bypass during surgery, sepsis and internal and external complications during cardiopulmonary bypass surgery (including but not limited to adverse hemodynamic effects following reversal of heparin as protamine sulfate (Pretorius, M.; Scholl, FG; McFarlane, JA; Murphey, LJ; Brown, NJ, Clin Pharmacol Ther. 2005 Nov;78(5):477-85). Blood diseases: In the present application, the expression “blood diseases” includes, but is not limited to, disorders such as coagulation, disseminated intravascular coagulopathy, hemorrhage, hemorrhagic diathesis, hypercholesterolemia and hyperlipidemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria. Lymphatic diseases: In this application, the term lymphatic diseases as used herein includes, but is not limited to, splenomegaly, lymphangitis, lymphadenitis, and hyperplastic adenoid glands. Central nervous system disorders: In the present application, the expression “central nervous system disorders” includes, but is not limited to, disorders such as inflammatory diseases of the central nervous system including encephalitis, meningitis, encephalomyelitis, meningoencephalitis, hydrocephalus, amyotrophic lateral sclerosis, spinal cord injury, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neurodegenerative disorders including aging, Alzheimer's disease and Parkinson's disease, neuritis, and peripheral neuropathy, depression, anorexia, anxiety and schizophrenia, sleep disorders. Brain Disorders: In this application, the term “brain disorders” includes, but is not limited to, disorders including nootropic or cognitive potentiation, cerebral amyloid angiopathy, stroke, head and brain injury, traumatic brain injury (Marmarou, A.; Guy, M.; Murphey, L.; Roy, F.; Layani, L.; Combal, JP; Marquer, C.; American Brain Injury Consortium J Neurotrauma 2005 Dec;22(12):1444-55), brain tumor, cerebral heat injury, cerebral ischemia, cerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, generalized cerebral edema, acute mountain sickness and preferably high altitude edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, post-surgical cerebral edema, cerebral edema associated with metabolic diseases, increased blood-brain barrier permeability blood-brain tumor. Musculoskeletal System Diseases: In this application, the term “musculoskeletal system diseases” includes, but is not limited to, disorders such as inflammatory musculoskeletal disorders, arthrosis, osteoarthritis, chondroporosis following trauma to the joints or relatively prolonged immobilization of a joint following meniscus or patellar injuries or ligament sprains, rheumatoid arthritis of any type, etiology, or pathogenesis, including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, vertebral arthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, Sjogren's syndrome, lumbago, spondylitis, ankylosing spondylitis, osteomyelitis, strains, tenosynovitis, inflammation-induced bone resorption, fracture or the like, osteoporosis,Musculoskeletal pain and stiffness, dorsal disc syndrome. Allergy disorders: In this application, the term “allergy disorders” includes, but is not limited to, disorders such as general allergic reactions, food allergy, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or chronic allergic rhinitis (Summers, CW; Pumphrey, RS; Woods, CN; McDowell, G.; Pemberton, PW; Arkwright, PD J Allergy Clin Immunol. 2008, 121(3), 632-638) Pain: In the present application, the term pain includes, but is not limited to, centrally and peripherally mediated pain, vascular pain, visceral pain, inflammation-mediated pain, neuralgic pain, referred pain, nociceptive pain, reflectory pain, psychosomatic pain, acute pain such as that caused by acute injury, trauma or surgery of bones, muscle, tissue, soft tissues, organs, pain after insect bites, post-stroke pain syndrome, post-surgical pain, progressive disease-related pain, chronic pain such as that caused by neuropathic pain disorders (including, but not limited to, complex regional pain syndrome (document WO 00 / 75107 A2; Yamaguchi-Sase, S.; Hayashi, I.; Okamoto, H.; Nara, Y.; Matsuzaki, S.; Hoka, S.; Majima, M. Inflamm. Res. 2003, 52, 164-9; Petersen, M.; Eckert, AS; Second von Banchet, G.; Heppelmann, B.; Klusch, A.; Kniffki, KD Neuroscience 1998, 83, 949-59; Birklein, F.; Schmelz, M.; Schifter, S.; Weber, M. Neurology 2001, 57, 2179-84; Weber, M.; Birklein, F.; Neundorfer, B.; Schmelz, M. Pain 2001, 91, 251-7), causalgia, algodystrophy, dystrophy simpática refleja), diabetic peripheral neuropathy, posherpétic neuralgia, trigéminal neuralgia, pain related to cancer, pain associated with rheumatoid arthritis, artrosis (Bond, AP; Lemon, M.; Dieppe, PA; Bhoola, KD Immunopharmacology 1997, 121-5; 1-5; Kaneyama, K.; Segami, N.; Sato, J.; Fujimura, K.; Nagao, T.; Yoshimura, H. J. Oral. Maxillofac. Surg. 2007, 65, 2427), tenosynovitis, gota, menstruation and angina, fibromyalgia, ocular pain, shoulder pain, head pain, headaches, migraine (Ebersberger, A.; Ringkamp, ​​M.; Reeh, PW; Handwerker, HO J Neurophysiol. 1997 Jun;77(6):3122-33.), inflammatory pain, which may be associated with acute or chronic inflammation. Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, arthritis-induced pain, muscle pain induced by acute or chronic inflammation, neuralgia caused by acute or chronic inflammation, and hyperalgesia. It also includes chemotherapy-induced peripheral neuropathy, opioid-induced hyperalgesia, and opioid-induced hyperalgesia and fever. Furthermore, the compounds of the invention are useful as analgesic agents for use during general and monitored anesthesia. Infectious Diseases: In this application, the term “infectious diseases” includes, but is not limited to, diseases mediated by bacteria, viruses, fungi, parasites, protozoa, prions, or mycobacterial infections. In particular, the present invention is useful for the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus, and Yersinia. Examples of bacterial infections intended to be included within the scope of the present invention include, but are not limited to, diseases such as plague, septicemia, epidemic typhus, food poisoning, tetanus, scarlet fever, pertussis, and diphtheria.Examples of viral infections intended to be included within the scope of the present invention include, but are not limited to, diseases such as fowlpox and herpes zoster, AIDS, influenza, chickenpox, and childhood diseases such as measles, rubella, mumps, and acute anterior poliomyelitis. The present invention is useful for the treatment of protozoan and parasitic infections caused by Schistosoma mansoni, Dermatophagoides farinae, and malaria-inducing Plasmodium. Examples of prion infections intended to be included within the scope of the present invention include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease and kuru, dengue fever, and hemorrhagic fever. Inflammatory disorders: In this application, the term “inflammatory disorders” includes, but is not limited to, disorders such as acute phase reaction, local and systemic inflammation, and inflammation caused by other diseases of any type, etiology or pathogenesis and caused by those inflammatory diseases specified in this application. Injuries: In this application, the term injuries includes, but is not limited to, multiple trauma, head trauma, lung injuries, external, internal, and surgical wounds. Immune disorders: In this application, the term “immune disorders” includes, but is not limited to, disorders such as hyperesthesia, autoimmune disorders, graft rejection during transplantation, transplant toxicity, granulomatous inflammation / tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, antibody overproduction and deficiency, vasculitis, delayed graft function, and lupus. Cancers: In this application, the term cancers includes, but is not limited to, disorders such as solid cancerous tumors including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, cancer of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and bile ducts, pancreas, larynx, lung, bone, osteosarcoma, connective tissue, skin cancer including Kaposi's syndrome, melanoma and cutaneous metastases, squamous cell carcinoma, basal cell carcinoma, cervix, endometrium, ovarian cancer, testes, bladder, ureter and urethra, kidney, eye, brain and central nervous system, pseudotumor cerebri, sarcoma, sarcoid, thyroid and other endocrine glands (including, but not limited to, carcinoid tumors), Hodgkin's disease, non-cellular lymphomas Hodgkin, multiple myeloma,Malignant hematopoietic neoplasms including leukemias and lymphomas including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis. Hereditary diseases: In this application, the expression “hereditary diseases” includes, but is not limited to, disorders such as hereditary angioedema (Davis, AE et al., 3rd Transfus. Apher. Sci. 2003, 29, 195-203; Zuraw, BL Immunol. Allergy Clin. North Am. 2006, 26, 691-708; Bas, M. et al. Allergy 2006, 61, 1490-2) and angioneurotic edema, chondrocalcinosis, Huntington's disease, and cystic fibrosis. Edema: In the present application, the term edema includes, but is not limited to, general edema and edema resulting from inflammation, edema induced by Factor XII deficiency, other drugs, for example, drug-induced angioedema, including, but not limited to, angioedema induced by an angiotensin-converting enzyme inhibitor (Mathelier-Fusade, P. Clin. Rev. Allergy Immunol. 2006, 30, 19-23; Finley, CJ et al. Am. J. Emerg. Med. 1992, 10, 550-2; Bielory, L. et al. Allergy Proc. 1992, 13, 85-7), infection, burns, injuries, trauma, frostbite, surgery, sprains, fractures, exposure to high altitude (for example, high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), inherited autoimmune diseases, and other diseases and disorders, especially but not limited to, such disorders specified in this application, stress-induced edema (significant swelling) of the bowel. Capillary leak syndrome(s): In this application, the term “capillary leak syndrome(s)” includes, but is not limited to, capillary leak syndrome during sepsis (Marx, G. Eur J Anaesthesiol. 2003 20(6):429-42; Traber, DL Crit Care Med. 2000, 28(3):8823), burns (Jonkam, CC; Enkhbaatar, P.; Nakano, Y.; Boehm, T.; Wang, J.; Nussberger, J. Esechie, A.; Traber, LD; Herndon, D.; Traber, DL Shock. 2007 Dec;28(6):704-9), allergy, drug / toxin-induced illnesses, organ transplantation, or IL-2 cytokine therapy. The compound according to the present invention can also be used in or for the manufacture of a diagnostic agent. This diagnostic agent is particularly useful in diagnosing the diseases and ailments disclosed herein, which can be addressed by the compound of the present invention, for therapeutic or prophylactic purposes. The compound according to the present invention is also useful in specific methodologies and diagnostics as disclosed later herein. Methodology and diagnosis: The compounds of the invention can be labeled with isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label such as nanobodies, aptamers, peptides, etc., enzymes, or enzyme substrates. These labeled compounds of the present invention are useful for mapping the location of bradykinin receptors in vivo, ex vivo, in vitro, and in situ (e.g., in tissue sections by autoradiography) and with radiotracers for imaging by positron emission tomography (PET), single-photon emission computed tomography (SPECT), and similar techniques to characterize said receptors in living subjects or other materials. The present invention also relates to methods for altering the signal transduction activity of bradykinin receptors in vitro and in vivo. For example, the compounds of the present invention and their labeled derivatives can be used as standards and reagents to determine the ability of a potential pharmaceutically active substance to bind to the BK2 receptor. The present invention also provides methods for locating or detecting a BK B2 receptor in a tissue, preferably a tissue section. These methods involve contacting the tissue sample containing the BK B2 receptor with a detectably labeled compound according to the present invention under conditions that allow the compound to bind to the BK B2 receptor and for the bound compound to be detected. These methods and their respective conditions are known to the art and include, for example, the binding assay described in Example 12.The present invention also provides a method for treating a patient suffering from an ailment or disease responsive to modulation of the BK2 receptor as previously mentioned. The method for treating a subject requiring such treatment comprises administering a compound according to the invention, for example, according to any of [1] to

