EA043330B1 - NEW BRADYKININ RECEPTOR ANTAGONISTS - Google Patents

Description

Field of technology to which the invention relates

The invention relates to a compound of general formula (I), which acts as an antagonist of the bradykinin (BK) B2 receptor; to a pharmaceutical composition containing one or more compounds proposed in the present invention; and the use of said compound(s) as a medicament for the treatment and/or prevention of a pathological condition or disease that responds to modulation of the BK B2 receptor.

State of the art

BK is a peptide hormone that is involved in inflammatory processes through the activation of endothelial cells, which leads to vasodilation, increased vascular permeability, nitric oxide formation and mobilization of arachidonic acid. BK also stimulates sensory nerve endings, causing burning dysesthesia. Thus, all the classic signs of inflammation (eg, redness, heat, swelling, and pain) can result from BK formation. BK is a rapidly degrading component of the kallikrein-kinin system. Under normal physiological conditions, the concentration of circulating BK is maintained low, but under pathological conditions it can rapidly increase due to the enzymatic degradation of circulating glycoprotein precursors called kininogens. The two most active enzymes involved in kininogen metabolism are trypsin-like serine protease, plasma kallikrein and tissue kallikrein. The precursors of these enzymes are commonly found in all tissues and are readily activated by physiological or pathophysiological processes (Sainz, I.M. et al. Thromb. Haemost. 2007, 98, 77-83). The BK receptor B2 is constitutively expressed in most cell types and tissues and mediates most of the known effects of BK when produced in plasma or tissues (Regoli, D. et al. Pharmacol. Rev. 1980, 32, 1-46). A large number of in vivo studies have shown that agents that block the BK B2 receptor are therapeutically useful in pathological conditions such as asthma, allergic rhinitis, pancreatitis, osteoarthritis, traumatic brain injury, Alzheimer's disease and angioedema.

The prior art describes numerous peptide and non-peptide BK B2 receptor antagonists. Hinolin derivatives with activity as antagonists of the BK B2 receptor are, for example, described in 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 0795547, EP 0796848, EP 0867432 and EP 1213289 However, as described in WO 2014/159637, these compounds have a number of disadvantages that prevent their use as drugs, including low metabolic stability, low bioavailability, formation of adducts with glutathione and bioactivation (toxicity).

Due to the shortcomings of the prior art compounds and the severe pathological conditions associated with pathophysiological concentrations of BK, both acute and chronic, new BK B2 receptor antagonists are needed.

Brief summary of the invention and description of the invention

The object of the present invention, in light of the prior art and the need described above, is to provide new BK B2 receptor antagonists of general formula (I), preferably BK B2 receptor antagonists, having one or more improved characteristics, for example improved pharmacokinetic and/or physicochemical characteristics including bioavailability, solubility, metabolic stability and LADME (release, adsorption, distribution, metabolism and excretion) characteristics. Other objects of the present invention are to provide a pharmaceutical composition containing at least one BK B2 receptor antagonist described in the present invention; and the use of the compound(s) of the present invention as a medicament for the treatment and/or prevention of a pathological condition or disease that responds to modulation of the BK B2 receptor.

These objects are achieved by the subject matter described in the appended claims, as will become apparent from the following description and definitions.

The present invention relates to:

[1] compound of general formula (I)

A

F (1) or its pharmacologically acceptable salt,

- 1 043330 where A denotes the group

And ¹ represents N or CH;

A ² is N or C-RA ² ;

A ³ is N or C-RA ³ ;

And ⁵ denotes N-RA ⁵ ;

R ^a1 represents a hydrogen atom or a methyl group;

R ^A2 and R ^A3 each independently represent a hydrogen atom, a halogen atom, CN, NH ₂ or (C ₁ -C ₃ )alkyl;

R ^A5 represents a hydrogen atom or a (C ₁ -C ₃ )alkyl group;

R ¹ denotes a (C ₁ -C ₃ )alkyl group, where the alkyl group may be substituted by one or more identical or different groups selected from deuterium atom and OH;

R ² represents a hydrogen atom or a deuterium atom;

R ³ represents a hydrogen atom or a methyl group;

E is CR ^E1 R ^E2 R ^E3 or Hce;

Hce denotes a monocyclic aromatic heterocycle containing from 3 to 10 C atoms and from 1 to 4 heteroatoms, each of which is independently selected from N, O or S, where the heterocycle is unsubstituted or may be mono-, di- or tri-substituted in in each case independently G;

G denotes a (C ₁ -C ₆ )alkyl group, in which from 1 to 7 H atoms in each case can independently be replaced by a halogen atom, ORG ¹ , CN,

NRG2RG ³ or (C ₃ -C ₆ )cycloalkyl, and/or in which one CH ₂ group or two non-adjacent CH ₂ groups can be replaced by C(O)O or C(O)NH;

R ^g1 , RG ² and RG ³ each independently represent a hydrogen atom or a (C1- _C4 )alkyl group;

R ^E1 and R ^E2 each independently represent a hydrogen atom, a halogen atom or a G or

R ^e1 and R ^e2 taken together form =O or Cyc;

R ^E3 represents a hydrogen atom, a halogen atom, G, OG or OH and

Cys denotes a mono- or bicyclic, saturated or partially unsaturated 3-10 membered cycloalkyl group or 4-10 membered heterocycloalkyl group containing from 1 to 3 heteroatoms, each of which is independently selected from N, O or S, where cycloalkyl or the heterocycloalkyl group is unsubstituted or may be mono-, di-, tri- or tetra-substituted, in each case independently of G and/or =O.

In the present invention, compounds are generally described using the standard nomenclature or definitions given below. In the case of compounds containing asymmetric centers, it should be understood that unless otherwise stated, all optical isomers and mixtures thereof are included. Compounds containing two or more asymmetric elements may also occur as mixtures of diastereoisomers. In addition, compounds containing carbon-carbon double bonds may be in Z and E forms, all isomeric forms being included in the present invention unless otherwise noted. If a compound exists in different tautomeric forms, then the compound is not limited to any one particular tautomer, but rather all of its tautomeric forms are included. It should be understood that the compound proposed in the present invention may optionally be in the form of a hydrate, solvate or non-covalent complex. In addition, various crystalline forms and polymorphs, as well as prodrugs of the compound of the present invention, are included within the scope of the present invention. These compounds also include compounds in which one or more atoms are replaced by an isotope, i.e. an atom having the same atomic number but a different mass number. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include ^PS , ^13C , and ^14C .

Compounds described by the formulas given in the present invention, which contain 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%. The compounds of some embodiments have an enantiomeric excess of at least 99%. It should be understood that individual enantiomers (optically active forms) can be obtained by asymmetric synthesis from optically pure precursors or by resolution of racemates. The separation of racemates can be carried out, for example, by conventional techniques such as crystallization in the presence of a resolving reagent or chromatography using, for example, a chiral HPLC column.

The compound of the present invention is described herein by a general formula which includes variables such as, for example, A, A1- ^A5 , E, R1- ^R3 , R ^A1 -R ^A5 , R ^B1 -R ^B2 , R ^C1 -R ^C2 , R ^E1 -R ^E3

- 2 043330 and R ^G1 -R ^G3 . Unless otherwise noted, each variable contained in a formula is defined independently of any other variable, and any variable that is contained in a formula more than once is defined independently in each case. Thus, for example, if a group is indicated to be substituted with 0-2 R*, then the group may be unsubstituted or substituted with 1 or 2 R* groups, wherein R* is in each case independently selected from groups meeting the definition of R*. In addition, combinations of substituents and/or variables are only permissible if such combinations provide stable compounds, i.e. compounds that can be isolated, characterized, and studied for their biological activity.

When used in the present invention, language defining the limits of a range of lengths, such as, for example, from 1 to 5 means any integer equal to 1 to 5, i.e. 1, 2, 3, 4 and 5. In other words, any range defined by two explicitly specified integers is meant to include and disclose any integer defining the specified limits and any integer included in the specified range. So, for example, the term Ci-C ₃ means from 1 to 3, i.e. 1, 2 or 3 carbon atoms; and the term C1-C6 means from 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. In addition, the prefix (C _x -C _y ) when used in the present invention means that the chain, ring or combination of chain and ring structure, as a whole, indicated in direct connection with the prefix, may contain a minimum amount equal to x, and a maximum amount , equal to y, carbon atoms (i.e. x < y), where x and y denote integers defining limits for chain length (number of carbon atoms) and/or ring size (number of ring carbon atoms).

The term pharmacologically acceptable salt of a compound disclosed herein is a salt formed with an acid or a base, which is generally considered in the art to be suitable for use in contact with human and animal tissues without exhibiting excessive toxicity or carcinogenicity, and preferably without exhibiting irritation, allergic reaction or other difficulties or complications. Such pharmaceutical salts include salts of inorganic and organic acids with basic moieties such as amino groups, as well as alkali metal or organic salts with acidic moieties such as carboxy groups.

Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, 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, pamic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkane, such as acetic, HOOC-(CH ₂ ) _p -COOH, where n is any integer between 0 and 4 (i.e. 0, 1, 2, 3 or 4), etc. Likewise, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium cations. Other pharmacologically acceptable salts of the compounds of the present invention will be apparent to those skilled in the art. Generally, a pharmacologically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acid moiety by any conventional chemical procedure. Typically, such salts can be prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the corresponding base or acid in water or an organic solvent or a mixture thereof. The use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is generally preferred.

The term substituent as used in the present invention means a molecular moiety that is covalently bonded to an atom contained in the molecule in question. For example, the ring substituent may be a moiety such as a halogen atom, an alkyl group, a haloalkyl group, a hydroxy group, a cyano group or an amino group, or any other substituent described in the present invention that is covalently bonded to an atom, preferably a carbon or nitrogen atom, which is an element of the ring.

The term substituted as used herein means that any one or more hydrogen atoms of a specified atom or group (e.g., alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heteroaryl) are replaced by said selected substituents, provided that the normal valency of said atom or the number of possible substitution positions of a group, and that the substitution results in a stable compound, i.e. a compound that can be isolated, characterized, and studied for its biological activity. If the substituent is an oxo group, i.e. =O, then 2 hydrogen atoms of this atom are replaced. The presence of an oxo group, which is a substituent for the aromatic carbon atom, leads to the conversion of -CH- to -C(=O)-, and this can lead to loss of aromaticity. For example, a pyridyl group substituted with an oxo group is pyridone. The term mono-, di-, tri- or tetra-substituted means groups containing one (mono-), two (di-), three (tri-) or four substituents, provided that the number of substituents does not exceed the number of possible substitution positions of the group and leads to stable

- 3 043330 connection. For example, a monosubstituted imidazolyl group may be an (imidazolidin2-on)yl group, and a disubstituted isoxazolyl group may be a ((3,5dimethyl)isoxazolyl) group.

When used in the present invention, the terms containing, including, characterized in that their grammatical equivalents are inclusive or variable terms that do not exclude additional, unspecified elements or steps of the method. In addition, containing, etc. also include the more limited terms consisting primarily of and consisting of, respectively.

When used in the present invention, the term consisting of excludes any element, step or ingredient not specifically listed in the claim.

When trade names are used in the present invention, they independently include the trade name product, the generic drug, and the active pharmaceutical ingredient(s) contained in the trade name product.

Unless otherwise defined, technical and scientific terms used in the present invention generally have the same meanings as are known to one of ordinary skill in the art to which the present invention pertains, and as specified in conventional manuals and dictionaries.

The term alkyl or alkyl group means a saturated straight- or branched-chain hydrocarbon group that contains 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, or the number of carbon atoms specified in the prefix. If alkyl is substituted, then the substitution may be a mono-, di- or tri-substitution of individual carbon atoms contained in the molecule, independently of each other, for example, 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms in each case independently may be replaced by the specified selected substituents. The above description also applies when the alkyl group is part of a group, for example, in the case of haloalkyl, hydroxyalkyl, alkylamino, alkoxy or alkoxyalkyl. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2,2dimethylbutyl or n-octyl, and examples of a substituted alkyl group or groups in which the alkyl group is part of the group include a haloalkyl group, for example a trifluoromethyl or difluoromethyl group; a hydroxyalkyl, for example a hydroxymethyl or 2hydroxyethyl group, and a methoxymethyl group. The term (C ₁ -C ₆ )-alkyl includes, for example, H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2- SCHCH3)-, N3C-CH(CH3)CH2, N3C-C(CH3)2-, N3C-CH2-CH2-CH2-CH2-, N3C-CH2-CH2-CH(CH3)-, N3C-CH2-CH( СНз)-СН2-, Н3СН(СНз)-СН2-СН2-, НзС-СН2-С(СНз)2-, НзС-С(СНз)2-СН2-, НзС-СН(СНз)-СН(СНз)- , H3C-CH2CH(CH2CH3)-, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, (H3CH2C)CH(CH2CH2CH3)-, -C(CH3)2(CH2CH2CH3), -CH(CH3)CH(CH3)CH2 СНз and - CH(CH3)CH2CH(CH3)2.

The term alkoxy group means an alkyl group linked by a single bond to oxygen, i.e. -O-alkyl. The term (C ₁ -C ₆ )-alkoxy group includes, for example, a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, tert-amyloxy group or n-hexyloxy group, and the term (C _{The 1} C ₃ alkoxy group includes a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group, respectively.

The term alkoxyalkyl or alkoxyalkyl group means an alkyl group linked by a single bond to one or more alkoxy groups, for example -alkyl-O-alkyl or -alkyl-O-alkyl-O-alkyl. The term (C ₂ -C ₅ )alkoxyalkyl includes, for example, methoxymethyl, methoxyethoxymethyl and 1-ethoxyethyl.

The term haloalkyl or haloalkyl group means an alkyl group in which 1, 2, 3 or more hydrogen atoms are independently replaced by a halogen atom. The term (C1-C3)haloalkyl includes, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, bromomethyl, dibromomethyl, iodomethyl, (1- or 2-)haloethyl (for example, (1- or 2-)fluoroethyl or (1- or 2)chloroethyl), (2- or 3-)halopropyl (for example, (2- or 3-)fluoropropyl or (2- or 3-)chloropropyl).

The term hydroxyalkyl or hydroxyalkyl group means an alkyl group in which 1, 2, 3 or more hydrogen atoms are independently replaced by a hydroxy group (OH). The term (C1- _C4 )hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

As used in the present invention, the term heteroalkyl or heteroalkyl group means a straight or branched chain alkyl group as defined above in which one or more, preferably 1, 2, 3 or 4 carbon atoms are each independently replaced by an oxygen, nitrogen atom , selenium, silicon or sulfur, preferably per oxygen, sulfur or nitrogen atom, per group C(O), OC(O), C(O)O, C(O)NH, NH, SO, SO2 or CH=CH, wherein said heteroalkyl group may be substituted. Thus, for example, a (C ₁ -C ₄ )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

- 4 043330 oxygen, nitrogen and sulfur (preferably oxygen and nitrogen). Examples of the heteroalkyl group include alkylamino group, dialkylamino group, alkylaminoalkyl, dialkylaminoalkyl, acyl, acylalkyl, alkoxycarbonyl, acyloxy group, acyloxyalkyl, carboxyalkylamide, alkoxycarbonyloxy group, alkylcarbamoyl, alkylamide group, alkylcarbamoylalkyl, alkylamidoalkyl, alk ylcarbamoyloxyalkyl, alkylureidoalkyl, alkoxy, alkoxyalkyl or alkylthio. The term alkylthio group means an alkyl group in which one CH2 group or more non-adjacent CH2 groups is replaced by a sulfur atom, where the alkyl moiety contained in the alkylthio group may be substituted. Specific examples of the heteroalkyl group include acyl, methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, di isopropylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl , butyryloxy group, acetyloxy group, methoxycarbonyl, ethoxycarbonyl, isobutyrylaminomethyl, K-ethyl-Kmethylcarbamoyl, N-methylcarbamoyl, cyano group, nitrile, isonitrile, thiocyanate, isocyanate, isothiocyanate and alkylnitrile.

The term cycloalkyl or cycloalkyl group means a saturated carbocyclic ring group comprising one or more rings (preferably 1 or 2), and containing from 3 to 14 ring carbon atoms, preferably from 3 to 10 (more preferably 3, 4, 5, 6 or 7 ) ring carbon atoms; the cycloalkyl group may be substituted and, as a substituent, may be attached through any suitable position of the ring system. Examples of cycloalkyl include monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirocyclic hydrocarbon rings. In a bicyclic cycloalkyl group, two rings are bonded together such that they share at least two carbon atoms. In a spirocyclic hydrocarbon ring, 2 or 3 rings are linked together by one shared carbon atom (spiroatom). If the cycloalkyl is substituted, the substitution may be a mono- or di-substitution of individual ring carbon atoms contained in the molecule, independently of each other, and the entire cycloalkyl group may contain 1, 2, 3 or 4 substituents selected from among these selected substituents, i.e. .e. 1, 2, 3 or 4 hydrogen atoms of the ring carbon atoms in each case can independently be replaced by a substituent selected from the specified list of substituents, this leads to the formation of a mono-, di-, tri- or tetra-substituted 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 the cycloalkyl is partially unsaturated, then the group contains one, two or more double bonds, 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 means a cycloalkyl group, saturated or partially unsaturated, as defined above, in which one or more, preferably 1, 2 or 3 ring carbon atoms, each independently of each other, are replaced by an oxygen, nitrogen or sulfur atom, preferably by an oxygen or nitrogen, or NO, SO or SO2; heterocycloalkyl may be substituted and, as a substituent, may be attached through any suitable position of the ring system; at least one carbon atom must be between two oxygen atoms and between two sulfur atoms or between an oxygen atom and a sulfur atom; and the entire ring must be chemically stable. The heterocycloalkyl group preferably includes 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 aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, tietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, azolyl, thiazolyl, isothiazolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil , dithiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, trioxanil, azepanil, oxepanil, tiepanil, homopiperazinyl, urotropinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, and examples substituted heterocycloalkyl include lactam, lactone and cyclic imide containing rings systems.

The terms aryl, Ar or aryl group mean an aromatic group which includes one or more aromatic rings containing from 6 to 14 ring carbon atoms ( _C6 - _C14 ), preferably 6 to 10 (C6-C10), more preferably 6 ring carbon atoms; aryl may be substituted and, as a substituent, may be attached through any suitable position of the ring system. Examples of aryl include phenyl, naphthyl, biphenyl, indanyl, indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and fluorenyl.

- 5 043330

The term heteroaryl or heteroaryl group means an aromatic group which includes one or more aromatic rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (more preferably 5 or 6) ring atoms, and contains one or more (preferably 1. 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur atoms (preferably O, S or N); heteroaryl may be substituted and, as a substituent, may be attached through any suitable position of the ring system. Examples of the unsubstituted heteroaryl group include 2-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'- bifuryl, 3-pyrazolyl and isoquinolinyl.

The term heterocycle refers to ring systems that include heterocycloalkyl and heteroaryl ring systems as defined above, for example partially unsaturated heterocycle is synonymous with partially unsaturated heterocycloalkyl and aromatic heterocycle is synonymous with heteroaryl. The heterocycle may be substituted and, as a substituent, may be attached through any suitable position of the ring system. Examples of the 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 in the present invention, unless otherwise defined, includes cyclic groups as defined above in the present invention, for example, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group and heterocycle.