[24] , a pharmaceutically acceptable salt thereof, a pharmaceutical composition as disclosed herein, or a combination preparation as disclosed herein.As used herein, the term treatment encompasses both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, to reduce the severity and / or duration of symptoms). A condition is sensitive to modulation of a BK2 receptor if modulation of BK2 receptor activity results in relief of the condition or a symptom thereof. Patients may include, but are not limited to, primates (especially humans), domesticated companion animals (such as dogs, cats, and horses), and livestock (such as cattle, pigs, and sheep), with dosages as described herein. The compounds of general formula (I) according to the present invention have improved properties when compared to known prior art BK2 receptor agonists, in particular, one or more improved pharmacokinetic and / or physicochemical properties, including, for example, bioavailability, metabolic stability, improved activity / selectivity, low toxicity, and low drug interactions. Accordingly, the compound (or pharmaceutically acceptable salt thereof), pharmaceutical composition, or combination preparation disclosed herein may be used as a medicament. For example, the compound (or pharmaceutically acceptable salt thereof), pharmaceutical composition, or combination preparation disclosed herein may be used in the treatment and / or prevention of a condition responsive to modulation of the BK2 receptor, including, for example, the conditions listed above. The present invention is further illustrated by the following examples, from which other features, embodiments, and advantages of the present invention may be derived. However, the invention shall not be considered limited to the examples, but shall encompass the subject matter defined in the claims. EXAMPLES The abbreviations used in the following examples are as follows: ACN is acetonitrile BuLi is n-butyllithium concentration. DCM is dichloromethane DIPEA is ethyl-diisopropyl-amine DMF is dimethylformamide EA is ethyl acetate HPLC is high-performance liquid chromatography MeOH is methanol NBS is N-bromosuccinimide NMP is N-methylpyrrolidone PyAOP is 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate PyBOP is (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TA is ambient temperature THF is tetrahydrofuran TLC is thin layer chromatography TFA is trifluoroacetic acid sat. The following examples provide specific examples for the preparation of compounds of formula (I). Unless otherwise specified, all starting materials and reagents are of standard commercial quality and were used without further purification or could be readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that the starting materials and reaction conditions may be varied to produce the compounds covered by the present invention. Example 1: Preparation of Compound No. 1 F R)- N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin49 8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide Step A. Synthesis of methyl 3-amino-5-fluoro-2-methylbenzoate Methyl 5-Fluoro-2-methyl-3-nitrobenzoate [Gillmore, AT et al. Org. Process Res. Dev. 2012, 16, 1897-1904] (4.69 g, 22 mmol) was dissolved in MeOH (100 mL) was added, and palladium over 10% Pd activated carbon (200 mg) was added. The solution was washed thoroughly and purged three times with nitrogen before being washed thoroughly with hydrogen. The reaction mixture was stirred vigorously under 1 atm of hydrogen. After the reaction was complete as indicated by TLC (21 h), the solution was filtered over silica gel. The filter cake was washed with methanol (5 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by ultrafast chromatography to yield the title compound. MS (m / z): 184.0 [M+H+]. Step B. Synthesis of methyl 3-chloro-5-fluoro-2-methylbenzoate NaNO2 (1.68 g, 24.4 mmol) was added to a solution of methyl 3-amino-5-fluoro-2-methylbenzoate (4.00 g, 18.8 mmol) in a semi-concentrated aqueous HCl solution (400 mL) at 0 °C. After stirring for 5 min at 0 °C, CuCl (3.72 g, 37.5 mmol) was added to the reaction mixture. After stirring for 2 h at 0 °C, the reaction mixture was extracted with DCM (2 x 100 mL). The combined organic layers were washed with a concentrated aqueous NaHCO3 solution (1 x), dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with DCM / heptane) to give the title compound. Step C. Synthesis of methyl 2-(bromomethyl)-3-chloro-5-fluorobenzoate Benzoyl peroxide (26 mg, 0.11 mmol) and N-bromosuccinimide (210 mg, 1.18 mmol) were added to a stirred solution of methyl 3-chloro-5-fluoro-2-methylbenzoate (200 mg, 0.99 mmol) in benzene (7.0 mL). After stirring under reflux for 1.5 h, the reaction mixture was diluted with EA (20 mL) and washed with a 10% aqueous solution of Na₂S₂O₃ (1 x 5 mL). The organic layer was dried with Na₂SO₄, filtered, and concentrated under vacuum to yield the title compound. Step D. Synthesis of methyl 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoate Cs₂CO₃ (617 mg, 3.20 mmol) was added to a stirred solution of 2-(bromomethyl)-3-chloro-5-fluorobenzoate (300 mg, 1.07 mmol) and 4-methoxyphenol (172 mg, 1.39 mmol) in ACN (7.0 mL). After stirring overnight at room temperature, the reaction mixture was filtered and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 342.1 [M+NH₄⁺]. Step E. Synthesis of 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoic acid A solution of LiOH (2.37 g, 57 mmol) in water (50 mL) was added to a stirred solution of methyl 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoate (9.16 g, 28 mmol) in dioxane (100 mL) at 0 °C. After stirring for 2 h at room temperature, the reaction mixture was concentrated under vacuum, and the pH was adjusted to 1–2 by adding a concentrated aqueous solution of HCl. The mixture was extracted with DCM (3 x 100 mL), the combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum to yield the title compound. Step F. Synthesis of 1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone A methyllithium solution (1.6 M, 30.2 mL) in diethyl ether was added dropwise to a solution of 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoic acid (5.00 g, 16 mmol) in anhydrous diethyl ether (110 mL) at 0 °C. After stirring for 30 min at 0 °C, the reaction was stopped by adding a saturated aqueous solution of NH₄Cl (15 mL) at 0 °C. The reaction mixture was diluted with water (15 mL), the organic layer was separated, and the aqueous layer was extracted with diethyl ether (3 x 50 mL). The combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. Step G. Synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide Titanium(IV) ethoxide (2.53 mL, 12.05 mmol) was added dropwise under an argon atmosphere to a solution of 1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone (1.24 g, 4.02 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (535.5 mg, 4.42 mmol) in anhydrous THF (10 mL). The mixture was heated under reflux until complete conversion (TLC). The mixture was then cooled to 0 °C, and L-Selectride (1 M solution, 12.05 mL, 12.05 mmol) was added dropwise. The mixture was stirred at this temperature until complete conversion (TLC). Methanol (~10 mL) was then added until gas evolution ceased. The solution was poured into a saturated aqueous solution of NaCl (30 mL). The mixture was then filtered over a layer of Celite and carefully clarified with DCM. The filtrate was washed with a saturated aqueous solution of NaCl. The aqueous layer was extracted with DCM. The combined organic layers were dried with Na₂SO₄, filtered, and evaporated to dryness.The remaining residue was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to give the title compound. MS (m / z): 458.2 [M+HCO2-]. Step H. Synthesis of (S )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine A solution of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.19 g, 5.29 mmol) in 3 M methanolic HCl (3.53 mL, 10.6 mmol) was stirred at room temperature until complete conversion (TLC). The solution was concentrated under vacuum. The remaining residue was dissolved in DCM (5 mL) and washed with a saturated aqueous solution of NaHCO3 (6 mL) and water (6 mL). The organic layer was dried with Na2SO4, filtered, and concentrated under vacuum to obtain the title compound. MS (m / z): 354.4 [M+HCO2-]. L-Stage Synthesis of (S )-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3-dione Phthalic anhydride (862 mg, 5.82 mmol) was added to a solution of (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (1.64 g, 5.26 mmol) in DCM (20 mL). The mixture was stirred for 15 min and then concentrated under vacuum. The remaining residue was heated for approximately 10 min at 175 °C in an open container. After 45 min at this temperature, the reaction mixture was cooled to room temperature and purified by ultrafast silica gel chromatography (heptane / EA elution) to give the title compound. MS (m / z): 484.3 [M+HCO2-]. Step J Synthesis of (S )-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione A solution of cerium(IV) ammonium nitrate (3.36 g, 6.12 mmol) in H₂O (4 mL) was added to a stirred solution of (S)-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3-dione (1.07 g, 2.45 mmol) in ACN (20 mL) at 0 °C. After stirring for 5 h at 0 °C, the reaction was stopped by the addition of brine (20 mL) and H₂O (5 mL). The mixture was extracted with EA (3 x 100 mL), the combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. Step K. Synthesis of (S )-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione SOCl2 (288 mL, 3.96 mmol) and water (4 mL) were added to a stirred solution of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione (662 mg, 1.98 mmol) in DCM (10 mL) at room temperature. The solution was stirred until complete conversion (TLC). The solvent was then removed under vacuum, and the residue was purified by ultrafast silica gel chromatography (EA / heptane elution) to give the title compound. MS (m / z): 396.1 [M+HCO2-]. Step L. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione Cs2CO3 (1.94 g, 5.95 mmol) was added to a stirred solution of (S)-2-(1(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione (698 mg, 1.98 mmol) and 4-(4-fluoro-1 H-pyrazol-1-yl)-2-methylquinolin-8-ol (482 mg, 1.98 mmol) in ACN (20 ml). After shaking overnight at room temperature, the reaction mixture was filtered and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 559.3 [M+H+]. Step M. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1-yl)2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine Hydrazine hydrate (371 ml) was added to a solution of (S)-2-(1-(3-chloro5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione (1.07 g, 1.91 mmol) in EtOH (30 ml). After stirring for 2 h at 85 °C, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum, and the residue was purified by ultrafast chromatography (elution with DCM / MeOH / concentrated aqueous NH3 solution) to produce the title compound. MS (m / z): 429.4 [M+H+]. Step N. Synthesis of (R)- N -((S )-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide PyAOP (90.7 mg, 174 pmol) and DIPEA (29.4 mg, 227 pmol) were successively added to a stirred solution of (S )-1-(3-chloro-5-fluoro-2-((4-(4fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine (55.1 mg, (137 pmol) and (R)-2-hydroxypropanoic acid (13.9 mg, 154 pmol) in DMF (4.5 mL) at 0 °C. After stirring for 2 h TA, the reaction mixture was concentrated under vacuum. Purification of the remaining residue by reversed-phase HPLC yielded the title compound. MS (m / z): 501.2 [M+H+]. Step O. Synthesis of 4-(4-fluoro-1 H-pyrazol-1-yl)-8-methoxy-2-methylquinoline K₂CO₃ (4.99 g, 36.1 mmol) was added to a stirred mixture of 4-chloro-8-methoxy-2-methylquinoline (5.00 g, 24.0 mmol) and 4-fluoro-1H-pyrazole (3.85 g, 28.8 mmol) in anhydrous MPN (12 mL). After stirring for 48 h at 140 °C, the reaction mixture was cooled to room temperature and filtered. The residue was clarified with DMF (13 mL). Water (90 mL) was then added to the combined filtrates. The precipitate was removed by filtration and purified by ultrafast chromatography on silica gel (elution with DCM / methanol) to give the title compound. MS (m / z): 258.0 [M+H+]. Step P. Synthesis of 4-(4-fluoro-1 H-pyrazol-1-yl)-2-methylquinolin-8-ol A solution of 4-(4-fluoro-1H-pyrazol-1-yl)-8-methoxy-2-methylquinoline (5.51 g, 21.4 mmol) in anhydrous toluene (37.8 mL) was heated to 80 °C and added dropwise to a vigorously stirred mixture of AlCl3 (8.58 g, 64.3 mmol) in anhydrous toluene (32.4 mL). After stirring for 8 h at 80 °C, the reaction mixture was cooled to 0 °C and inactivated by the addition of water (106 mL) and a concentrated aqueous solution of NH3 (27 mL). After stirring overnight at room temperature, the mixture was centrifuged. The supernatant was extracted with EA (3 x 200 mL), and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with DCM / methanol) to give the title compound. Example 2: Preparation of Compound No. 2 F (S)- N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin8-yloxy)methyl)phenyl)ethyl)-2-hydroxy-N -methylpropanamide Stage TO. Synthesis of (2 S)- N -((S )-1-(3-chloro-5-fluoro-2-((4 methoxyphenoxy)methyl)phenyl)ethyl)-2-(tetrahydro-2 H-pyran-2-yloxy)propanamide (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (100 mg, 323 pmol) was reacted with (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propanoic acid [Garner P. et al. J. Org. Chem. (2002), 67(17), 6195-6209] (84.3 mg, 484 pmol) according to the synthesis of N-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-3-hydroxy-2-methylpropanamide. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 488.5 [M+Na]. Step B. Synthesis of (2S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-N-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanamide (2S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-(tetrahydro-2H-pyran-2-yloxy)propanamide (50 mg, 107 pmol) was dissolved in anhydrous DMF (approx. 5 ml / mmol). Under an argon atmosphere, sodium hydride [60% in paraffin] (4.7 mg, 118 pmol) was added and the mixture was stirred for 20 min. Iodomethane (33.3 pL, 535 pmol) was then added, and stirring continued until complete conversion (TLC). Water was added, and the EA extraction was performed several times. The combined organic layers were dried with Na₂SO₄, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 502.3 [M+Na]. Step C. Synthesis of (S)-N-((S)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)2-hydroxy-N-methylpropanamide (2 S)- N -((S )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)- N -methyl-2(tetrahydro-2 H-pyran-2-yloxy)propanamide (41.0 mg, 85 pmol) was reacted with ammonium nitrate and cerium(IV) (117.1 mg, 214 pmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3dione. The crude product was dissolved in methanol, a 3 M HCl methanolic solution was added, and stirring at room temperature was continued until the reaction was complete (TLC). Evaporation under reduced pressure yielded the title compound. MS (m / z): 312.4 [M+Na]. Step D. Synthesis of (S)-N-((S)-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2-hydroxy-N-methylpropanamide (S)-N-((S)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-hydroxy-N-methylpropanamide (13.70 mg, 47 pmol) was reacted with SOCl2 (6.82 pl, 11.18 mg, 156 pmol) according to the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 330.4 [M+Na]. Step E. Synthesis of (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxy-N-methylpropanamide (S)-N-((S)-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2-hydroxy-N-methylpropanamide (14.6 mg, 47 pmol) was reacted with 4-(4-fluoro-1H pyrazol-1-yl)-2-methylquinolin-8-ol (12 mg, 47 pmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 515.5 [M+H+]. Example 3: Preparation of Compound No. 3 (R )-3-amino-N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2 methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide Step A. Synthesis of (R)-3-(tert-butoxycarbonylamino)-2-hydroxypropanoic acid K₂CO₃ (107 mg, 0.78 mmol) and NaHCO₃ (107 mg, 1.27 mmol) were added to mixtures of (R)-3-amino-2-hydroxypropanoic acid (668 mg, 6.36 mmol) in dioxane and water (3:1, v / v, 10 mL). Di-tert-Butyl dicarbonate (998 mg, 6.99 mmol) was added, and stirring was continued overnight at room temperature. The mixture was then acidified to pH 2 using 1 M HCl. Subsequently, the mixture was extracted several times with EA. The combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum to provide the title compound. MS (m / z): 206.2 [M+H+]. Step B. Synthesis of tert-butyl (R)-3-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-2-hydroxy-3-oxopropylcarbamate (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine (25 mg, 0.06 mmol) was reacted with (R)3-(tert-butoxycarbonylamino)-2-hydroxypropanoic acid (18.0 mg, 0.09 mmol) according to the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1Hpyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to give the title compound. The crude product was used without further purification. Step C. Synthesis of (R)-3-amino-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide The tere-butyl (R)-3-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-2-hydroxy-3-oxopropylcarbamate was dissolved in DCM (1.5 mL) and TFA (200 mL) was added. The mixture was stirred for 1 h. The mixture was then diluted with toluene (1.5 mL) and concentrated under vacuum. Purification of the residue by reversed-phase HPLC yielded the title compound. MS (m / z): 516.5 [M+H+]. Example 4: Preparation of Compound No. 4 (S)- N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin8-yloxy)methyl)phenyl)ethyl)-2,3-dihydroxypropanamide Step A. Synthesis of (S)-N -((S )-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2,2-dimethyl-1,3-dioxolane-4carboxamide (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine (25.0 mg, 0.06 mmol) was reacted with (S)2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (12.8 mg, 0.09 mmol) according to the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to give the crude title compound. The crude product was used without further purification. Step B. Synthesis of (S)-N -((S )-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2,3-dihydroxypropanamide The crude (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide was dissolved in MeOH (1.0 mL) and concentrated HCl (5 drops) was added. The mixture was stirred for 20 h. The mixture was then concentrated under vacuum. Purification of the residue by reversed-phase HPLC yielded the title compound. MS (m / z): 517.1 [M+H+]. Example 5: Preparation of Compound No. 5 (S)-N -((R )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin-8 yloxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide Step A. Synthesis of 3-bromo-5-fluoro-2-methylaniline 1-Bromo-5-fluoro-2-methyl-3-nitrobenzene (3.04 mL, 22.0 mmol) was dissolved in a 4:1 mixture of dioxane and water (110 mL). The solution was cooled to 0 °C, and powdered Zn (14.4 g, 220 mmol) and NH₄Cl (11.8 g, 220 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. After complete conversion, the mixture was filtered over a layer of Celite. It was carefully rinsed with EA, and the filtrate was washed with water. The organic phase was dried with Na₂SO₄, filtered, and concentrated under vacuum to obtain the title compound. Step B. Synthesis of 1-bromo-3-chloro-5-fluoro-2-methylbenzene NaNO2 (1.93 g, 28.0 mmol) was added to a solution of 3-bromo-5-fluoro-2-methylaniline (4.40 g, 21.6 mmol) in acetic acid (100 mL) and a semi-concentrated HCl solution (400 mL) at 0 °C. After stirring for 5 min at 0 °C, CuCl (3.72 g, 37.5 mmol) was added to the reaction mixture. After stirring for 2 h at 0 °C, the reaction mixture was heated to room temperature and stirring was continued for a further 3 h. Subsequently, the mixture was extracted with Et2O. The combined organic layers were washed with a concentrated aqueous solution of NaHCO3 (1x), dried with Na2SO4, filtered, and concentrated under vacuum (maximum bath temperature 30 °C, vacuum >150 mbar) to give the title compound. Step C. Synthesis of 1-bromo-2-(bromomethyl)-3-chloro-5-fluorobenzene NBS (4.61 g, 25.9 mmol) and AIBN (531 mg, 3.23 mmol) were added to a stirred solution of 1-bromo-3-chloro-5-fluoro-2-methylbenzene (5.43 g, 21.6 mmol) in ACN (150 mL). After stirring for 8 h under reflux, the mixture was concentrated under vacuum. The residue was purified by ultrafast silica gel chromatography (heptane / EA elution) to give the title compound. Step D. Synthesis of 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene. Cs₂CO₃ (14.5 g, 44.5 mmol) was added to a stirred solution of 1-bromo-2-(bromomethyl)-3-chloro-5-fluorobenzene (4.48 g, 14.8 mmol) and 4-methoxyphenol (2.39 g, 19.3 mmol) in ACN (250 mL). After stirring overnight at room temperature, the reaction mixture was filtered and concentrated under vacuum. The residue was dissolved in DCM and washed with water (1x). The organic phase was dried with Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. Step E. Synthesis of (R)-N-((R)-2-(tere-butyldimethylsilyloxy)-1-(3-chloro-5fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide AlMe3 (2 M in toluene, 741 pl, 1.48 mmol) was added to a solution of (R, E)-N-(2-(tere-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (325 mg, 1.17 mmol) in anhydrous toluene (1 ml) at -78 °C. Then, in a second vial, BuLi (2.5 M in hexanes, 544 pl, 1.36 mmol) was added to a solution of 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene (427 mg, 1.24 mmol) in dry toluene at -78 °C. The solution was stirred for 15 min at this temperature. The solution containing 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene was slowly added to the solution containing (R,E)-N-(2-(tere-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide at 78 °C. The mixture was stirred for 22 minutes and allowed to reach room temperature. After complete conversion, the reaction mixture was inactivated with a saturated aqueous solution of NH4Cl. The mixture was extracted with EA, and the combined organic phases were dried with Na2SO4, filtered, and concentrated under vacuum.The crude product was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to produce the title compound. MS (m / z): 544.6 [M+H+]. Step F. Synthesis of (R )-2-amino-2-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanol (R)-N-((R)-2-(tere-butyldimethylsilyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (149 mg, 0.27 mmol) was reacted with a methanolic solution of 3 M HCl (274 μL, 0.82 mmol) according to the synthesis of (S )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to give the title compound. MS (m / z): 370.3 [M+HCO2-]. Step G. Synthesis of (S)-N -((R )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide PyBOP (279 mg, 0.53 mmol) and DIPEA (114 μl, 0.67 mmol) were successively added to a stirred solution of (R)-2-amino-2-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanol (87.0 mg, 0.27 mmol) and (S)-(+)-2-hydroxy-3-methylbutyric acid (47.3 mg, 0.40 mmol) in DMF (1 ml) at 0 °C. After stirring for 16 h at room temperature, the reaction mixture was concentrated under vacuum. The residue was redissolved in a saturated methanolic ammonia solution, stirred at room temperature for 3 h, and concentrated under vacuum. Purification of the remaining residue by ultrafast chromatography on silica gel (elution with EA / heptane) yielded the title compound. MS (m / z): 426.4 [M+H+]. Step H. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate Pyridine (300 μg) and benzoyl chloride (89.3 μg 0.77 mmol) were successively added to a stirred solution of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide (131 mg, 0.31 mmol) in DCM (1 ml). After stirring for 23 h TA, the reaction mixture was concentrated under vacuum. The remaining residue was redissolved in toluene (2 ml) and concentrated under vacuum. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 634.3 [M+H+]. Step I. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (141 mg, 0.22 mmol) in ACN (2 ml) was reacted with ammonium nitrate and cerium(IV) (304 mg, 0.56 mmol) in water (400 ml) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 528.5 [M+H+]. Step J. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (48.3 mg, 0.09 mmol) was reacted with SOCl2 (13.3 pl, 0.18 mmol) according to the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 546.6 [M+H+]. Step K. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5fluoro-2-((4-(4-fluoro-1 H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethylamino)3-methyl-1-oxobutan-2-yl benzoate Cs₂CO₃ (89.4 mg, 0.28 mmol) was added to a stirred solution of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (46.8 mg, 0.09 mmol) and 4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-ol (24.5 mg, 0.10 mmol) in dry ACN (1 mL). After stirring overnight, water (3 mL) was added, and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to give the title compound. MS (m / z): 753.4 [M+H+]. Step L. Synthesis of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide A solution of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl benzoate (46.2 mg, 0.06 mmol) in concentrated methanolic ammonia was stirred overnight at room temperature. After complete conversion (TLC), the reaction mixture was concentrated under vacuum. Purification of the residue by reversed-phase HPLC yielded the title compound. MS (m / z): 545.2 [M+H+]. Step M. Synthesis of (R, E)-N-(2-(tere-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide A solution of titanium(IV) ethoxide (363 pL, 1.73 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (210 mg, 1.73 mmol), and (tere-butyldimethylsilyloxy)acetaldehyde (300 pL, 1.58 mmol) in dry DCM (15 mL) under a nitrogen atmosphere was stirred at room temperature for 22 h. After complete conversion (TLC), the reaction was stopped with water (15 mL) and filtered over a layer of celite. The filter was then carefully rinsed with DCM (2 x 15 mL). The aqueous phase was extracted with DCM (10 mL), and the combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum to yield the title compound. Example 6: Preparation of Compound No. 6 (S)- N -(1 -(3-chloro-5-fluoro-2-((2-methyl-4-(1 -methyl-1 H -1,2,4-triazol-5-yl)quinolin 8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide Step A. Synthesis of 8-methoxy-2-methyl-4-(1-methyl-1H-1,2,4-triazol-5yl)quinoline 4-Chloro-8-methoxy-2-methylquinoline (5.00 g, 24.15 mmol), 1-methyl-1,2,4-triazole (42.74 mL, 48.30 mmol), K₂CO₃ (6.67 g, 48.30 mmol), Pd(OAc)₂ (0.54 g, 2.41 mmol), tricyclohexylphosphine tetrafluoroborate (1.87 g, 5.07 mmol), and trimethylacetic acid (2.47 g, 24.15 mmol) were suspended in dry xylene (20 mL). The flask was evacuated and subsequently vented with nitrogen. The degassing procedure was repeated twice. The mixture was heated at 140 °C for 18 h. After complete conversion, the mixture was evaporated and purified by ultrafast chromatography on silica gel (elution with DCM / methanol) to give the title compound. MS (m / z): 255.4 [M+H+]. Step B. Synthesis of 2-methyl-4-(1-methyl-1 H-1,2,4-triazol-5-yl)quinolin-8-ol A solution of 8-methoxy-2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinoline (3.14 g, 12.35 mmol) in anhydrous toluene (25 mL) was heated to 80 °C and added dropwise to a vigorously stirred mixture of AlCl3 (4.94 g, 37.06 mmol) in anhydrous toluene (25 mL). After stirring for 8 h at 80 °C, the reaction mixture was cooled to 0 °C and inactivated by the addition of water (68 mL) and subsequently a concentrated aqueous solution of NH3 to pH 10 (~1.7 mL). The mixture was centrifuged. The supernatant was extracted with EA, and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with DCM / methanol) to give the title compound. MS (m / z): 239.2 [M-H+]. Etapa C. Síntesis de (S)-2-(1-(3-cloro-5-fluoro-2-((2-metil-4-(1-metil-1 H1,2,4-triazol-5-il)quinolin-8-iloxi)metil)fenil)etil)isoindolina-1,3-diona (S )-2-(1-(3-cloro-2-(clorometil)-5-fluorofenil)etil)isoindolina-1,3-diona (34,3 mg, 97 pmol) se hizo reaccionar con 2-metil-4-(1-metil-1 H -1,2,4-triazol-5il)quinolin-8-ol (23,4 mg, 97 pmol) de acuerdo con la síntesis de (S )-2-(1-(3chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-diona to give the composition of the title. MS (m / z): 556.3 [M-H+]. Etapa D. Síntesis de (S)-1-(3-cloro-5-fluoro-2-((2-metil-4-(1-metil-1 H-1,2,4triazol-5-il)quinolin-8-iloxi)metil)fenil)etanamina (S)-2-(1-(3-cloro-5-fluoro-2-((2-metil-4-(1-metil-1H-1,2,4-triazol-5-il)quinolin8-iloxi)metil)fenil)etil)isoindolina-1,3-diona (45,5 mg, 82 pmol) se desprotegió de acuerdo con la síntesis de (S)-1-(3-cloro-5-fluoro-2-((4-(4-fluoro-1H-pirazol-1-yl)2-metilquinolin-8-iloxi)metil)fenil)etanamina para dar el compuesto del título. MS (m / z): 448,3 [M+Na+]. Etapa E. Síntesis de (S)-N-(1-(3-chloro-5-fluoro-2-((2-metil-4-(1-metil-1 H1,2,4-triazol-5-il)quinolin-8-iloxi)metil)fenil)etil)-2-(difluorometoxi)acetamida (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5yl)quinolin-8-yloxy)methyl)phenyl)ethanamine (28.9 mg, 68 pmol) and 2-(difluoromethoxy)acetic acid (11.1 mg, 88 pmol) were reacted according to the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to give the title compound. MS (m / z): 535.0 [M+H+]. Example 7: Preparation of Compound No. 7 (S)- N -(1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin-8 yloxy)methyl)phenyl)ethyl)-2-hydroxy-2-methylpropanamide Step A. Synthesis of (3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)methanol. LiBH4 (200 mg, 9.3 mmol) was added in several portions to a stirred solution of methyl 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoate (347 mg, 0.81 mmol) in THF (8.9 mL) and MeOH (2 mL) at room temperature for 3 h. After stirring for 1 h at room temperature, the reaction mixture was partitioned between DCM (20 mL) and water (10 mL). The aqueous layer was extracted with DCM (2 x 15 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. Step B. Synthesis of 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzaldehyde. (3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)methanol (1.70 g, 5.73 mmol) was dissolved in a 1:1 mixture of dioxane and toluene (70 mL) and manganese(IV) oxide (9.96 g, 114.59 mmol) was added. The reaction mixture was stirred at room temperature until the reaction was complete (TLC). After filtration over Celite, the filtrate was evaporated under reduced pressure to give the title compound. Step C. Synthesis of (R, E)-N-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzylidene)-2-methylpropane-2-sulfinamide Under an argon atmosphere, 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzaldehyde (317 mg, 1.08 mmol) and (R)-tBu-sulfinilamide (143 ml, 1.18 mmol) were dissolved in anhydrous THF (5 mL). Titanium(IV) ethoxide (676.5 mL, 3.23 mmol) was then added dropwise. The reaction mixture was stirred at 65 °C overnight. After the reaction was complete, the reaction mixture was inactivated with water. The aqueous layer was extracted 3x with DCM. The combined organic layers were dried with Na₂SO₄, filtered, and evaporated to dryness under reduced pressure to give the title compound. MS (m / z): 420.1 [M+Na]. Step D. Synthesis of (R)-N-((R)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propyl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propyl)-2-methylpropane-2-sulfinamide. (R, E)-N-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzylidene)-2-methylpropane-2-sulfinamide (352.0 mg, 884.67 pmol) was dissolved in THF (20 mL). A 1 M solution of ethylmagnesium bromide in THF (2.21 mL, 2.21 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. Ice was carefully added before diluting with a saturated aqueous solution of NH4Cl. The aqueous phase was extracted 3x with DCM. The combined organic layers were dried with Na2SO4 and, after filtration, evaporated to dryness under reduced pressure. The crude product was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the titration compounds. R isomer: MS (m / z): 428.3 [M+H+] and S isomer: MS (m / z): 428.0 [M+H+]. Step E. Synthesis of (S )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propan-1-amine (R)-N -((S )-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propyl)-2-methylpropane-2-sulfinamide (182 mg, 425 pmol) was reacted with methanolic solution of 3 M HCl according to the synthesis of (S )-1-(3-chloro-5-fluoro-2((4-methoxyphenoxy)methyl)phenyl)ethanamine to give the title compound. MS (m / z): 324.1 [M+H+]. Step F. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propyl)isoindoline-1,3-dione (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propan-1-amine (95.4 mg, 295 pmol) was reacted with phthalic anhydride (48 mg, 324 pmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 454.6 [M+H+]. Step G. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)propyl)isoindoline-1,3-dione (S)-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propyl)isoindoline-1,3-dione (102 mg, 225 pmol) was reacted with ammonium nitrate and cerium(IV) (308 mg, 562 pmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 370.3 [M+Na]. Step H. Synthesis of (S )-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)propyl)isoindoline-1,3-dione (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)propyl)isoindoline-1,3-dione (52.9 mg, 152 pmol) was reacted with SOCl2 (22.06 μL, 304 pmol) according to the synthesis of (S )-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 388.3 [M+Na]. Etapa I. Síntesis de (S)-2-(1-(3-cloro-5-fluoro-2-((4-(4-fluoro-1 H-pirazol-1-yl)2-metilquinolin-8-iloxi)metil)fenil)propil)isoindolina-1,3-diona (S )-2-(1-(3-cloro-2-(clorometil)-5-fluorofenil)propil)isoindolina-1,3-diona (53,3 mg, 146 μmol) se hizo reaccionar con 4-(4-fluoro-1H-pirazol-1-yl)-2metilquinolin-8-ol (35,4 mg, 146 μmol) de acuerdo con la síntesis de metil (S )-2(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-diona to give the composition of the title. MS (m / z): 573.4 [M+H+]. Etapa J. Síntesis de (S)-1-(3-cloro-5-fluoro-2-((4-(4-fluoro-1 H-pirazol-1-yl)-2metilquinolin-8-iloxi)metil)fenil)propan-1-amina (S)-2-(1-(3-cloro-5-fluoro-2-((4-(4-fluoro-1H-pirazol-1-yl)-2-metilquinolin-8iloxi)metil)fenil)propil)isoindolina-1,3-diona (80,8 mg, 141 μmol) se hizo reaccionar con hidrazina hidrato (27.5 μ^ 282 μmol) de acuerdo con la síntesis de (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethanamine to give the composition of the title. MS (m / z): 444.1 [M+H+]. Step K. Synthesis of (S)-N-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1yl)-2-methylquinolin-8-yloxy)methyl)phenyl)propyl)-2-hydroxy-2-methylpropanamide (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)propan-1-amine (18 mg, 41 μmol) was reacted with alpha-hydroxyisobutyric acid (4.9 mg, 47 μmol) according to the synthesis of (R)-N 72 ((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1 -yl)-2-methylquinolin-8 yloxymethylphenylethyl-2-hydroxypropanamide to give the title compound. MS (m / z): 529.6 [M+H+]. Example 8: Preparation of Compound No. 8 EITHER OH (R)-N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1 H-pyrazol-1 -yl)-2 methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide Step A. Synthesis of 4-(4-fluoro-5-methyl-1 H-pyrazol-1-yl)-8-methoxy-2methylquinoline A mixture of 4-hydrazinyl-8-methoxy-2-methylquinoline (100 mg, 0.493 mmol) and 3-fluoro-4,4-dimethoxybutan-2-one (110 mg, 0.739 mmol) [Funabiki, K. et al. J. Chem. Soc., Perkin Trans. 