The term halogen or halogen atom as used in the present invention means fluorine, chlorine, bromine or iodine.

The term heteroatom as used in the present invention preferably means an oxygen, nitrogen or sulfur atom, more preferably a nitrogen or oxygen atom.

The term 8-benzyloxyquinoline as used in the present invention means the compounds of general formula (I) according to the present invention, as well as their salts, and preferably pharmaceutically acceptable salts. It should be understood that such compounds may be further substituted as indicated.

The present invention preferably relates to one or more of the following embodiments:

[2] a compound or pharmacologically acceptable salt corresponding to [1] as above, wherein A represents:

[3] a compound or pharmacologically acceptable salt corresponding to [1] or [2], where A represents:

[4] a compound or pharmacologically acceptable salt corresponding to any of [1]-[3], where A represents:

[5] a compound or pharmacologically acceptable salt corresponding to any of [1]-[4], where R ¹ denotes (C1-C ₂ )alkyl, where the alkyl group may be replaced by one or more identical or different groups selected from a deuterium atom and he;

- 6 043330

[6] a compound or pharmacologically acceptable salt corresponding to any of [1]-[5], where R ¹ denotes a methyl or ethyl group, which may be substituted by one or more of the same or different groups selected from deuterium atom and OH;

[7] a compound or pharmacologically acceptable salt corresponding to any of [1]-[6], where R ¹ denotes CH ₃ , C2H ₅ , CD ₃ , C2D5, CH2OH or CH2CH2OH;

[8] a compound or pharmacologically acceptable salt corresponding to any of [1]-[7], where R ¹ denotes CH ₃ , C2H ₅ , CD ₃ or CH2OH;

[9] a compound or pharmacologically acceptable salt corresponding to any of [1]-[8], where R ³ represents a hydrogen atom or a methyl group;

[10] a compound or pharmacologically acceptable salt corresponding to any of [1]-[9], where R ² denotes a hydrogen atom;

[11] a compound or pharmacologically acceptable salt corresponding to any of [1]-[9], where R ² denotes a deuterium atom;

[12] a compound or pharmacologically acceptable salt corresponding to any of [1]-[11], where E is CR ^E1 R ^E2 R ^E3 and each of R ^E1 , R ^E2 and R ^E3 is as defined in [1];

[13] a compound or pharmacologically acceptable salt corresponding to any of [1]-[12], where R ^e1 represents a hydrogen atom, a fluorine atom, methyl or ethyl;

[14] a compound or pharmacologically acceptable salt corresponding to any of [1]-[13], where R ^e2 denotes a hydrogen atom, a fluorine atom, a (C1-C6)alkyl group, preferably a (C1-C3)alkyl group, in which from 1 to 4 H atoms in each case can independently be replaced by a fluorine atom, OH or NR ^C1 R ^C2 ; or a (C2- _C6 )alkoxyalkyl group, preferably a ( _C2 - _C5 )- or ( _C2 - _C4 )alkoxyalkyl group; and each of ^RC1 and ^RC2 independently represents a hydrogen atom or a (C ₁ -C ₃ )alkyl group;

[15] a compound or pharmacologically acceptable salt corresponding to any of [1]-[14], where R ^e3 denotes a hydrogen atom, a fluorine atom, OH, a (C1-C6)alkyl group, preferably a (QC3)alkyl group, in which from 1 to 5 H atoms in each case can independently be replaced by a fluorine atom, OH or NR ^C1 R ^C2 ; (C1- _C6 )alkoxy group in which from 1 to 5 H atoms in each case can independently be replaced by a fluorine atom, OH, NR ^C1 R ^C2 or cyclopropyl; a (C2-C6)alkoxyalkyl group, preferably a (C2-C5) or (C2-C4)alkoxyalkyl group, in which from 1 to 5 H atoms in each case can independently be replaced by a fluorine atom, OH, NR ^C1 R ^C2 or cyclopropyl; and each of ^RC1 and ^RC2 independently represents a hydrogen atom or a (C1- _C3 )alkyl group;

[16] a compound or pharmacologically acceptable salt corresponding to [12], where R ^E1 and R ^E2 are linked together to form =O or Cyc, where Cyc is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1 ,3-dioxolanyl, morpholinyl, azetidinyl pyrrolidinyl, piperidinyl, piperazinyl, (imidazolidin-2-one)yl and (oxazolidin-2-one)yl, and is unsubstituted or may be mono-, di- or tri-substituted in each case independently G and/or =O;

[17] a compound or pharmacologically acceptable salt corresponding to [16], wherein Cys is unsubstituted or may be mono-, di- or tri-substituted in each case independently with OH, (C ₁ C ₃ )alkyl and/or =O;

[18] a compound or pharmacologically acceptable salt corresponding to [16] or [17], where Cys is oxetanyl, tetrahydrofuranyl, 1,3-dioxolanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, (imidazolidin-2-one)yl or (oxazolidin-2-on)yl, which is unsubstituted or may be mono-, di- or tri-substituted in each case independently with OH and/or (C1C ₃ )alkyl;

[19] a compound or pharmacologically acceptable salt corresponding to any of [16]-[18], where R ^e3 denotes a hydrogen atom, a fluorine atom, OH or a (C ₁ -C ₃ )alkyl group;

[20] a compound or pharmacologically acceptable salt corresponding to any of [1]-[11], where E is Hce;

[21] a compound or pharmacologically acceptable salt corresponding to [20], where Hce denotes a monocyclic aromatic heterocycle containing from 3 to 5 C atoms and from 1 to 3 N atoms; from 3 to 5 C atoms, 1-2 N atoms and 1 O atom; or from 3 to 5 C atoms, 1-2 N atoms and 1 S atom; where the heterocycle is unsubstituted or may be mono-, di- or tri-substituted in each case independently with (C ₁ -C ₃ )alkyl and/or (C ₁ -C ₃ )haloalkyl;

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[22] a compound or pharmacologically acceptable salt corresponding to [20] or [21], where E is selected from:

[23] a compound or pharmacologically acceptable salt corresponding to any of [1]-[15] and [20]-[22], where E represents the group:

[24] a compound or pharmacologically acceptable salt corresponding to any of [1]-[23], where the compound is selected from the group:

- 8 043330

Thus, suitable compounds are described herein, including suitable combinations of preferred embodiments, i.e. [2]-[23] a compound of general formula (I) or a pharmacologically acceptable salt thereof; for example, a compound or a pharmacologically acceptable salt thereof, including a combination of [1], [3], [6] and [9] disclosed in the present invention. In other words, all possible combinations [1]-[23] mentioned above that result in a stable connection are specifically included within the scope of the present invention.

8-Benzyloxyquinoline, a BK B2 receptor antagonist according to any of the embodiments [1]-[24] of the present invention, has high activity on the human BK B2 receptor, for example, according to the study described below, has an inhibition constant IC ₅₀ (half a maximum inhibitory concentration) for inhibiting BK-induced BK B2 receptor activity of 1 micromolar (µM) or less, for example, 251 nanomoles (nM) to 1 µM; preferably IC ₅₀ equal to 250 nM or less, for example from 51 to 250 nM; even more preferably, IC ₅₀ equal to 50 nM or less; even more preferably, the IC ₅₀ is about 10 nM or less, or 1 nM or less. 8-Benzyloxyquinolines BK B2 receptor antagonists according to any of embodiments [1]-[24] may be highly active at the human BK B2 receptor as well as at the BK B2 receptors of non-human species, e.g. rat, mouse, gerbil, guinea pig, rabbit, dog, cat, pig or cynomolgus monkey.

The activity, or more precisely, the biological activity of the compounds proposed in the present invention, can be studied using appropriate tests known to specialists in the art, for example, by in vitro or in vivo studies. For example, the inhibitory effect (expressed as IC ₅₀ value) of a compound of the present invention on B2 receptor activity can be determined by an intracellular calcium mobilization assay, such as the assay described in Example 12, which is thus a modification of the standard assay in vitro B2 receptor-mediated response. A particularly preferred compound or salt according to any of embodiments [1]-[24] has an IC ₅₀ value of 50 nM or less in a standard in vitro BK B2 receptor assay, such as in Example 12.

The present invention includes the therapeutic use of a compound of general formula (I), a pharmacologically acceptable salt, solvate or hydrate thereof; as well as a product or pharmaceutical composition containing these compounds. The present invention also relates to the use of a compound of general formula (I) as an active ingredient for the preparation or production of a medicinal product.

The pharmaceutical composition proposed in the present invention contains at least one compound of formula (I) or a pharmacologically acceptable salt thereof, preferably a compound according to any of embodiments [1]-[24], or a pharmacologically acceptable salt thereof, and at least one, i.e. one or more carriers, excipients and/or auxiliaries. In particular, the pharmaceutical composition proposed in

- 9 043330 of the present invention, may contain one or more compounds according to the present invention, for example, compounds corresponding to any of embodiments [1]-[24], and at least one carrier, excipient and/or auxiliary substance. The pharmaceutical composition may further contain, for example, one or more substances including water, buffers (for example, neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (for example, glucose, mannose, sucrose or dextrans), mannitol, proteins, excipients, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, and/or preservatives.