1 1997, 18, 2679-2680] in an aqueous solution of 5 M HCl (5.3 mL) was stirred at 90 °C for 1.5 h. The reaction mixture was concentrated under vacuum, partitioned between a saturated aqueous solution of NaHCO3 (3 mL) and DCM (5 mL). The aqueous layer was extracted with DCM (2 x 5 mL), the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with MeOH / DCM) to give the title compound. MS (m / z): 272.0 [M+H+]. Step B. Synthesis of 4-(4-fluoro-5-methyl-1 H-pyrazol-1-yl)-2-methylquinolin-8-ol 4-(4-fluoro-5-methyl-1 H-pyrazol-1 -yl)-8-methoxy-2-methylquinoline (118 mg, 0.436 mmol) is desmethylated with the synthesis of 4-(4-fluoro-1 H-pyrazol1-yl)-2-methylquinolin-8-ol to give the composition of the title. MS (m / z): 258.1 [M+H+]. Etapa C. Síntesis de (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1 Hpirazol-1-yl)-2-methylquinolin-8-iloxi)methyl)phenyl)ethyl)isoindoline-1,3-diona 4-(4-fluoro-5-metil-1 H-pirazol-1-il)-2-metilquinolin-8-ol (21,0 mg, 82 pmol) se hizo reaccionar con (S )-2-(1-(3-cloro-2-(clorometil)-5-fluorofenil)etil)isoindolina1,3-diona (28,8 mg, 82 pmol) de acuerdo con la síntesis de (S )-2-(1-(3-cloro-5fluoro-2-((4-(4-fluoro-1H-pirazol-1-il)-2-metilquinolin-8iloxi)metil)fenil)etil)isoindolina-1,3-diona para dar el compuesto del título. MS (m / z): 573,1 [M+H+]. Etapa D. Síntesis de (S )-1-(3-cloro-5-fluoro-2-((4-(4-fluoro-5-metil-1 H pirazol-1-il)-2-metilquinolin-8-iloxi)metil)fenil)etanamina (S)-2-(1-(3-cloro-5-fluoro-2-((4-(4-fluoro-5-metil-1H-pirazol-1-il)-2metilquinolin-8-iloxi)metil)fenil)etil)isoindolina-1,3-diona (31,1 mg, 54 pmol) se desprotegió de acuerdo con la síntesis de (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine to give the composition of the title. MS (m / z): 465.4 [M+Na+]. Step E. Synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinolin8-yloxy)methyl)phenyl)ethanamine (20.5 mg, 46 pmol) was coupled with (R)-2hydroxypropanoic acid (4.8 mg, 53 pmol) according to the synthesis of (R)-N -((S )-1(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8 yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to give the title compound. MS (m / z): 515.9 [M+H+]. Example 9: Preparation of Compound No. 9 and Compound No. 10 Compound No. 9 Compuesto n.° 10 (S)- N -(1 -(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1 H -1,2,4-triazol-1 -yl)quinolin8-iloxi)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamida (9) y (S)-N -(1-(3-chloro-5 fluoro-2-((2-methyl-4-(3-methyl-1 H -1,2,4-triazol-1 -yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2(difluoromethoxy)acetamida (10) Etapa A. Síntesis de 8-methoxi-2-methyl-4-(5-methyl-1 H -1,2,4-triazol-1yl)quinoline and 8-methoxi-2-methyl-4-(3-methyl-1 H -1,2,4-triazol-1-yl)quinoline 4-chloro-8methoxy-2-methylquinoline (100 mg, 0.481 mmol) if reacted with 3-methyl1H-1,2,4-triazol (46.0, 0.554 mmol) in combination with the synthesis of 4-(4-fluoro1H-pyrazol-1-yl)-8-methoxy-2-methylquinoline to give a mixture of the components of the title. MS (m / z): 255.3 [M+H+]. Etapa B. Synthesis of 2-methyl-4-(3-methyl-1 H-1,2,4-triazol-1-yl)quinolin-8-ol and 2methyl-4-(5-methyl-1 H -1,2,4-triazol-1 -yl)quinolin-8-ol Una mezcla de 8-metoxi-2-metil-4-(5-metil-1 H-1,2,4-triazol-1-il)quinolina y 8-metoxi-2-metil-4-(3-metil-1 H -1,2,4-triazol-1-il)quinolina (153 mg, 0,602 mmol) se desmetiló de acuerdo con la síntesis de 4-(4-fluoro-1H-pirazol-1-il)-2 metilquinolin-8-ol para dar una mezcla de los compuestos del título. MS (m / z): 241,1 [M+H+]. Etapa C. Síntesis de (S)-2-(1-(3-chloro-5-fluoro-2-((2-metil-4-(5-metil-1 H1,2,4-triazol-1 -il)quinolin-8-iloxi)metil)fenil)etil)isoindolina-1,3-diona y (S)-2-(1 (3-chloro-5-fluoro-2-((2-metil-4-(3-metil-1 H -1,2,4-triazol-1 -il)quinolin-8iloxi)metil)fenil)etil)isoindolina-1,3-diona A mixture of 2-methyl-4-(3-methyl-1 H -1,2,4-triazol-1-yl)quinoline-8-ol and 2-methyl4-(5-methyl-1 H -1,2,4-triazol-1-yl)quinoline-8-ol (48.3 mg, 0.201 mmol) was reacted with (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3diona (70.7 mg, 0.201 mmol) from the synthesis of (S )-2-(1-(3-chloro-5fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-diona to give a mixture of the components of the title. MS (m / z): 556.4 [M+H+]. Etapa D. Síntesis de (S)-1-(3-cloro-5-fluoro-2-((2-metil-4-(5-metil-1 H-1,2,4triazol-1-il)quinolin-8-iloxi)metil)fenil)etanamina y (S)-1-(3-cloro-5-fluoro-2-((2metil-4-(3-metil-1 H -1,2,4-triazol-1 -il)quinolin-8-iloxi)metil)fenil)etanamina Una mezcla de (S)-2-(1-(3-cloro-5-fluoro-2-((2-metil-4-(5-metil-1 H-1,2,4triazol-1-il)quinolin-8-iloxi)metil)fenil)etil)isoindolina-1,3-diona y (S)-2-(1-(3-cloro5-fluoro-2-((2-metil-4-(3-metil-1 H -1,2,4-triazol-1 -il)quinolin-8iloxi)metil)fenil)etil)isoindolina-1,3-diona (111 mg, 201 pmol) se desprotegió de acuerdo con la síntesis de (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine to give the components of the title. MS (m / z): 448.3 [M+Na+]. Etapa E. Síntesis de (S)-N-(1-(3-chloro-5-fluoro-2-((2-metil-4-(5-metil-1 H1,2,4-triazol-1-il)quinolin-8-iloxi)metil)fenil)etil)-2-(difluorometoxi)acetamida y (S)-N -(1-(3-chloro-5-fluoro-2-((2-metil-4-(3-metil-1 H -1,2,4-triazol-1 -il)quinolin-8iloxi)metil)fenil)etil)-2-(difluorometoxi)acetamida A mixture of (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1 H -1,2,4-triazol1-yl)quinolin-8-yloxy)methyl)phenyl)ethanamine and (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4(3-methyl-1 H -1,2,4-triazol-1 -yl)quinolin-8-yloxy)methyl)phenyl)ethanamine (19 mg, pmol) was reacted with 2-(difluoromethoxy)acetic acid (7.2 mg, 56 pmol) according to the synthesis of (R)-N -((S )-1-(3-chloro-5-fluoro-2-((4-(4fluoro-1 H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2hydroxypropanamide and was purified by HPLC to produce (S)- N -(1-(3-chloro-5fluoro-2-((2-methyl-4-(5-methyl-1 H -1,2,4-triazol-1 -yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2(difluoromethoxy)acetamide (MS (m / z): 534.2 [M+H+]) and (S)- N-(1-(3-chloro-5-fluoro2-((2-methyl-4-(3-methyl-1 H -1,2,4-triazol-1 -yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2(difluoromethoxy)acetamide (MS (m / z): 534.0 [M+H+]) Example 10: Preparation of Compound No. 11 / =NN^N . Ck cl^g. Xj F (S)- N -(1 -deutero-1 -(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1 H -1,2,4-triazol-5yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide Step A. Synthesis of (R)-N -((S )-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide Preparation of deutero-L-Selectride solution: Anhydrous MeCH (0.591 ml, 14.6 mmol) was added to a stirred suspension of LiAlD4 (203 mg, 4.86 mmol) at 0 °C for 10 min. The reaction mixture was allowed to reach room temperature (RT) and a tri-sec-butylborane solution (1 M in THF, 3.6 mL, 3.6 mmol) was then added. The deutero-L-Selectride solution was used after stirring for 15 min at RT. Titanium(IV) ethoxide (1.02 mL, 4.86 mmol) was added dropwise under an argon atmosphere to a solution of 1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone (0.500 g, 1.62 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (216 mg, 1.78 mmol) in anhydrous THF (1.7 mL). The mixture was heated under reflux to complete conversion (TLC). The mixture was then cooled to 0 °C, and deutero-L-Selectride solution was added dropwise. The mixture was stirred at this temperature until complete conversion (TLC). Methanol (~10 mL) was then added until gas evolution ceased. The solution was poured into a saturated aqueous solution of NaCl (5 mL). The mixture was then filtered over a layer of Celite and carefully clarified with DCM. The filtrate was washed with a saturated aqueous solution of NaCl. The aqueous layer was extracted with DCM. The combined organic layers were dried with Na2SO4, filtered, and evaporated to dryness.The remaining residue was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to give the title compound. MS (m / z): 415.3 [M+H+]. Step B. Synthesis of (S )-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (R)-N -((S )-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (323 mg, 779 pmol) was hydrolyzed according to the synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to give the title compound. MS (m / z): 311.7 [M+H+]. Step C. Synthesis of (S)-N -(1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (S )-1-Deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (50.0 mg, 161 pmol) was coupled with 2-(difluoromethoxy)acetic acid (26.4 mg, 209 pmol) according to the synthesis of (R)-N -((S )-1-(3-chloro-5-fluoro-2-((4-(4fluoro-1 H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2hydroxypropanamide to give the title compound. MS (m / z): 419.2 [M+H+]. Step D. Synthesis of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (38 mg, 91 pmol) was deprotected according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3dione to give the title compound. MS (m / z): 312.7 [M+H+]. Step E. Synthesis of (S)-N-(1-deutero-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2-(difluoromethoxy)acetamide. (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (19 mg, 61 pmol) was chlorinated according to the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 330.7 [M+H+]. Step F. Synthesis of (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1methyl-1H-1,2,4-triazol-5-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2(difluoromethoxy)acetamide (S)-N-(1-deutero-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2(difluoromethoxy)acetamide (20 mg, 57 pmol) was reacted with 2-methyl-4-(1methyl-1 H-1,2,4-triazol-5-yl)quinolin-8-ol (14 mg, 57 pmol) according to the synthesis of (S )-2-(1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazole-1 -yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 535.4 [M+H+]. Example 10A: Preparation of Compound No. 11A / =N NH Cl D.C. F N -[(1S)-1 -[3-chloro-5-fluoro-2-({[2-methyl-4-(1 -methyl-1 H -1,2,4-triazol-5yl)quinolin-8-yl]oxy}methyl)phenyl](1,2,2,2-2H4)ethyl]-2-(difluoromethoxy)acetamide Step A: (S)-N-[(1,2,2,2-2H4)ethylidene]-2-methylpropane-2-sulfinamide (1,2,2,2-2H4)Acetaldehyde (1.00 g, 15.6 mmol) was reacted with (S)-2-methylpropane-2-sulfinamide (2.07 g, 17.1 mmol) according to the synthesis of (R,E)-N-(2-(tere-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide to give the title compound. Step B: Synthesis of (S)-N-[(1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(1,2,2,2-2H4)ethyl]-2-methylpropane-2-sulfinamide 1-Bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene (272.0 mg, 0.79 mmol) was reacted with (S)-N-[(1,2,2,2-2H4)ethylidene]-2-methylpropane-2-sulfinamide (113 mg, 0.75 mmol) according to the synthesis of (R)-N-((R)-2-(tere-butyldimethylsilyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide to give the title compound. MS (m / z): 440.5 [M+Na+] Step C: Synthesis of (1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(2H4)ethan-1-amine. (S)-N-[(1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(1,2,2,22H4)ethyl]-2-methylpropane-2-sulfinamide (86.5 mg, 0.21 mmol) dissolved in methanol (1 ml) was reacted with methanolic solution of 3 M HCl (207 ml, 0.62 mmol) according to the synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to produce the title compound. MS (m / z): 314.9 [M+H+] Step D: Synthesis of N -[(1S )-1-{3-chloro-5-fluoro-2-[(4methoxyphenoxy)methyl]phenyl}(1,2,2,2-2H4)ethyl]-2-(difluoromethoxy)acetamide The reaction of (1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(2H4)ethan-1-amine (32 mg, 0.10 mmol) with 2-(difluoromethoxy)acetic acid (14 mg, 0.11 mmol), PyAOP (70 mg, 0.13 mmol) and DIPEA (21 pl, 0.18 mmol) according to the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide provided the crude titrant. This was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the titrant. MS (m / z): 444.4 [M+Na+]. Step E: Synthesis of N-[(1S)-1-[3-chloro-5-fluoro-2-(hydroxymethyl)phenyl](1,2,2,22H4)ethyl]-2-(difluoromethoxy)acetamide N-[(1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(1,2,2,2-2H4)ethyl]-2(difluoromethoxy)acetamide (29 mg, 0.070 mmol) was reacted with ammonium nitrate and cerium(IV) (95.7 mg, 0.175 mmol) according to the synthesis of (S)2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. Step F: Synthesis of N-[(1S)-1-[3-chloro-2-(chloromethyl)-5-fluorophenyl](1,2,2,2812H4)ethyl]-2-(difluoromethoxy)acetamide N -[(1S )-1 -[3-chloro-5-fluoro-2(hydroxymethyl)phenyl](1,2,2,2-2H4)ethyl]-2-(difluoromethoxy)acetamide (18 mg, 0.057 mmol) was reacted with SOCl2(17 pl, 0.23 mmol) according to the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3dione to give the title compound. Step G: Synthesis of N-[(1S)-1-[3-chloro-5-fluoro-2-({[2-methyl-4-(1-methyl-1 H1,2,4-triazol-5-yl)quinolin-8-yl]oxy}methyl)phenyl](1,2,2,2-2H4)ethyl]-2-(difluoromethoxy)acetamide N-[(1S)-1-[3-chloro-2-(chloromethyl)-5-fluorophenyl](1,2,2,22H4)ethyl]-2-(difluoromethoxy)acetamide (14.3 mg, 43 pmol) was reacted with 2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-ol (11 mg, 47 pmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione. The crude product was purified by HPLC to produce the title compound. MS (m / z): 539.2 [M+H+]. Example 10B: Preparation of Compound No. 11B / =N Cl Foho (R)-N -(1 -Deutero-1 -(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1 H -1,2,4-triazol-5yl)quinolin-8-yloxy)methyl)phenyl)-2-hydroxyethyl)-2-(difluoromethoxy)acetamide Step A. Synthesis of tere-butyldimethyl[2-oxo(2-2H)ethoxy]silane