In addition, one or more other active ingredients may (optionally) be included in the pharmaceutical composition of the present invention. Thus, for example, one or more compounds of the present invention may preferably be contained in a combination product that contains at least one additional active pharmaceutical ingredient. The other or additional active agent or active pharmaceutical ingredient is preferably an active agent or active pharmaceutical ingredient that is used to prevent or treat one or more pathological conditions responsive to modulation of the BK B2 receptor, including a pathological condition selected from the group consisting of a disorder skin; eye disease; ear disease; mouth, throat, and respiratory disease; gastrointestinal disease; disease of the liver, gall bladder and pancreas; urinary tract and kidney disease; disease of the male genital organs and female genital organs; disease of the hormonal system; metabolic disease; cardiovascular disease; blood disease; disease of the lymphatic system; central nervous system disorder; brain disorder; disease of the musculoskeletal system; allergic disorder; pain; infection; inflammatory disorder; damage; immunological disorder; cancer; hereditary disease and edema. Thus, for example, at least one compound or pharmaceutically acceptable salt according to the present invention may preferably be contained in a combination product which, as another or additional active agent or active pharmaceutical ingredient, includes an antibiotic, antifungal or antiviral agent, antihistamine, non-steroidal anti-inflammatory drug a disease-modifying agent, an antirheumatic drug, a cytostatic drug, a drug with smooth muscle modulating activity, an antibody, or mixtures of the above.

The pharmaceutical composition provided by the present invention can be formulated for any suitable route of administration, including, for example, topical (eg, transdermal or ocular), oral, buccal, nasal, vaginal, rectal, or parenteral administration. The term parenteral administration as used herein includes subcutaneous, intradermal, intravascular (eg, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intraarticular, and intraperitoneal injection, as well as any similar injection or infusion technique. In some embodiments, compositions are preferred if they are in a form suitable for oral administration. Such forms include, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups or elixirs. In other embodiments, the compositions of the present invention may be formulated as lyophilisates. Products intended for oral administration may be preferred for certain pathological conditions (eg, for the treatment of pathological skin conditions such as burns or itching). In summary, the pharmaceutical composition may be formulated, for example, as an aerosol, cream, gel, tablet, capsule, syrup, solution, transdermal patch, or pharmaceutical delivery device.

In the case of the prevention and/or treatment of diseases mediated by BK or its analogues, the dose of the biologically active compound proposed in the present invention can vary widely and can be adjusted according to individual needs. The active compounds of the present invention are typically administered in a therapeutically effective amount. Preferred dosages range from about 0.1 to about 140 mg/(kg body weight)/day (from about 0.5 mg to about 7 g per patient per day). The daily dose may be administered as a single dose or as multiple doses. The amount of active ingredient that is combined with the carrier material to prepare the unit dosage form depends on the subject being treated and the particular route of administration. Unit dosage forms typically contain from about 1 to about 500 mg of active ingredient.

However, it should be understood that the specific dosage for any given patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, patient's diet, time of administration, route of administration and rate of elimination, combination medications (i.e., other medications used to treat the patient) and the severity of the specific disease being treated.

The 8-benzyloxyquinolines of the present invention can also be used as BK B2 receptor antagonists in a variety of settings in vitro and in vivo. The BK B2 receptor antagonists of the present invention can be used to inhibit the binding of BK B2 receptor ligands (eg, BK) to the BK B2 receptor in vitro or in vivo. This use includes, for example, a method of inhibiting the binding of BK to the BK B2 receptor in vitro or in vivo, wherein the method includes contacting the BK B2 receptor with at least one compound or salt of the present invention, for example, corresponding to any of the options implementation [1]-[24], under such conditions and in such an amount that are sufficient to inhibit the binding of BK or any other substance to the BK receptor B2. The BK B2 receptor antagonists of the present invention are preferably administered orally or topically to a patient (eg, a human) and are present in at least one body fluid or tissue of the patient to modulate the activity of the BK B2 receptor.

BK B2 receptor antagonists according to any of embodiments [1] to [24] or the pharmaceutical composition of the present invention are useful as a medicine. In particular, BK B2 receptor antagonists or the pharmaceutical composition of the present invention are useful for the treatment and/or prevention and/or prophylaxis of a pathological condition or disease that responds to modulation of the BK B2 receptor. A pathological condition or disease that responds to modulation of the BK B2 receptor may be a skin disorder; eye disease; ear disease; mouth, throat, and respiratory disease; gastrointestinal disease; disease of the liver, gall bladder and pancreas; urinary tract and kidney disease; disease of the male genital organs and female genital organs; disease of the hormonal system; metabolic disease; cardiovascular disease; blood disease; disease of the lymphatic system; central nervous system disorder; brain disorder; disease of the musculoskeletal system; allergic disorder; pain; infection; inflammatory disorder; damage; immunological disorder; cancer; hereditary disease; swelling or syndrome(s) of increased capillary permeability. The following description further defines the above diseases and pathological conditions that respond to modulation of the BK B2 receptor.

Skin disorders.

As used herein, the term skin disorders includes, but is not limited to, disorders such as skin aging, skin surface changes including bedsores, irritated, sensitive and painful-looking skin, erythema, rash, skin swelling, psoriasis, eczema, lichen, caused by bacteria, viruses, fungi and parasites, infectious skin diseases, including boils, abscess, cellulitis, erysipelas, folliculitis and impetigo, pediculosis, scabies and herpes simplex, acne, exanthema, dermatitis, including atopic dermatitis, allergic contact dermatitis (Scholzen , T.E.; Luger, T.A. Exp Dermatol. 2004; 13 Suppl 4:22-6), neurodermatitis, radiation injury, sunburn, pruritis, itching, urticaria (EP 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, M.W.J. Am. Acad. Dermatol. 2005, 53, 373-88; quiz 389-92), psoriasis, mycosis, tissue ulceration, epidermolysis bullosa, wounds, including atypical wound healing, burns (Nwariaku, F.E.; Sikes, P.J.; Lightfoot, E.; Mileski, W. J.; Baxter, S. Burns 1996, 22, 324-7; Neely, A.N.; Imwalle, A.R.; Holder, I.A. Burns 1996, 22, 520-3), frostbite, poisoning-induced skin inflammation and swelling, alopecia, scaly hair, callus, wart and whitlow.

Eye diseases.

As used herein, the term eye disease 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 eye infections, nonspecific conjunctivitis and eye irritations, retrolethal fibroplasia, proliferative vitreoretinopathy, macular degeneration (including age-related macular degeneration and including both wet and dry forms), corneal diseases including corneal graft rejection, corneal damage, corneal scarring, corneal ulcer, opacities corneas, keratoconus, glaucoma (preferably open-angle glaucoma), myopia, ocular hypertension, ocular vascular injury, angiogenesis, pupillary fibrosis (eg, anterior subcapsular fibrosis, posterior subcapsular opacities, posterior capsular opacities, post-laser corneal opacities, post-laser subconjunctival scarring glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial eye infections, including styes and ptilosis.

Ear diseases.

As used herein, the term ear diseases includes, but is not limited to, disorders such as Meniere's disease, otitis media, ear canal inflammation, and acute hearing loss.

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Mouth, throat and respiratory diseases.

As used herein, the term oral, throat and respiratory diseases includes, but is not limited to, disorders such as inflammation of the oral mucosa and gums, including aphthae (rashes on the mucous membrane) and stomatitis, periodontitis, epiglottitis, pharyngitis , laryngotracheitis, tonsillitis, runny nose, sore throat, rhinitis, including seasonal allergic rhinitis or perennial allergic rhinitis, rhinorrhea, sinusitis of any type, etiology or pathogenesis, or sinusitis that is a member of the group consisting of the following: purulent or non-purulent sinusitis, acute and chronic sinusitis, and sinusitis of the ethmoid bone, frontal, maxillary or sphenoid sinus, sputum production, pneumoconiosis of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tobaccoosis, and especially byssinosis, bronchitis, cough, tracheitis, congestion, pneumonia, eosinophilic infiltration of the lungs, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other pulmonary fibrosis, treatment-related pulmonary fibrosis, e.g. associated with radiation, methotrexate treatment, chemotherapy, amiodarone or nitrofurantoin treatment, sarcoidosis, acute respiratory distress syndrome (ARDS), bronchoconstriction, asthma of any type (Akbary, A.M.; Wirth, K. J.; Scholkens, V.A. Immunopharmacology 1996, 33, 238-42; WO 00/75107 A2), etiology or pathogenesis, or asthma, which is a member of the group including asthma such as atopic asthma, non-atopic asthma, allergic and non-allergic asthma, acquired asthma caused by environmental factors, hereditary asthma caused by pathophysiological disorders, bronchial asthma, IgE-mediated asthma, essential asthma and essential asthma of unknown or hidden cause, true asthma, emphysematous asthma, stress asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, incipient asthma, infantile bronchitis syndrome , bronchial hyperresponsiveness, chronic obstructive pulmonary disease (COPD), COPD that is characterized by irreversible progressive airway obstruction, acute respiratory distress syndrome (ARDS) and exacerbation of airway hyperresponsiveness after treatment with another drug, shortness of breath, hyperoxic alveolar damage, pulmonary emphysema, pleurisy, tuberculosis, being at high altitude, i.e. acute mountain sickness and preferably high altitude pulmonary edema (HAPE), persistent cough, bronchial hyperresponsiveness.

Gastrointestinal diseases.

As used herein, the term gastrointestinal diseases includes, but is not limited to, disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcers, intestinal obstruction, irritable bowel syndrome, inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastro- and colopathy, colitis, peritonitis, appendicitis, proctitis, gastrointestinal bleeding caused by portal hypertension, collateral circulation or hyperemia, post-gastrectomy dumping syndrome, discomfort after eating, diarrhea, hemorrhoids, diseases caused by helminths, abdominal colic and colic in parts of the gastrointestinal tract.

Diseases of the liver, gall bladder and pancreas (Cugno, M.; Salerno, F.; Nussberger, J.; Bottasso, V.; Lorenzano, E.; Agostoni, A. Clin. Sci. (Lond) 2001, 101, 651 -7; WO 01/56995 A1; EP 0797997 B1; Wirth, K.J.; Bickel, M.; Hropot, M.; Gunzler, V.; Heitsch, H.; Ruppert, D.; Scholkens, B.A. Eur. J. Pharmacol 1997, 337, 45-53).