A solution of 2-(tere-butyldimethylsilyloxy)methyl acetate (2.0 g, 10 mmol) in anhydrous Et2O (8.9 ml) was added dropwise to a stirred suspension of LiAlD4 (0.49 g, 12 mmol) was added to anhydrous Et2O (35 mL) at -78 °C. After stirring for 40 min at -78 °C, the reaction was stopped by adding water (0.45 mL) and 15% aqueous NaOH solution (0.45 mL) at -78 °C. Water (1.34 mL) was then added, and the mixture was heated to room temperature. The mixture was filtered over a Celite layer, and the filtrate was concentrated under vacuum. The remaining residue was purified by ultrafast silica gel chromatography (EA / heptane elution) to give the title compound. Step B. Synthesis of (R)-N-[(1E)-2-[(tere-butyldimethylsilyl)oxy](1-2H)ethylidene]2-methylpropane-2-sulfinamide A solution of titanium(IV) ethoxide (794 ml, 3.79 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (344 mg, 2.84 mmol), and tetra-butyldimethyl[2-oxo(22H)ethoxy]silane in anhydrous DCM (10 ml) was stirred in a nitrogen atmosphere at room temperature for 16 h. After complete conversion (TLC), the reaction was stopped by the addition of water (20 ml) at 0 °C, and the resulting mixture was filtered through a Celite film. The filter was then carefully cleared with DCM (2 x 20 ml). The aqueous layer was extracted with DCM (20 ml), and the combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum. The remaining residue was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to give the title compound. MS (m / z): 279.2 [M+H+]. Step C. Synthesis of (R)-N-(2-(tere-butyldimethylsilyloxy)-1-deutero-1-(3-chloro5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)pivalamide AlMe3 (2 M in toluene, 551 pl, 1.10 mmol) was added to a solution of (R)-N-[(1E)-2-[(terebutyldimethylsilyl)oxy](1-2H)ethylidene]-2-methylpropane-2-sulfinamide (279 mg, 1.00 mmol) in anhydrous toluene (1.6 ml) at -78 °C and the resulting solution was stirred for 30 min at -78 °C. Then, in a second flask, BuLi (2.5 M in hexanes, 508 μi, 1.27 mmol) was added to a solution of 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene (381 mg, 1.10 mmol) in anhydrous toluene (3.8 ml) at -78 °C and the resulting solution was stirred for 15 min at 78 °C. The solution containing (R)-N-[(1E)-2-[(tere-butyldimethylsilyl)oxy](12H)ethylidene]-2-methylpropane-2-sulfinamide was then slowly added to the solution containing 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene at -78 °C. The reaction mixture was allowed to reach TA for 4.5 h and was inactivated by the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with EA and the combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum.The remaining residue was purified by ultrafast chromatography on silica gel (elution with EA / heptane) to produce the title compound. MS (m / z): 567.0 [M+Na+]. Etapa D. Síntesis de (R)-N-(1-Deutero-1-(3-cloro-5-fluoro-2-((2-metil-4-(1metil-1 H -1,2,4-triazol-5-il)quinolin-8-iloxi)metil)fenil)-2-hidroxietil)-2(difluorometoxi)acetamida (R)-N-(2-(tere-butildimetilsililoxi)-1-deutero-1-(3-cloro-5-fluoro-2-((4metoxifenoxi)metil)fenil)etil)pivalamida (388 mg, 0.714 mmol) was deprotected according to the synthesis of (R)-2-amino-2-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanol, followed by amidation with 2-(difluoromethoxy)acetic acid according to the synthesis of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide, followed by benzoylation, elimination of 4-methoxyphenol and chlorination according to the synthesis of benzoate from (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-284 (hydroxymethyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-yl, followed by reaction with 2-methyl-4-(1-methyl-1 H-1,2,4-triazol-5-yl)quinolin-8-ol and subsequent debenzoylation according to the synthesis of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide to give the title compound. MS (m / z): 551.3. [M+H+]. Example 10C: Preparation of Compound No. 11C D Cl NH OR F (R)-N-((S)-1 -deutero-1 -(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4 triazol-1-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-fluoropropanamide Step A. Synthesis of 8-methoxy-2-methyl-4-(5-methyl-1H-1,2,4-triazol-1yl)quinolinaol. Acetic anhydride (0.645 ml, 0.692 g, 6.78 mmol) was added to a stirred mixture of formamidine acetate salt (0.705 g, 6.78 mmol) in anhydrous DMF (23.1 ml) at room temperature. After stirring for 5 min at room temperature, Et3N (1.56 ml, 1.14 g, 11.3 mmol) was added. After stirring for 5 min at room temperature, the reaction mixture was heated to 80 °C and stirred until the reaction mixture became a clear solution. The reaction mixture was then cooled to room temperature followed by the addition of acetic acid (3.10 mL, 3.25 g, 54.2 mmol) and 4-hydrazinyl-8-methoxy-2-methylquinoline [AA Avetisyan et al. Russ. J. of Org. Chem. 2010 46(3), 427-431] (0.918 g, 4.52 mmol). After stirring for 17 h at 80 °C, the reaction mixture was concentrated under vacuum. The residue was purified by ultrafast chromatography on silica gel (elution with DCM / MeOH) to give the title compound. MS (m / z): 255.2 [M+H+]. Etapa B. Synthesis of 2-methyl-4-(5-methyl-1 H-1,2,4-triazol-1-yl)quinolin-8-ol 2Metil-4-(5-methyl-1 H -1,2,4-triazol-1-yl)quinolin-8-ol (0.750 g, 2.95 mmol) if desmethylated with AlCl3 (1.18 g, 8.85 mmol) made with the synthesis of 4-(4fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-ol to give the composition of the title. MS (m / z): 240.8 [M+H+]. Etapa C. Síntesis de (S)- N -((S )-1-deutero-1-(3-chloro-5-fluoro-2-((4methoxifenoxi)methyl)phenyl)ethyl)-2-hidroxipropanamida (S )-1 -deutero-1 -(3-chloro-5fluoro-2-((4-methoxifenoxi)methyl)phenyl)ethanamine (250 mg, 0.804 mmol) if reacted with L-(+)láctic acid (76 pl, 76 mg, 0.85 mmol) from the synthesis of (R)-N -((S )-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hidroxypropanamida to give the composition of the title. MS (m / z): 383.7 [M+H+]. Step D. Synthesis of (R)- N -((S)-1-deutero-1-(3-chloro-5-fluoro-2-((4methoxyphenoxy)methyl)phenyl)ethyl)-2-fluoropropanamide 1,8-Diazabicyclo[5.4.0]undec7-ene (170 pl, 173 mg, 1.14 mmol) and fluoride perfluoro-1-butanesulfonyl (200 pl, 343 mg, 1.14 mmol) was subsequently added to a stirred solution of (S)-N-((S)-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2hydroxypropanamide (290 mg, 0.758 mmol) in anhydrous toluene (8 ml) at 0 °C. After stirring for 30 min at 0 °C, the reaction mixture was allowed to reach room temperature and stirred overnight at room temperature. The reaction mixture was then poured onto ice / water and extracted with DCM (3 x 20 mL). The combined organic layers were dried with Na₂SO₄, filtered, and concentrated under vacuum. The remaining residue was purified by ultrafast chromatography on silica gel (EA / heptane elution) to give the title compound. MS (m / z): 385.9 [M+H+]. Step E. Synthesis of (R)-N -((S )-1-deutero-1-(3-chloro-5-fluoro-2(hydroxymethyl)phenyl)ethyl)-2-fluoropropanamide (96 mg, 0.25 mmol) was reacted with ammonium nitrate and cerium(IV) (342 mg, 0.624 mmol) according to the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 276.8 [M-H+]. Step F. Synthesis of (R)-N-((S)-1-deutero-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2-fluoropropanamide (R)-N-((S)-1-deutero-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-fluoropropanamide (47 mg, 0.17 mmol) was reacted with SOCl2 (49 pl, 0.68 mmol) according to the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione to give the title compound. MS (m / z): 294.8 [M-H+]. Etapa G. Síntesis de (R)-N-((S)-1-deutero-1-(3-cloro-5-fluoro-2-((2-metil-4(5-metil-1 H -1,2,4-triazol-1 -il)quinolin-8-iloxi)metil)fenil)etil)-2-fluoropropanamida (R)-N-((S)-1-deutero-1-(3-cloro-2-(clorometil)-5-fluorofenil)etil)-2fluoropropanamida (29 mg, 0,10 mmol) se hizo reaccionar con 2-metil-4-(5metil-1 H -1,2,4-triazol-1-il)quinolin-8-ol (26 mg, 0,11 mmol) de acuerdo con la síntesis de (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-diona to give the composition of the title. MS (m / z): 501.8 [M+H+]. Example 11: Compuestos Nros 12 a 213 Compounds Nos. 12 to 213 shown in Table 1 below are further representative examples of compounds according to the general formula (I) of the present invention. These compounds have been synthesized using the methods described above, together with synthetic methods disclosed in the references cited herein or known in the art of synthetic organic chemistry, and variations thereof as will be appreciated by those skilled in the art. Each of the references cited herein relating to the synthetic routes described in Examples 1 to 10C is incorporated by reference in its entirety into this specification. In any case, those skilled in the art of organic synthesis will recognize the starting materials and reaction conditions, including variations, for producing the compounds. Table 1: Example Compounds Nos. 12 to 2 Comp. N.° Structure Mass# 12. N CXa Χ / Ύ'Χ O. A Ξ O ck.U\ / AA / O^ Xx YNL l| h F 501.1 13. < ,NN ΓΧχ O\ Ί Ξ o ckAa NT\[ NYH Oh F 501.0 14. NO^ > = O CIVVn\o |l \ h Yy F 527.1 15. °=< / zz LJ-. ,----( .....( CYcry= / o 527.0 16. N ¿:h°°i° F 515.1 17. / O o 515.1 18. o IZ / f° o 515.1 19. YNYF 527,1 20. cQy °=< / zz LJ-. ,----( ..... / z— / =\ o 528,0 21. N^ N y^N^^ °> Ξ O Ck TH N NH2 OH Oh F 516,5 22. YN 'P^'N^^ °Ί Ξ o I CkJ\ / < it H OH F 530 23. XO Ο=^~ / ζ:Ε u-. _ .---( ..... / ζ— / =\ ο 516,1 24. ¿ϊ N % = O ciW^nV^ H OH F 515,2 25. F ¿1 N ^P^N^^ % = O Cl^X^N^^ H OH F 516,1 C^N^ 26. A^iI^n ^^oh LI] h F 516,1 27. XP? / zz _ .—( ( z— / =\ o 516.1 28. / r^ N. ,NN γ^Ν^^ % O ClW^N^ H OH F 499,1 29. / O o=^” :··^.Α· o 498.6 30. O'-nxA^ XAN , 5 , / r^ HOF 511.0 31. / ΓΛ N. ,NN ^p^N^^ C'XjVH 485,0 32. / TA N ,NN ^Y^N^^ Cl'-mV F 484,5 33. / r^ N. ,NN % 0 c'yVs1^ XJ H . OH F 3 49, 0 CV^nX^ kX H OH F 499.1 35. nJ N ^P^N^^ % . 0 c'jAXnX-0yf UHFF 537.5 36. O zC / znX ) / —' ZZ ' ^=O —OO ΞΕ 531.1 37. o X o 529.6 38. X o 4 / zx LJ- ___~_—( oo ….. / 39. o ^Tp° H -> h; \_h\X )..... y— / -n ΞΕΖ ' ^=O —2 / __O 556,3 40. O 4>af° o 541.5 41. / ” Z. i ( 111 · < \_ 1 z—C z / =\ o H ^N °, = r^ o.^ F 498.2 43. rN V ^p^N^^ ί^ΑΙ F 498,2 44. rN < ,NN o Cl>A^N^ H Oh F 498,2 45. 47. Fh N ^p^N^^ 543.3 48. Fh NP^P^ XjCH^XCF3 567.1 49. X o / zz Z. ! ( κι··< 1 z \ z / =\ Ch° o 487.1 50. Fh N 0. _ Cx^^ / \ / AJ H °HF 529.2 51. the ^=° the 555.3 52. the ^Tp° M \=< z 5—z | >••111 \—f Z. zz / 5=0 x' ° -1- Tl co 569.2 53. Fh N γ^Ν^^ °> . 0 CIYV^N^CF3 [5!! H / 'oh F 569.1 54. O -^rP° M \=< z 5—z 1 \.. 111 \—fz XZ / 553.5​ 55. Fh N ^Y^N^^ C'pr4V 499,1 56. o -44^ 4° Vo 513,4 57. F4 N y^N^^ 'ΖΓ'Η^··· F 513,4 58. F4 N ^P^N^^ CY / nYo 59. X θ_^Ο * Y44o 515,2 60. Fh N Πή Yn^ NF 529,3 61. Ή N CXa 4Ύ F 557,5 62. NN ccx γΎ^°Ί = o c'4ñAc<, o F 63. N=\ -N^N ςά °? = 0 ci^aV H OH F 498.2 64. o 4V h lz A..... XZ / o X 512.1 65. nJ NY^XN^X' α^Α F 526.1 66. CM X z J / zz Ά. .. / I III·· / nA A Π-with 530.3 67. o . / VH '“C CUCi )..... y—' -n ΞΕΖ / \=° O—< ΞΕ \___ 529,1 68. FJn N ^p^N^^ CI^\^nAa Ll| H V-NH F 512> Fh0 N ^9. ciAa^yo^ H o F 559,1 70. Fh N y^N^^ °> = 0 OH CI^AAA°x H o F 559,1 71. o Άί-^0 Η / V 3..... y>\J ZZ / \=O o > 1 oZ X 531.2 72. NN °! ? Or 1 CW^^ / x / x / ··. kV H °h F 558.4 73. o ,γΑΑγΖγ 3..... yA\J IZ ' ,a 537.5 74. . N OlX °Ί ° Ck Ax Vil H i^n kJJ H °7 F 524,1 75. nJ N °>H°- ° c'^^nV H °HF 517,1 76. d NY^N^^ °^ > ° ° °H CKxWm^VxxNH2 IT N Tf kV H ° F 544,1 77. CN XX r / zx LL --- / ….\=7 z5— / 4. 3> or 524.1 79. Fh N OCX γ'^Ν'^·'73⁄4 F 537.1 80. O ^=o ó ΞΕ 515.2 81. 7° o X 501.2 82. Ή N OlX Y^n'xX'' cxJ / nNN F 524.1 83. / o / / 7X / r~^ .....\__ |l / >—{ γ >=\ r\-iryj o 498,5 84. o ...... )-----f -T.-Z. > I 7 o 512.4 85. LL >-°o ..... / / 71 ^'7 .....\_ IL. \ 7 / =^ )—( !—(x ft— LL \~y— ° o 548.3 86. < ,NN OlX Y'^N'^ χηγ F 551.2 87. Q yj o=\ / zi f-zh.....ho 552,1 88. Fh N CXa γ^Ν'χΧ' CW^Aq F 538,1 89. OH / ^ \=< z / >—Z 1 \ \\ / / >ίιz.