As used herein, the term liver and gallbladder diseases includes, but is not limited to, disorders such as hepatitis, liver cirrhosis, liver fibrosis (e.g. due to viral infections (hepatitis B virus/hepatitis C virus), toxins (alcohol) , fatty liver infiltration, biliary stasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatogenic edema, cholangitis, cholecystitis, acute and chronic pancreatitis and hepatic colic.

Diseases of the urinary tract and kidneys.

As used herein, the term urinary tract and kidney diseases includes, but is not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis (Campbell, D. J. Clin. Exp. Pharmacol. Physiol. 2001, 28, 1060- 5; Meini, S.; Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, D.; Maggi, C.A.; Lecci, A. Eur. J. Pharmacol. 2000, 388, 177-82; Zuraw , B.L.; Sugimoto, S.; Parsons, C.L.; Hugli, T.; Lotz, M.; Koziol, J.J. Urol. 1994, 152, 874-8; Rosamilia, A.; Clements, J.A.; Dwyer, P.L.; Kende, M.; Campbell, D. J. J. Urol. 1999, 162, 129-34), irritable bladder, overactive bladder (WO 2007003411 A2), incontinence including, but not limited to, stress, urge and reflex urinary incontinence, benign prostatic hyperplasia glands (Srinivasan, D.; Kosaka, A.H.; Daniels, D.V.; Ford, A.P.; 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, calciumuresis, fluid imbalance, electrolyte imbalance, acid-base imbalance and renal colic, renal fibrosis, chronic renal allograft dysfunction caused by nephrocontrast agent

- 12 043330 party.

Diseases of the male genital organs and female genital organs.

As used herein, the term diseases of the male genital organs and female genital organs include, but are not limited to, changes in sperm motility, male infertility, orchitis, prostatitis, enlarged prostate gland, mastitis, inflammatory diseases of the renal pelvis, vaginal infections and pain, adnexitis, colpitis, chancroid, syphilis, gonorrhea and ovarian hyperstimulation syndrome (Ujioka, T.; Matsuura, K.; Tanaka, N.; Okamura, H. Hum Reprod. 1998 Nov; 13(11):3009-15).

Diseases of the hormonal system.

As used herein, the term hormonal system diseases includes, but is not limited to, menstrual irregularities and menstrual pain, menopausal disorders, vomiting, premature uterine contractions, preterm labor, endometriosis, endometritis, fibroids, preeclampsia.

Metabolic diseases.

As used herein, 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, M.L.; Danis, R.P.; Criswell, M. ; Pratt, L. Expert Opin. Emerg. Drugs 2003, 8, 239-50; Gao, V.V.; Clermont, A.; Rook, S.; Fonda, S.J.; Srinivasan, V.J.; Wojtkowski, M.; Fujimoto , J.G.; Avery, R.L.; Arrigg, P.G.; Bursell, S.E.; Aiello, L.P.; Feener, E.P. Nat. Med. 2007, 13, 181-8; Tranos, P.G.; Wickremasinghe, S.S.; Stangos, N.T.; Topouzis, F. ; Tsinopoulos, I.; Pavesio, S.E. Surv. Ophthalmol 2004, 49, 470-90), diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulcers, disorders of protein metabolism and purine metabolism, such as gout and fat disorders metabolism, hypoglycemia.

Cardiovascular diseases.

As used herein, the term cardiovascular disease includes, but is not limited to, disorders including vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders including aortic aneurysm, abdominal aortic aneurysm, cerebral aortic aneurysm, hypertension and hypotension , associated with sepsis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis, including rupture of atherosclerotic plaques (Fernando, A.N.; Fernando, L.P.; Fukuda, Y.; Kaplan, A.P. Am J Physiol Heart Circ Physiol. 2005 Jul; 289(1): H251-7), hemangioma, angiofibroma, venous disorders such as thrombosis, varicose veins, phlebitis, thrombophlebitis, phlebothrombosis, cardiopathy, congestive heart failure, coronary artery disease, carcinoid syndrome, angina pectoris, cardiac arrhythmia, inflammatory heart diseases including endocarditis, pericarditis and constrictive pericarditis, myocarditis, myocardial infarction, post-infarction syndrome, left ventricular dilatation, 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, G.E. Am J Obstet Gynecol. 2005 Oct; 193(4): 1508-12), systemic inflammatory response syndrome (SIRS), including SIRS caused by cardiac bypass surgery, sepsis, and internal and external complications during cardiopulmonary bypass surgery (including but not limited to , adverse hemodynamic effects after discontinuation of heparin with protamine sulfate (Pretorius, M.; Scholl, F.G.; McFarlane, J.A.; Murphey, L.J.; Brown, N.J. Clin Pharmacol Ther. 2005 Nov; 78(5):477-85).

Blood diseases.

As used herein, the term blood diseases includes, but is not limited to, disorders such as coagulation, disseminated intravascular coagulopathy, hemorrhage, bleeding diathesis, hypercholesterolemia and hyperlipemia, hypovolemic shock, paroxysmal nocturnal hemoglobinuria.

Diseases of the lymphatic system.

As used herein, the term lymphatic system diseases includes, but is not limited to, splenomegaly, lymphangitis, lymphadenitis, and hyperplastic adenoids.

Central nervous system disorders.

As used herein, the term 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.

As used herein, the term brain disorders includes, but does not

- 13 043330 is limited only by them, disorders requiring treatment with nootropics or improvement of cognitive ability, amyloid angiopathy of the brain, stroke, head and brain trauma, traumatic brain injury (Marmarou, A.; Guy, M.; Murphey, L.; Roy, F.; Layani, L.; Combal, J.P.; Marquer, C.; American Brain Injury Consortium J Neurotrauma 2005 Dec; 22(12):1444-55), brain tumor, thermal brain injury, cerebral ischemia , intracerebral hemorrhage, post-traumatic and post-ischemic cerebral edema, generalized cerebral edema, acute mountain sickness, and preferably high altitude cerebral edema (HACE), cytotoxic cerebral edema, vasogenic cerebral edema, postoperative cerebral edema, associated cerebral edema with metabolic diseases, increased permeability of the blood-brain barrier or blood-brain barrier in brain tumors.

Diseases of the musculoskeletal system.

As used herein, the term diseases of the musculoskeletal system includes, but is not limited to, disorders such as inflammatory disorders of the musculoskeletal system, arthrosis, osteoarthritis, osteoarthritis, chondroporosis after joint trauma or relatively prolonged immobilization of the joint after damage to the meniscus or patella, or ligament rupture, 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, spondyloarthritis, ankylosing spondylitis, osteomyelitis, sprain, tenosynovitis, inflammation-induced bone resorption, fracture, etc., osteoporosis, musculoskeletal pain and hardening, intervertebral disc syndrome.

Allergic disorders.

As used herein, the term allergic disorders includes, but is not limited to, disorders such as general allergic reactions, food allergies, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis, and seasonal or perennial allergic rhinitis ( Summers, C.W.; Pumphrey, R.S.; Woods, C.N.; McDowell, G.; Pemberton, P.W.; Arkwright, P.D. J Allergy Clin Immunol. 2008, 121(3), 632-638).

Pain.

As used herein, the term pain includes, but is not limited to, pain mediated by the central and peripheral nervous system, vascular pain, visceral pain, inflammatory pain, neuralgic pain, repercussion pain, nociceptive pain, reflex pain, psychosomatic pain, acute pain such as caused by acute injury, trauma or surgery to bones, muscles, tissues, soft tissues, organs, pain after insect bites, post-impact pain syndrome, post-operative pain, pain associated with progressive disease, chronic pain such as caused by pathological conditions with neuropathic pain (including, but not limited to, complex regional pain syndrome (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, A. S.; Segond von Banchet, G.; Heppelmann, V.; Klusch, A.; Kniffki, K. D. Neuroscience 1998, 83, 949-59; Birklein, F.; Schmelz, M.; Schifter, S.; Weber, M. Neurology 2001, 57, 2179-84; Weber, M.; Birklein, F.; Neudorfer, W.; Schmelz, M. Pain 2001, 91, 251-7), causalgia, Sudek's disease, reflex sympathetic dystrophy), diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, pain associated with cancer, pain associated with rheumatoid arthritis, osteoarthritis ( Bond, A.P.; Lemon, M.; Dieppe, P.A.; Bhoola, K.D. Immunopharmacology 1997, 36, 209-16; Cassim, V.; Naidoo, S.; Ramsaroop, R.; Bhoola, K.D. Immunopharmacology 1997, 36, 121- 5; Calixto, J.B.; Cabrini, D.A.; Ferreira, J.; Campos, M.M. Pain 2000, 87, 1-5; Kaneyama, K.; Segami, N.; Sato, J.; Fujimura, K.; Nagao, T. .; Yoshimura, H.J. Oral. Maxillofac. Surg. 2007, 65, 242-7), tenosynovitis, gout, menstruation and sore throat, fibromyalgia, eye pain, back pain, headache, severe paroxysmal headache with periodic relapses, migraine ( Ebersberger, A.; Ringkamp, M.; Reeh, P.W.; Handwerker, H.O. J Neurophysiol. 1997 Jun; 77(6):3122-33), inflammatory pain, which may be associated with acute inflammation or chronic inflammation. Inflammatory pain includes, but is not limited to, neuropathic pain, ischemic pain, pain caused by arthritis, muscle pain caused by acute or chronic inflammation, neuralgia caused by acute or chronic inflammation, hyperalgesia. Also included are chemotherapy-induced peripheral neuropathy, hyperalgesia, opioid-induced hyperalgesia, and fever. In addition, the compounds proposed in the present invention are useful as an analgesic agent intended for use during general and controlled anesthesia.

Infectious diseases.

As used herein, the term infectious diseases includes, but is not limited to, diseases including those mediated by bacteria, viruses, fungi, parasites

- 14 043330 mi, protozoa, prions or mycobacterial infections. In particular, the present invention is applicable to the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus and Yersinia. Examples of bacterial infections within the scope of the present invention include, but are not limited to, diseases such as plague, sepsis, typhus, food poisoning, tetanus, scarlet fever, whooping cough, diphtheria. Examples of viral infections within the scope of the present invention include, but are not limited to, diseases such as chickenpox and herpes zoster, AIDS (acquired immunodeficiency syndrome), influenza, smallpox, and childhood diseases such as measles, rubella, mumps, acute poliomyelitis of the anterior horns of the spinal cord. The present invention is also useful for the treatment of protozoal and parasitic infections caused by Schistosoma mansoni, Dermatofagoides farinae and Plasmodium causing malaria. Examples of prion infections within the scope of the present invention include, but are not limited to, diseases such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob and kuru disease, Dengue fever, hemorrhagic fever.

Inflammatory disorders.

As used herein, the term inflammatory disorders includes, but is not limited to, disorders such as acute inflammation, local and systemic inflammation, and inflammation caused by other diseases of any type, etiology or pathogenesis, and inflammatory diseases caused by such diseases as specified in this application.

Damage.

As used herein, the term injury includes, but is not limited to, multiple trauma, head trauma, lung injury, external, internal and surgical wounds.

Immunological disorders.

As used herein, the term immunological disorders includes, but is not limited to, disorders such as hyperesthesia, autoimmune disorders, graft rejection after transplantation, graft toxicity, granulomatous inflammation/tissue remodeling, myasthenia gravis, immunosuppression, immune complex diseases, excessive and insufficient antibody production, vasculitis, delayed graft function, lupus.

Cancer diseases.

As used herein, the term cancers includes, but is not limited to, disorders such as solid tumor cancers, including breast cancer, lung cancer (non-small cell lung cancer and small cell lung cancer), prostate cancer, oral cancers, and pharynx (lips, tongue, mouth, pharynx), esophagus, stomach, small intestine, colon, colon, rectum, gallbladder and bile ducts, prostate, larynx, lung, bone, osteosarcoma, connective tissue cancer, cancer skin, including Kaposi's syndrome, melanoma and skin metastases, epidermoid cancer, basal cell carcinoma, cervical, endometrial, ovarian, testicular, bladder, ureter and urethra, kidney, eye, brain and central nervous system cancers , pseudobrain tumor, sarcoma, sarcoid, cancer of the thyroid and other endocrine glands (including, but not limited to, carcinoid tumors), Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, hematopoietic malignancies, including leukemia, and lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, formation of metastases, ascites, tumor growth and angiogenesis.

Hereditary diseases.

As used herein, the term hereditary diseases includes, but is not limited to, disorders such as hereditary angioedema (Davis, L.E. et al., 3rd Transfus. Apher. Sci. 2003, 29, 195-203; Zuraw, B.L. Immunol. Allergy Clin. North Am. 2006, 26, 691708; Bas, M. et al. Allergy 2006, 61, 1490-2) and angioedema, chondrocalcinosis, Huntington's disease, cystic fibrosis.

Edema.

As used herein, the term edema includes, but is not limited to, general and inflammatory edema, edema due to absence of factor XII, edema caused by other drugs, such as drug-induced angioedema, including but not limited to only them, caused by angiotensin converting enzyme inhibitor angioedema (Mathelier-Fusade, P. Clin. Rev. Allergy Immunol. 2006, 30, 19-23; Finley, C.J. et al. Am. J. Emerg. Med. 1992, 10, 550 -2; Bielory, L. et al. Allergy Proc. 1992, 13, 85-7), swelling caused by infection, burns, injury, trauma, frostbite, surgery, sprains, fractures, exposure to high altitude (eg, high-altitude pulmonary edema (HARE) and high altitude cerebral edema (HACE)), hereditary, autoimmune and other diseases and disorders, preferably, but not limited to, the disorders mentioned herein, stress-induced edema (severe swelling) of the intestines.

Capillary leak syndrome(s).

As used herein, the term capillary leak syndrome(s) includes, but is not limited to, systemic capillary leak syndrome in sepsis (Marx, G. Eur J Anaesthesiol. 2003 20(6):429-42; Traber, D.L. Crit Care Med. 2000, 28(3):882-3), burn (Jonkam, C.C.; Enkhbaatar, P.; Nakano, Y.; Boehm, T.; Wang, J.; Nussberger, J. Esechie, A.; Traber , L.D.; Herndon, D.; Traber, D.L.. Shock. 2007 Dec; 28(6):704-9), in allergy, drug/toxin-induced conditions, organ transplantation, and IL-2 cytokine treatment.

The compound of the present invention can also be used as a diagnostic agent or for the preparation of a diagnostic agent. Such a diagnostic agent is particularly useful for diagnosing diseases and pathological conditions disclosed in the present invention for which the compound of the present invention is used for therapeutic and prophylactic purposes. The compound of the present invention is also useful in the specific diagnostic methodologies and techniques disclosed below in the present invention.

Methodology and diagnostic techniques.

The compounds of the present invention can be labeled with isotopes, fluorescent or luminescent 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 (eg, in tissue sections) and as radiotracers for positron emission tomography (PET) single-photon imaging. emission computed tomography (SPECT), etc. to characterize these receptors in living subjects or other materials.

The present disclosure also relates to methods for altering bradykinin receptor signaling activity in vitro and in vivo. For example, the compounds of the present invention and their labeled derivatives can be used as a standard and reagent to determine the ability of a possible pharmaceutical agent to bind to the BK B2 receptor.

The present disclosure also relates to methods of localizing or detecting the BK B2 receptor in a tissue, preferably a tissue section, which comprises contacting a tissue sample containing the BK B2 receptor with a detectably labeled compound of the present invention under conditions that allow the compound to bind to BK B2 receptor, and detecting the bound compound. Such techniques and appropriate conditions for performing them are known to those skilled in the art and include, for example, the binding assay disclosed in Example 12.

The present description also relates to a method of treating a patient suffering from a pathological condition or disease responsive to modulation of the BK B2 receptor described above. A method of treating a subject in need of such treatment includes administering a compound of the present invention, for example, corresponding to any of embodiments [1]-[24], a pharmacologically acceptable salt thereof, a pharmaceutical composition disclosed in the present invention, or a combination product, disclosed in the present invention. As used herein, the term treatment includes both disease-modifying treatment and symptomatic treatment, each of which may be prophylactic (i.e., given before the onset of symptoms to delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms). symptoms to reduce the severity and/or duration of symptoms). A pathological condition is responsive to modulation of the BK B2 receptor if modulation of the activity of the BK B2 receptor leads to an attenuation of the pathological condition or its symptoms. Patients may include, but are not limited to, primates (especially humans), companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), when using the doses described in the present invention.

The compounds of general formula (I) proposed in the present invention have improved characteristics compared to the characteristics of BK B2 receptor antagonists known in the art, in particular one or more improved pharmacokinetic and/or physicochemical characteristics, including, for example , bioavailability, metabolic stability, improved activity/selectivity, low toxicity and negligible drug interactions. Accordingly, the compound (or a pharmacologically acceptable salt thereof) or pharmaceutical composition disclosed in the present invention can be used as a medicament for the treatment and/or prevention of a pathological condition responsive to modulation of the BK B2 receptor, including, for example, the pathological conditions listed above .

The present invention is further illustrated by the following examples, from which additional features, embodiments and advantages of the present invention may be identified. However, the present invention is not limited to examples, but

- 16 043330 the essence is defined in the claims.

Examples

The abbreviations used in the examples below are as follows:

ACN stands for acetonitrile,

BuLi stands for n-butyllithium,

DCM stands for dichloromethane,

DIPEA stands for ethyldiisopropylamine,

DMF stands for dimethylformamide,

EA stands for ethyl acetate,

HPLC stands for High Performance Liquid Chromatography,

MeOH stands for methanol,

NBS stands for N-bromosuccinimide,

NMP stands for N-methylpyrrolidone,

PyAOP stands for 7-azabenzotriazol-1-yloxy)tripyrrolidine phosphonium hexafluorophosphate,

pyBOP stands for (benzotriazol-1-yloxy)tripyrrolidine phosphonium hexafluorophosphate,

CT stands for room temperature,

THF stands for tetrahydrofuran,

TLC stands for thin layer chromatography,

TFA stands for trifluoroacetic acid.

The following examples provide specific examples of the preparation of compounds of formula (I). Unless otherwise stated, all starting materials and reagents were standard commercially available materials and were used without further purification or were readily prepared from such materials by standard procedures. It will be obvious to those skilled in the field of organic synthesis that in the preparation of compounds within the scope of the present invention, starting materials and reaction conditions may vary, including additional steps.

Example 1. Preparation of compound No. 1

(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.

Stage A. Synthesis of methyl 3-amino-5-fluoro-2-methylbenzoate.

Methyl 5-fluoro-2-methyl-3-nitrobenzoate [Gillmore, A.T. et al. Org. Process Res. Dev. 2012, 16, 18971904] (4.69 g, 22 mmol) was dissolved in MeOH (100 ml) and palladium on activated charcoal - 10% Pd (200 mg) was added. The vessel with the solution was purged with nitrogen three times and evacuated, then it was purged with hydrogen. The reaction mixture was vigorously stirred under a hydrogen pressure of 1 atm. After completion of the reaction according to TLC (21 h), the solution was filtered through silica gel. The filter cake was washed with methanol (5x20 ml). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to give the title compound. MS (mass spectrometry) (m/z): 184.0 [M+H+].