^-ι 2 ' ^>=OZ z~~~~~ O 538,1 90. Fh N OlX γ'Ή''^ ° Ξ ° ei^ÁA Α^_^\ Tit nnn s-^ F 540,1 91. Fh N (Υχ γ''^Ν''Χ' hJhN^¿NF 538,1 92. Jr / H:c fvhz .....V “ ryiTyj O 538,5 93. LL h^ oh hí-ho 551,5 9_^__ h__^__ o __^__}—ς z 'Y hj / zvA ...... / T| xz )=° f 625.0 / 95. , / “* ---A ,N N ^y^íN^^ °> = O CK^k / A-.A^x Ίφ« N F 521,0 96. < ,N N ^^ / ^^ c'^n^On 521,4 97. / N^ -Ά ,N N % ° O clAA a___χ IF II N T H OH F 498,3 98. < ,N N γ^Ν^^ % 3 O %A^n^t kUI H OH F 498,4 99. \ X / ° o 512,3 100. znY < ,N N ^^ / ^^ β'χ^Αί 512,4 101. ¿1F N ^p^N^^ N F 529,3 102. o AAa A o X 501,1 103. N. J N ^P^N^^ C'rjSV F 533,1 104. X o O zi LI- ____ / \ 1,. ( 'AA—Z / =\ O-° o 545,2 105. X o / ° ZZE LL ____ / \ 1 I. / 'AA—A”Z / =\ ¿ ;—( / —ó / >— l*- ^A_ryj ^^^B o 531,1 106. o _rG°O m—(f m—' / —\ ^=( VA zUl / \ / H zz O Z r T| 553,1 107. o aXa aa ^=( aA / . / \ / H ZZ O r o \ 531,2 108. o=\ zz LL. / Im· / 'A^z—z / =\ AVcTyA ^^^B o 537,1 109. oy °=( zz LL ___ / Illi' / x )---( >--- / / )—LL 0-cTyA o 555,2 110. Y zx LL / Im· / Ύ^ζ— ^VcTyA ^^^B o 541,2 100 111. cr _ / x ZI LL ____ / iii·· / T^z—z / =\ ^^^B o 542,2 112. ιτζ N. > N ccx γ n O\ Ί o o Ck II h'X0H HN·^ Í 0 542,1 113. X Cr° _ / X °A XX LL / lin· / Vj^z—z / =\ ^X )---( / ----(\ / )--L*- O 'y— / ^^^B o 541,2 114. o m—( / γ— / ]—( z ^=( Va^zUx y..... ) ΤΊ XX ^)=° / zz O 540,2 115. o XX / a=\ XX LL ___ / Illi· / Y^x- ) / / ά / )—LL ^^^B o 540,2 116. LL \ i / 71 T V H λ<<τρ^ o 552,0 117. 5 4 / / / ZZE .....$=. Q-ó3 o 538,3 118. by o=\ / / / HX (WÍ .....C 1 rX-ryjo 552,4 101 119. o „^fO M = CMJ )..111 )—f TZ. / / )=o \—o 538,4 120. z^ u o=\ / / Z'\ .....\ [1 / )—C >=\ ^z )---( ,---G, λ--LL θ-cry~r o 521,3 121. LL LL / O °· / zz £\-ΖΛ .....$= “ “ o 555,1 122. <^o \ 1 y^'z. o=\ / / / zx .....C\ o 521,3 123. o )=° 0 534,4 124. ifj N γ^ιψ^ “t / »*© F 534,4 125. O ¿r 534,4 126. z^ / / / zx [Wz.....C z o 535,9 102 127. o -ηΓΡ° M )..111 )—f TZ / / \=o ^=\ 1 \ 535,8 128. Z'p o=\ / / Λχ [W> .....V zo 522,2 129. o ^ / VH ...... z5 )—< / \= ZZ 130. o A=C CH1 ΞΕΖ ' / 'Z0 536,2 103 135. Ή Ν, Λ-., N γ^Ν^^ -^13⁄4 F 536,2 136. O -AW* 1 \ o^> 1X 550.2 N ^P^N^ O> 3 O C1^^^^ kJ HN^0 F 550.3 138. O \=o ' o ΞΕ 527.4 139. Vx N. XN γ^Ν^^ 0> 3 0 Cl^S^OxF LJ HFFF 567,3 140. ll os / / H=c O 548,9 141. o ~y) χΖ CH1 =EZ / ¿ \= 1= N 4.2 / . Ncs / N-^ py 0> 3 0 Cl^A\% H '0 H n= / F 549,0 104 143. / =N . N <<, NS °Ί = ° L l| h / \ F 527,0 144. o -HpO3 M ...... y——' Z ZCZ ' / cT 537,4 145. o „ / V ~y) z Μ Ό-Q ZEZ / / Y :x° m 566,8 146. LL / --0 / Z=4-lo=\ 147. o -Tp° M \=c zQ^li )..111 )—f / / m— τι 504,4 148. o -^P° M \ zi_H^ \ / / \=° T-1 “Π 518,0 149. o jr- / ll / z) n—\c y- l / \ / / \=° °f 549.5 150. \ 1 ° \ / / \ / ZI |l / >—<( z >=\ )---( i---ά / )—ll / A— O o 535.5. 105 151. Nx > N ΓΥχ γ'^Ν'''^ O\ / - | Ξ O ckJ\ F N'T Y Nrr LH 1F F 521,1 152. NN y^N^X “'ψΗ^ΐν F 552,4 153. o Oa j” 538,4 154. u_ ----L*O °xo 551,4 155. z^O ° \ / / \ / ZT o 535.5 156. / TN N. Λ-... N ^p^N^x O> c'^hV^ 535,9 157. ^N\ N. >--. NY^N^X =13⁄43⁄4 F 521.9 158. O \=° Z=A 1 \ 535.9 106 159. Nx XN ° = ° YtnV UJ H N- / ° F 521,9 160. rN N, Xx. NP^pN^ °> = 0 CWATM L IJ h / \ F 512.9 161. XN\ N. XN ppP^ % . 0 C'XX^NOyF LI] H F'F F 553,2 162. / =N NyN-. X ΧηΫ 531.0 163. A / / …..$=\ ' γΡοΛτ o 531.0 164. oo=\ / / iXfy…..X z )χοχχ o 531.0 165. rN Νχ Xxx N °? ° ci^J^A..X-\ || H ° HN= / F 535.4 166. The LL 549.3 107 167. o TI 566.9 168. LL o A / / Qs / Z=E x'A L x \ z / =\ \--( / —(\ λ— LL r\_ <TyJ o 535,4 169. N. X / N ΓΥχ y^N'''^ ° ° CkJ\A JL O F y^ if n γ ψ H F F 549,2 170. N. Y / N °> — C'^h^QF 536.2 171. / TN\ / N, JY- / N °? 3 ° C'vVsAcOH L 1] h / \ F 527,2 172. YN N. Yy N OCX N·^ °Ί zo UHFF 514,9 173. :í o 518,1 174. yN\ N, JY N CíX yn °\ ° ° C.\A . JC / F XjX h OF 505.1 108 175. ll o / / Hz: ^^^B o 534.2 176. ll / ---L*- °=( / / / ZT XA \ XAA A _J=\ Q° o 503.8 177. o „ a^O5 ΤΊ —U n-- )= / -( H \) <f 'll \..... XA 'z 2 ΞΕΖ / / σ -Π -π 536,1 178. oA / / / ζχ - Z. / < 111' < t k z o 518,1 179. N. N OCX χγΝ''^'' O\ Ί Ξ O F\Y ckA\ / -^ Ά / Κ Y N F L l| H F 536,1 180. YN N, Y-N °Ί = o A'Yn'V O H F F F 518,0 181. / =N NyN^ N °\ Ί z'- > D ° F\ / F αχΑΧ A_„XNFL l| h F 537.8 182. o ^^^^B _________ z ξεζΆ / / -π / ^θ X 519.8 109 183. LL. / -- O=\ Z'Z\ > . LL v—\ / =\ fVcryj ^^^B o 505,8 184. / =N ^jz'N'- γί^'Ήί7 O\ > = O ciyMnA <oh l 1) h \ f 512,3 185. =n nh h^x οί="o" n u h 533,9 186. = n yynh cxx γ^ n'xx % z o 504,2 187. -ά^ γ^ν^>c^h^QF 520,8 188. / = N ^4x / Nh OCX n'^'' ΟΊ zo C - N ' i H OH F 497,9 189. / =H ^•Asz Nh N^C % = O CvO'N^xOH LI] h / X,9 F 5 \= / οz\y— <za -X.-Z. / / F° o m 549,9 110 191. o , / ί-ς Μ Λ=€ / ° CAU ZZ ' / \=o z'^O 537,1 192. \ X / ° °=( / / 7ZT J=v Ko^FO 497,9 193. ^0\ Nb Λ-. H 0 = OC1 °9 n4 / =NC / n^. γΧ n^X % = O ckJx.A.iJix^oh V |f NL l h F 483.9. 195. o4,s / / 7ZT Z'Zx / uA .....\_ LZx 7 λ=\ fOcfy^ O 498,2 196. o ^rO° M \= / ¿L \-^Ti >..... 'p / V2 zz / / \=° C z^= O-N 5'^7. 0 F ckÁA JC A nf II] HF 518.1 198. o° °=( 7 AV zAz O 523.2 111 199. o ^ / V Η ^=<7 <>11 IZσ / / \=O 523,2 200. Z^OO=\ co ^τ / Q / 4 ,__ / oi< Z' \ O \_. IL WP _J=\ r\-iryj ^^^BO 525,1 201. o TI--(Z ')---' )---< Z^, \= / <? z \—(z H \.o \\ / / xz.z iz'^ / Z Uo °7z 526,2 202. o ti—<z ')---z )---< Z. \= / z y^z ii )nO 2 -rA C Z / ZZ ω r o T| 538,0 203. / =NN^N-^ ΓΧλ °Ί ο ckJxA Ά / V n VUHFF 500,2 204. t11O=\ / / / ZI .....( [1^ / )~\ z >=\ Z )----( / ----(5 o O / 0,-°--ll <4 5' .....Γ (µryj O 559.2 206. o µ1 H \ AHA / F CkAX A „X. ynf L l| h F 538,1 209. VN NN (XX Νγ n °Ί z'->d OF ck YX A_A NFL l| h F 520,1 210. / =NN<^N. (XX ANY N °Ί z->xAJ,>HFDOF .5 211. / =NN^N 44 °Ί d O ck ΑΧ ir ni UHFF 501,2 212. VN N. N (XX Ny N O'! -- DO οίχΑΛ n UHFF 501,7 213. / =NN^N / 44 d O3 ci-\ -4 501.7 # Mass: Mass spectrometry data (derived from liquid chromatography spectra 5 mass spectrometry) are indicated as (m / z) and represent the values ​​of protonated molecular ions [M+H+] 113 114 Example 12: Antagonist activity of test compounds toward human B2R The following cell-based human bradykinin B2 receptor calcium mobilization assay (hB2R-CaM) was used to determine the antagonistic activity of compounds selected from Example Compounds 1 to 168 with respect to the human bradykinin B2 receptor (hB2R). The assay is defined herein as a standardized in vitro B2 receptor activity assay, which can be used to determine the IC50 values ​​of compounds according to the present invention, for example, the compounds shown in Examples 1-11. The antagonistic activity of the compounds according to the present invention was investigated using the hB2R-CaM assay with the HTS041C cell line stably expressing the bradykinin B2 receptor (Eurofins, St. Charles MO) and the FLIPR Calcium 6 Assay Kit (Molecular Devices, Wokingham, UK) according to the suppliers' instructions. CaM assay measurements were performed using a Flexstation 3 System (Molecular Devices) that allows for the precise addition of compounds (B2R antagonists) and bradykinin (B2R agonist) to the cells and continuous, adjacent recording of the time-dependent CaM assay signals. Cell culture, plating, and food deprivation: HTS041C cells were cultured in high-glucose DMEM cell culture medium (Lonza) supplemented with 10% thermally inactivated FBS (PAN Biotech), 10 mM HEPES, penicillin / streptomycin (200 U / ml, 200 pg / ml), 1x non-essential amino acids (Lonza), and 250 pg / ml G418 (Invivogen) in a cell incubator at 37 °C in a 5% CO2 atmosphere. One day before the CaM assay experiments, cells were seeded onto 200 pl of DMEM cell culture medium with reduced (5%) FBS and without G418 in 96-well transparent black-bottom plates (ThermoFisher No. 165305). Food deprivation of the cells was performed by incubation (37 °C, 5% CO2) of 70,000 cells / well for 24–28 h. Immediately before loading the calcium dye, the medium was carefully aspirated and the cells were washed with Hank's equilibrated saline solution (HBSS, Gibco) containing Ca2+, Mg2+ and 20 mM HEPES, adjusted to pH 7.4 (HBSS+). Calcium dye load of cells: For calcium dye loading, an aliquot of the FLIPR 6 assay was dissolved in 20 ml of HBSS+. 150 lp of the dye loading solution were added to a cell plate and incubated for 120 min at 37 °C and 5% CO2. After dye loading, the cell plate was immediately transferred to the preheated Flexstation 3 System (37 °C) for CaM evaluation. Intracellular calcium mobilization assay (CaM assay): Serial dilutions (8pt, n=2) of the freshly prepared compound (β2 receptor antagonists) and bradykinin solution (β2 receptor agonist) were transferred from non-binding plates (Costar) to the Flexstation System (source plate) shortly before the start of the experiment. Bradykinin was added at a concentration EC80 determined in n>3 preliminary experiments with concentration response curves of 8pt (n=8). 115 performed the CaM assay using the Flexstation 3 System, starting with the recording of calcium-sensitive dye fluorescence in Flex mode with bottom reading at ex / em=485 nm / 525 nm, cutoff (em)= 515 nM. After 20 s, 50 lp of 4x dilutions of the compound were added to the cells, resulting in a final DMSO (Sigma) concentration of 0.1% in the cell plate. CaM signals were monitored for 80 s after the additions to detect potential agonist activities. Prior to bradykinin stimulation, the vehicle-treated cells and compound were incubated for 25 min at 37 °C in the Flexstation System. Next, 50 ml of a 5-fold concentrated bradykinin solution (HBSS+, 0.1% DMSO) was added to trigger CaM signals (Reading: Max.-Min. values) which were measured for 80 s after bradykinin stimulation. IC50 determinations were performed using the 4-parameter logistic model curve fitted to the compound concentration response curves of 8 points (n=2) using XLFIT software (IDBS). Measurement results: The illustrative compounds numbers 2, 6, 9, 11, 11A, 11B, 11C, 12, 14, 15, 16, 17, 18, 19, 20, 26, 27, 29, 30, 56, 57, 58, 59, 60, 61, 63, 64, 70, 71, 82, 83, 84, 85, 90, 91, 92, 94, 95, 101, 102, 104, 106, 107, 110, 116, 117, 118, 120, 121, 122, 124, 126, 127, 128, 129, 130, 131, 132, 133, 134, 139, 140, 141, 142, 143, 144, 145, 147, 148, 149, 150, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212 116 and 213 showed an IC50 value equal to or below 50 nM towards the human bradykinin B2 receptor (hB2R). The illustrative compounds numbers 1, 8, 10, 22, 23, 24, 25, 28, 31, 32, 33, 34, 46, 48, 49, 50, 51, 54, 62, 66, 67, 68, 69, 86, 87, 88, 89, 93, 96, 97, 99, 103, 105, 108, 109, 111, 112, 113, 114, 115, 119, 123, 125, 135, 136, 137, 138, 146, 151, 152, 153, and 186 showed an IC50 value between 51 and 250 nM towards the human bradykinin B2 receptor (hB2R). The illustrative compounds numbers 3, 13, 21, 47, 52, 53, 55, 65, 72, 98 and 100 showed an IC50 value between 251 nM and 1000 nM towards the human bradykinin B2 receptor (hB2R). None of the compounds tested showed any toxic effects in the cell-based assay system. Example 13: Determination of biological activity, permeability, and metabolic stability For a more detailed evaluation of their therapeutic potential, illustrative compounds numbers 1, 6, 11 and 13 according to the present invention were tested for their antagonist activity towards hB2R, their permeability and their metabolic stability. No structurally similar compounds have been disclosed in the prior art patent applications cited above or elsewhere herein. Prior art patent WO 2008 / 116620 discloses heteroaryl-quinolin-8-yloxymethyl-pyridine compounds that may have similar substituents on the pyridine ring. However, WO 2008 / 116620 makes no mention of the pharmacokinetic properties, such as permeability and metabolic stability, of 117 of its compounds. WO 2010 / 031589 discloses second-generation compounds developed on the basis of the compounds in WO 2008 / 116620, which demonstrated low metabolic stability, low bioavailability, glutathione adduct formation and bioactivation (toxicity) as disclosed in WO 2014 / 159637. In the absence of known structurally related compounds, and in order to demonstrate the advantageous effects of the novel structural elements of the invention, virtual comparator compounds containing elements suggested in WO 2008 / 116620 and WO 2010 / 031589, respectively, were evaluated for their antagonistic activity toward hB2R, permeability, and metabolic stability. The virtual comparator compounds used were numbers 169, 170, 171, 172, 173, and 174, shown in Table 2 below. Comparator compounds 169, 170, and 171 are based on the structural elements suggested in WO 2008 / 116620.Comparative compounds 172, 173, and 174 virtually combine the structural elements suggested in WO 2008 / 116620 with a structural modification to the pyridine ring remainder (substitution with a phenyl ring) as suggested in WO 2010 / 031589 and WO 2014 / 159637. In this regard, however, it should be noted that both WO 2010 / 031589 and WO 2014 / 159637 provide no guidance or suggestion regarding the claimed substituents at the m position of the chlorine atom on the phenyl ring remainder. In fact, WO 2010 / 031589 and WO 2014 / 159637 make no mention of a fluorine substituent at the m position of the chlorine atom on the remainder. 