Step B. Synthesis of methyl 3-chloro-5-fluoro-2-methylbenzoate.

NaNO ₂ (1.68 g, 24.4 mmol) was added at 0°C to a solution of methyl 3-amino-5-fluoro-2-methylbenzoate (4.00 g, 18.8 mmol) in a halved aqueous solution HCl (400 ml). After stirring at 0°C for 5 min, CuCl (3.72 g, 37.5 mmol) was added to the reaction mixture. After stirring at 0°C for 2 h, the reaction mixture was extracted with DCM (2x100 ml). The combined organic layers were washed with concentrated aqueous NaHCO ₃ (1x), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting 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 the solution of methyl 3-chloro-5-fluoro-2-methylbenzoate (200 mg, 0.99 mmol) with stirring. in benzene (7.0 ml). After stirring at reflux for 1.5 hours, the reaction mixture was diluted with EA (20 ml) and washed with 10% aqueous Na ₂ S ₂ O ₃ solution (1x5 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound.

Step D. Synthesis of methyl 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoate.

Cs ₂ CO ₃ (617 mg, 3.20 mmol) was added with stirring to a solution of 2-(bromomethyl)-3-chloro-5fluorobenzoate (300 mg, 1.07 mmol) and 4-methoxyphenol (172 mg, 1.39 mmol ) in ACN (7.0 ml). After stirring at RT overnight, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) and floor

- 17 043330 found the required connection. MS (m/z): 342.1 [M+NH ₄ +].

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 solution of methyl 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzoate (9, 16 g, 28 mmol) in dioxane (100 ml). After stirring at RT for 2 hours, the reaction mixture was concentrated in vacuo and the pH value was adjusted to 1-2 by adding concentrated aqueous HCl solution. The mixture was extracted with DCM (3x100 ml), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound.

Step F. Synthesis of 1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone.

A solution of methyllithium (1.6 M, 30.2 ml) in diethyl ether at 0°C 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). After stirring at 0°C for 30 minutes, the reaction was stopped by adding saturated aqueous NH ₄ Cl solution (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 (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound.

Step G. Synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2methylpropane-2-sulfinamide.

Under argon, titanium(IV) ethoxide (2.53 mL, 12.05 mmol) was added dropwise to a solution of 1-(3chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone (1.24 g, 4.02 mmol) and (R)-(+)-2-methyl-2propanesulfinamide (535.5 mg, 4.42 mmol) in anhydrous THF (10 ml). The mixture was refluxed until complete conversion (TLC) was achieved. 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) was achieved. Methanol (~10 ml) was then added until gas evolution ceased. The solution was poured into saturated aqueous NaCl solution (30 ml). The mixture was then filtered through a pad of celite and washed gently with DCM. The filtrate was washed with saturated aqueous NaCl solution. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (mz): 458.2 [M+HCO2'].

Step H. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine.

Solution of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2sulfinamide (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 in vacuo. The resulting residue was dissolved in DCM (5 ml) and washed with saturated aqueous NaHCO ₃ (6 ml) and water (6 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound. MS (m/z): 354.4 [M+HCO2 ^- ]

Stage I. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3dione

Phthalic anhydride (862 mg, 5.82 mmol) was added to a solution of (S)-1-(3-chloro-5-fluoro-2-((4methoxyphenoxy)methyl)phenyl)ethanamine (1.64 g, 5.26 mmol ) in DCM (20 ml). The mixture was stirred for 15 minutes and then concentrated in vacuo. The resulting residue was heated in an open vessel for approximately 10 minutes to 175°C. After 45 minutes at this temperature, the reaction mixture was cooled to room temperature and purified by flash chromatography on silica gel (eluting with heptane/EA) 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 H ₂ O (4 ml) was added to the solution of (S)-2-(1-(3-chloro- 5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3dione (1.07 g, 2.45 mmol) in ACN (20 ml). After stirring at 0°C for 5 hours, the reaction was stopped by adding brine (20 ml) and H ₂ O (5 ml). The mixture was extracted with EA (3x100 ml), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound.

Step K. Synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione.

SOCl ₂ (288 µl, 3.96 mmol) and water (4 µl) were added to the (S)-2(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl) solution with stirring at RT. isoindoline-1,3-dione (662 mg, 1.98 mmol) in DCM (10 ml). The solution was stirred until complete conversion (TLC) was achieved. The solvent was then removed in vacuo and the residue was purified by flash chromatography on silica gel (eluting with EA/heptane) 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-1H-pyrazol-1-yl)-2-methylquinoline-8

- 18 043330 yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione.

Cs ₂ CO ₃ (1.94 g, 5.95 mmol) was added to the solution of (S)-2-(1-(3-chloro-2(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3 with stirring -dione (698 mg, 1.98 mmol) and 4-(4-fluoro-1H-pyrazol-1yl)-2-methylquinolin-8-ol (482 mg, 1.98 mmol) in ACN (20 ml). After stirring at RT overnight, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) 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-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl )ethanamine.

Hydrazine hydrate (371 μl) was added to a solution of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol1-yl)-2-methylquinoline-8- yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione (1.07 g, 1.91 mmol) in EtOH (30 ml). After stirring at 85°C for 2 hours, the reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (elution with DCM/MeOH/conc. aqueous NH3) to give 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-1H-pyrazol-1-yl)-2-methylquinolin- 8yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide.

RuAOP (90.7 mg, 174 µmol) and DIPEA (29.4 mg, 227 µmol) were sequentially added to the solution of (S)-1-(3-chloro-5-fluoro-2-(( 4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethanamine (55.1 mg, 137 µmol) and (R)-2-hydroxypropanoic acid (13.9 mg , 154 µmol) in DMF (4.5 ml). After stirring at RT for 2 hours, the reaction mixture was concentrated in vacuo. Purification of the resulting residue by reverse phase HPLC provided the title compound. MS (m/z): 501.2 [M+H+].

Step O. Synthesis of 4-(4-fluoro-1H-pyrazol-1-yl)-8-methoxy-2-methylquinoline K ₂ CO ₃ (4.99 g, 36.1 mmol) was added to the 4-chloro mixture with stirring -8-methoxy-2-methylquinoline (5.00 g, 24.0 mmol) and 4-fluoro-1H-pyrazole (3.85 g, 28.8 mmol) in anhydrous NMP (12 ml). After stirring at 140°C for 48 h, the reaction mixture was cooled to RT and filtered. The residue was washed with DMF (13 ml). Water (90 ml) was then added to the combined filtrates. The precipitate was filtered and purified by flash chromatography on silica gel (eluting with DCM/methanol) to give the title compound. mS (m/z): 258.0 [M+H+].

Step P. Synthesis of 4-(4-fluoro-1H-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 with vigorous stirring, added dropwise to a mixture of AlCl ₃ (8.58 g, 64.3 mmol) and anhydrous toluene (32.4 ml). After stirring at 80°C for 8 hours, the reaction mixture was cooled to 0°C and the reaction was stopped by adding water (106 ml) and concentrated aqueous NH3 solution (27 ml). After stirring at RT overnight, the mixture was centrifuged. The supernatant was extracted with EA (3x200 ml) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/methanol) to give the title compound.

Example 2. Preparation of compound No. 2

(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-hydroxy-N-methylpropanamide.

Step A. Synthesis of (2S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2(tetrahydro-2H-pyran-2 -yloxy)propanamide.

(S)-1-(3-Chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (100 mg, 323 μmol) 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 µmol) in accordance with the synthesis procedure No. (1-(3-chloro-5-fluoro-2-((4-(4-fluoro1H -pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-3-hydroxy-2-methylpropanamide. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) 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-methyl2-(tetrahydro-2H- pyran-2-yloxy)propanamide.

(2S)-N-((S)-1-(3-Chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-(tetrahydro-2H-pyran-2yloxy)propanamide ( 50 mg, 107 µmol) was dissolved in anhydrous DMF (approximately 5 ml/mmol). Sodium hydride [60% in paraffin] (4.7 mg, 118 µmol) was added under argon and the mixture was stirred in

- 19 043330 for 20 minutes. Iodomethane (33.3 µl, 535 µmol) was then added and stirring was continued until complete conversion (TLC) was achieved. Water was added and extracted several times with

EA. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) 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-Nmethylpropanamide.

(2S)-N-((S)-1-(3-Chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-N-methyl-2-(tetrahydro-2Hpyran-2- Iloxy)propanamide (41.0 mg, 85 μmol) was reacted with cerium(IV)-ammonium nitrate (117.1 mg, 214 μmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro -5-fluoro-2(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione. The crude product was dissolved in methanol, 3 M methanolic HCl was added and stirring at RT was continued until the reaction was complete (TLC). Evaporation under reduced pressure gave the desired 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-Nmethylpropanamide.

(S)-N-((S)-1-(3-Chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-hydroxy-N-methylpropanamide (13.70 mg, 47 μmol) was added to reaction with SOCl ₂ (6.82 μl, 11.18 mg, 156 μmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline -1,3-dione and obtained the desired compound. MS (m/z): 330.4 [M+Na].

Stage E. Synthesis of (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin- 8yloxy)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 µmol) was reacted with 4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-ol (12 mg, 47 µmol) according to the procedure for the synthesis of (S)-2-(1-(3-chloro- 5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione to obtain the desired compound. MS (m/z): 515.5 [M+H+].

Example 3. Preparation of compound No. 3

(R)-3-Amuho-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-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 NaHCO ₃ (107 mg, 1.27 mmol) were added to a mixture of (R)-3-amino-2hydroxypropanoic 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 at RT overnight. The mixture was then acidified to pH 2 using 1 M HCl solution. The mixture was then extracted several times with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS (m/z): 206.2 [M+H+].