118 of the phenyl ring, and further suggest completely different substituents at the second meta position of the chlorine atom on the phenyl ring. A: Preparation of comparative compounds numbers 169 to 174 The comparative illustrative compounds numbers 169 to 174 shown in Table 2 below were prepared according to the methods described above and those disclosed in documents WO 2010 / 031589 and WO 2008 / 116620 with suitable variations of the above that are appreciated and known by experts in the technique of synthetic organic chemistry to produce the compounds. B: Antagonistic activity of the test compounds against hB2R The relative IC50 values ​​of the test compounds were determined using the same hB2R-CaM assay as in Example 12. The results are shown in Table 2 below. C: Permeability of the test compounds The permeability of the test compounds was determined using a Caco-2 cell permeability assay according to Hubatsch I. et al (Nat. Protoc. 2007, 2 (9), 2111-2119). The Caco-2 cell line is a continuous cell line of heterogeneous human epithelial colorectal adenocarcinoma cells. When cultured as a confluent monolayer on a permeable support such as a cell culture insert filter, the cells differentiate to form a monolayer of polarized epithelial cells that provides a physical and biochemical barrier to the passage of ions and small molecules. In the confluent monolayer form, Caco-2 cells serve in the pharmaceutical industry as a well-established in vitro model of the small intestinal mucosa. 119 Humans to predict the absorption of orally administered drugs. Evaluating transport in both directions (apical to basolateral (AB) and basolateral to apical (BA)) across the cell monolayer allows the determination of an efflux ratio, which provides an indicator of whether a compound undergoes active efflux. A higher efflux ratio indicates that the compound is more susceptible to active efflux. As will be seen, active efflux substantially compromises oral bioavailability. Table 2 below shows the results of the determined output relationships. D: Metabolic stability of the test compounds Hepatic clearance is the most important drug elimination mechanism in the body, and many marketed compounds are cleared by cytochrome P450-mediated hepatic metabolism. The excretion or elimination property of the test compounds was determined using a metabolic stability assay according to Obach RS (Drug Metab. Dispos. 1999, 27(11), 1350-1359). Deep 96-well plate assays were performed using pooled liver microsomes from male Wistar rats (Corning). Rat liver microsome incubations were performed in duplicate, and the incubation mixtures consisted of liver microsomes (0.5 mg of microsomal protein / ml), assay compound (1 μM), MgCl₂ (2 mM), and NADPH (1 mM) in a total volume of 0.7 ml of sodium phosphate buffer (100 mM, pH 7.4). Reactions were initiated with the addition of NADPH and stirred on a horizontal shaker with a mixing block. 120 heater set to 37 °C. At t = 0 min and time points: 10 min, 30 min and 60 min; Aliquots (70 μL) were removed from the incubations and added to 140 μL of the termination mixtures. The termination mixtures consisted of acetonitrile supplemented with diazepam, diclofenac, and griseofulvin as internal analytical standards. The inactivated samples were processed by mixing and centrifugation (2,200 x g, 5 minutes). The particle-free supernatant was diluted 1:1 with deionized water and subsequently subjected to LC-MS for quantitative bioanalysis in terms of exhaustion of the test compound (pump flow rate: 600 lp / min; Kinetex Phenyl-Hexyl analytical column, 2.6 μm, 50 x 2.1 mm (Phenomenex, Germany)).Incubations containing verapamil at a concentration of 1 μM were used as a high clearance positive control (PC; n=2), and incubations without NADPH (70 μl of phosphate buffer (supplemented with 2 mM MgCl2) instead of 70 μl of NADPH solution), in order to verify that any apparent loss of the test item in the incubation assay was due to metabolism, were used as a negative control (NC; n = 2). In the metabolic stability assay, the rate of disappearance of a test compound over time is measured in liver microsomes, and these data are used to calculate the intrinsic in vitro clearance (Clint). Clint data can predict hepatic clearance in vivo, or, in other words, can be used as an indicator of a compound's in vivo half-life and oral bioavailability. Highly cleared compounds are generally considered unfavorable because they are rapidly cleared in vivo, resulting in a short duration of action. Put another way, a lower intrinsic in vitro clearance is typically indicative of 121 a longer in vivo half-life and better oral bioavailability. Table 2 below shows the data for Clintobtenidos. 122 Table 2: Biological activity, permeability, and metabolic stability Comparative Compuesto N.° 169 Comparative Compuesto N.° 172 Illustrative Compuesto N.° 13 .r 0 a í- 0 Fh N cxx γ n °Ί i ° cikÁA JC / n UH °H Fh N Coi γ N °> - Cl^AAN^ ψ H °HF Relative CI50* 57 29 7.6 Clint (μI / min / mg protein)** 427 56 13 Caco-2 BA / AB*** 3.4 1.6 0.6 Comparative composition No. 170 Comparative composition No. 173 Illustrative composition No. 1 Fh N Col γ N ciCyCv LHH °HN h. N Col γ n °a í ° Cl^Jx-X r π ny LJ H °H Fh N Col γ n °^ CI^Ón\^ OH °HF Relative CI50* 37 34 8.0 Clint (μI / min / mg protein)** 329 132 56 Caco-2 BA / AB*** 2.9 1.1 0.7 123 Comparative composition N.° 171 Comparative composition N.° 174 Illustrative composition N.° 6 0 - A 0 A TI z=NN^N^ γ n % > O CkJ\ A -AO ,F u HT u_ 0 A / ZI 7* / ( 11' · · < V \ / / \ Z )——( 7—<\ / )— LL \ 0 CI50 relative* 4.3 2.6 1.0 Clint (pl / min / mg protein)** 497 135 28 Caco-2 BA / AB*** 7.7 1.3 1.0 Illustrative compound No. 11 / =N. N-.N-...B OCX NO^ D >DO Cl\A'vXC AxOvxF il N v T kJ HFF relative IC50* 1.1 Clint (pl / min / mg protein)** 20 Caco-2 BA / AB*** 1.3 IC50 / (IC50 of Compound No. 6) ** Metabolic stability in liver microsomes of Wistar rats, according to Obach RS Drug Metab. Dispos. 1999, 11, 1350-1359. *** Caco-2 BA / AB: PappB to A / PappA to AB in a monolayer assay of 124 differentiated Caco-2 cells according to Hubatsch I. et al Nat. Protoc. 2007, 2, 2111-2119. As can be seen from Table 2 above, the compounds of general formula (I) according to the invention offer numerous important advantages, the existence of which might not have been foreseen. Compared with compounds comprising the structural elements proposed in the prior art, the compounds of the invention demonstrate: > high agonist activity towards hB2R; > significantly improved output ratio; and > significantly improved metabolic stability. More specifically, the illustrative compounds of general formula (I) according to the invention, namely Illustrative Compounds 1, 6, and 13, exhibit improved antagonistic activity against hB2R. For example, Illustrative Compound 13 has a relative IC50 value of 7.6, which is 7.5 times and 3.8 times better compared to the relative IC50 value of Comparative Compound 169 and Comparative Compound 172, respectively, which lack the structural elements of the invention: a fluorine atom in the m position relative to a chlorine atom, along with the defined stereochemical configuration of the benzyl stereocenter. The illustrative compounds of general formula (I) according to the invention, namely Illustrative Compounds Nos. 1, 6, and 13, also exhibit an improved yield ratio compared to the corresponding comparative compounds. In fact, all the comparative compounds exhibit a highly favorable yield ratio of less than 1.5, whereas comparative compounds Nos. 169 to 171 exhibit a 125 unfavorable high exit ratio greater than 2, indicating that the compounds will be subject to active exit. The illustrative compounds of general formula (I) according to the invention, namely Illustrative Compounds 1, 6, and 13, also exhibit significantly improved metabolic stability compared to the corresponding Comparative Compounds. In fact, all the Illustrative Compounds show substantially lower intrinsic clearance than the corresponding Comparative Compounds lacking the combination of structural elements of the invention. For example, Illustrative Compound No. 6 has a Clint value of 28, which is 17.8 times and 4.8 times lower compared to the Clint values ​​of Comparative Compound No. 171 and Comparative Compound No. 174, respectively. Furthermore, a compound having the stereochemical configuration according to the invention at the benzyl stereocenter will demonstrate more predictable pharmacokinetics, safety, toxicity, and tolerability since all compounds would be metabolized in a similar manner as opposed to compounds with a different stereochemistry that may be metabolized differently or at different rates. All things considered, the results demonstrate that the compounds of general formula (I) according to the invention are superior to compounds lacking the combination of structural elements of the invention (e.g., a fluorine atom in position m relative to a chlorine atom in the phenyl moiety together with the stereochemical configuration of the alkyl-type substituent in the benzyl stereocenter according to the invention) in their activity and pharmacokinetic properties such as 126 absorption and elimination. Furthermore, these results show that the compounds of general formula (I) according to the invention are suitable as active ingredients in oral drugs. The features of the present invention disclosed in the descriptive memorandum 5 and / or the claims may, either separately or in any combination thereof, be a material for carrying out the invention in different forms thereof.< / oh>

Claims

1. A compound of general formula (I): FOLLOWS FORMULA 1, or one of its salts, wherein A represents a group: FOLLOW FORMULAS 2 AND 3; A1 is N, or CH, or C-CH3; A2 is N or CR A2; A3 is N or CR A3; A5 is NR A5; RA1 represents a hydrogen atom or a methyl group; RA2 represents a hydrogen atom, a halogen atom, CN, NH2, or (C1-3) alkyl; RA3 represents a hydrogen atom, a halogen atom, or (C1-3) alkyl; RA5 represents a hydrogen atom or a (C1-3) alkyl group; R1 represents a (C1-3) alkyl group that may be substituted with one or more identical or different groups selected from a deuterium atom and OH; R2 represents a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, or an alkyl group (C1-3); E represents CR E1 R E2 R E3 or Hce; Hce represents a monocyclic, partially unsaturated or aromatic heterocycle, having 3 to 5 C atoms and 1 to 3 N atoms;of 3 to 5 C atoms, 1-2 N atom(s) and 1 O atom; or of 3 to 5 C atoms, 1-2 N atom(s) and 1 S atom; wherein said heterocycle is unsubstituted or may be monosubstituted, disubstituted or trisubstituted, on each occasion independently, with a halogen atom, OH, (C1-3) alkyl, (C1-3) haloalkyl, (C1-3) alkoxy, (C1-3) haloalkoxy and / or =O; G represents an alkyl (C1-6) group, in which 1 to 7 H atoms may, on each occasion independently, be substituted with a halogen atom, OR G1 , CN, NR G2 R G3 or cycloalkyl (C3-6), and / or in which a CH2 group, or two non-adjacent CH2 groups, may be substituted with O, C(O), OC(O), C(O)O, or C(O)NH; R G1 , R G2 and R G3, each independently of each other, represent a hydrogen atom, an alkyl (C1-4) group, a haloalkyl (C1-4) group, a hydroxyalkyl (C1-4) group, or a heteroalkyl (C1-4) group; R E1 and R E2, each independently of each other, represent a hydrogen atom, a halogen atom, or G;or RE1 and RE2 taken together form =O or Cyc; RE3 represents a hydrogen atom, a halogen atom, G, OG or OH; and Cyc represents a 3- to 10-membered, saturated or partially unsaturated monocyclic cycloalkyl group or a 4- to 10-membered heterocycloalkyl group having 1 to 3 heteroatom(s) each independently selected from N, O or S, said cycloalkyl or heterocycloalkyl group being unsubstituted or may be monosubstituted, disubstituted, trisubstituted, or tetrasubstituted, each time independently with a halogen atom, OH, (C1-3) alkyl, (C1-3) haloalkyl, (C1-3) alkoxy, (C1-3) haloalkoxy and / or =O. 10 Claims follow;