Stage B. Synthesis of tert-butyl-(R)-3-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)- 2methylquinolin-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)-2hydroxypropanoic acid (18.0 mg, 0.09 mmol) according to the procedure for the synthesis of (R)-N-((S )-1-(3chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide and obtained the desired 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-fluoro-1H-pyrazol-1-yl)- 2methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide.

Crude tert-butyl-(R)-3 -((S)-1 -(3 -chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)-2- Methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-2-hydroxy-3-oxopropylcarbamate was dissolved in DCM (1.5 ml) and TFA (200 μl) was added. The mixture was stirred for 1 hour. The mixture was then diluted with toluene (1.5 ml) and concentrated in vacuo. Purification of the residue by reverse phase HPLC provided the title compound. MS (m/z): 516.5 [M+H+].

Example 4. Preparation of compound No. 4

- 20 043330 (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.

Stage A. Synthesis of (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin- 8yloxy)methyl)phenyl)ethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide.

(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 procedure ( 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 obtain the crude title compound. The crude product was used without further purification.

Stage B. Synthesis of (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin- 8yloxy)methyl)phenyl)ethyl)-2,3-dihydroxypropanamide.

Crude (S)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)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 hours. The mixture was then concentrated in vacuo. Purification of the residue by reverse phase HPLC provided 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-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy) methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide.

Stage 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 Zn dust (14.4 g, 220 mmol) and NH4Cl (11.8 g, 220 mmol) were added. The reaction mixture was stirred at RT for 3 hours. After completion of the transformation, the mixture was filtered through a pad of celite. It was washed carefully with EA and the filtrate was washed with water. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound.

Stage B. Synthesis of 1-bromo-3-chloro-5-fluoro-2-methylbenzene.

NaNO ₂ (1.93 g, 28.0 mmol) was added at 0°C to a solution of 3-bromo-5-fluoro-2-methylaniline (4.40 g, 21.6 mmol) in acetic acid (100 ml) and half-diluted aqueous solution of HCl (400 ml). After stirring at 0°C for 5 min, CuCl (3.72 g, 37.5 mmol) was added to the reaction mixture. After stirring at 0°C for 2 hours, the reaction mixture was warmed to RT and stirring was continued for another 3 hours. The mixture was then extracted with Et ₂ O. The combined organic layers were washed with concentrated aqueous NaHCO ₃ solution (1 x), dried over Na2SO4 , filtered and concentrated in vacuo (maximum bath temperature 30°C, vacuum >150 mbar) to obtain the desired compound.

Step C. Synthesis of 1-bromo-2-(bromomethyl)-3-chloro-5-fluorobenzene.

NBS (4.61 g, 25.9 mmol) and AIBN (azo-bis-isobutyronitrile, 531 mg, 3.23 mmol) were added to a solution of 1-bromo-3-chloro-5-fluoro-2-methylbenzene ( 5.43 g, 21.6 mmol) in ACN (150 ml). After stirring at reflux for 8 hours, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with heptane/EA) to give the title compound.

Step D. Synthesis of 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene.

Cs ₂ CO ₃ (14.5 g, 44.5 mmol) was added with stirring to a solution of 1-bromo-2-(bromomethyl)-3chloro-5-fluorobenzene (4.48 g, 14.8 mmol) and 4-methoxyphenol (2.39 g, 19.3 mmol) in ACN (250 ml). After stirring at RT overnight, the reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in DCM and washed with water (1x). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound.

Step E. Synthesis of (R)-N-((R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-fluoro-2-((4methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane -2-sulfinamide.

AlMe ₃ (2 M solution in toluene, 741 μl, 1.48 mmol) at -78°C was added to a solution of (R,E)-N-(2(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (325 mg, 1.17 mmol) in anhydrous toluene (1 ml). Then, in a second vessel of BuLi (2.5 M solution in hexanes, 544 μl, 1.36 mmol) at 78°C, 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl )benzene (427 mg, 1.24 mmol) in dry toluene. The solution was stirred at this temperature for 15 minutes. A solution containing 1-bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene at -78°C was slowly added to containing (R,E)-N-(2-(tert-butyldimethylsilyloxy) ethylidene)-2-methylpropane-2-sulfinamide solution. The mixture was stirred for 22 hours and allowed to warm to RT. After completion of the transformation, the reaction was stopped with a saturated aqueous solution of NH ₄ Cl. The mixture was extracted with EA and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with

EA/heptane) and the desired compound was obtained. 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-(tert-Butyldimethylsulyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2methylpropane-2-sulfinamide (149 mg, 0.27 mmol) was reacted with 3 M methanolic HCl solution (274 μl, 0.82 mmol) according to the procedure for the synthesis of (S)-1-(3-chloro-5-fluoro-2-( (4-methoxyphenoxy)methyl)phenyl)ethanamine and the desired compound was obtained. MS (m/z): 370.3 [M+HCO2 ^- ].

Step G. Synthesis of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2hydroxyethyl)-2-hydroxy-3-methylbutanamide

RuBOP (279 mg, 0.53 mmol) and DIPEA (114 μl mg, 0.67 mmol) were sequentially added to the (R)-2-amino-2-(3-chloro-5-fluoro) solution with stirring at 0°C -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). After stirring at RT for 16 h, the reaction mixture was concentrated in vacuo. The residue was redissolved in saturated methanolic ammonia, stirred at RT for 3 hours and concentrated in vacuo. Purification of the resulting residue by flash chromatography on silica gel (eluting with EA/heptane) gave the title compound. MS (m/z): 426.4 [M+H+].

Step H. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)-3-methyl -1-oxobutan-2-ylbenzoate.

Pyridine (300 µl) and benzoyl chloride (89.3 µl, 0.77 mmol) were added successively to the 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 at RT for 23 h, the reaction mixture was concentrated in vacuo. The resulting residue was redissolved in toluene (2 ml) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (mz): 634.3 [M+H+].

Stage I. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethylamino)3-methyl-1-oxobutane-2 -ylbenzoate.

(S)-1-((R)-2-(Benzoyloxy)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutane -2-yl benzoate (141 mg, 0.22 mmol) in ACN (2 ml) was reacted with cerium(IV)-ammonium nitrate (304 mg, 0.56 mmol) in water (400 μl) according to the synthesis procedure (S)-2-(1-(3chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) 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)-3methyl-1-oxobutan-2-ylbenzoate .

(S)-1-((R)-2-(Benzoyloxy)-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-ylbenzoate ( 48.3 mg, 0.09 mmol) was reacted with SOCl ₂ (13.3 μl, 0.18 mmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl )-5-fluorophenyl)ethyl)isoindoline-1,3-dione and obtained the desired compound. MS (m/z): 546.6 [M+H+].

Step K. Synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl )-2methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-ylbenzoate.

Cs ₂ CO ₃ (89.4 mg, 0.28 mmol) was added to the solution of (S)-1-((R)-2-(benzoyloxy)1-(3-chloro-2-(chloromethyl)-5) with stirring -fluorophenyl)ethylamino)-3-methyl-1-oxobutan-2-ylbenzoate (46.8 mg, 0.09 mmol) and 4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinoline-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 over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (m/z): 753.4 [M+H+].

Stage L. Synthesis of (S)-N-((R)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin- 8yloxy)methyl)phenyl)-2-hydroxyethyl)-2-hydroxy-3-methylbutanamide.

Solution (S)-1 -((R)-2-(benzoyloxy)-1 -(3-chloro-5-fluoro-2-((4-(4-fluoro-1 H-pyrazol-1 -yl)- 2-Methylquinolin-8-yloxy)methyl)phenyl)ethylamino)-3-methyl-1-oxobutan-2-ylbenzoate (46.2 mg, 0.06 mmol) in concentrated methanol ammonia solution was stirred at RT overnight. After conversion was complete (TLC), the reaction mixture was concentrated in vacuo. Purification of the residue by reverse phase HPLC provided the title compound. MS (m/z): 545.2 [M+H+].

Step M. Synthesis of (R,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2sulfinamide.

A solution of titanium(IV) ethoxide (363 μl, 1.73 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (210 mg,

- 22 043330

1.73 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (300 μl, 1.58 mmol) in dry DCM (15 ml) were stirred under nitrogen at RT for 22 h. After completion of the conversion (TLC), the reaction was quenched with water (15 ml) and the mixture was filtered through a pad of celite. The filter was then washed gently with DCM (2x15 ml). The aqueous phase was extracted with DCM (10 ml) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound.

Example 6. Preparation of compound No. 6

(S)-N-(1-(3-Chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8 -yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

Stage A. Synthesis of 8-methoxy-2-methyl-4-(1-methyl-III-1,2,4-triazol-5-yl)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), K ₂ CO ₃ (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) was suspended in dry xylene (20 ml). The flask was evacuated and then purged with nitrogen. The degassing procedure was repeated twice. The mixture was heated at 140°C for 18 hours. Once the conversion was complete, the mixture was evaporated and purified by flash chromatography on silica gel (eluting with DCM/methanol) to give the title compound. MS (m/z): 255.4 [M+H+].

Step B. Synthesis of 2-methyl-4-(1-methyl-1H-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, with vigorous stirring, added dropwise to a mixture of AlCl ₃ (4.94 g, 37.06 mmol) in anhydrous toluene (25 ml). After stirring at 80°C for 8 hours, the reaction mixture was cooled to 0°C and the reaction was stopped by adding water (68 ml) and then adding concentrated aqueous NH3 solution until pH 10 (~1.7 ml). The mixture was centrifuged. The supernatant was extracted with EA and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/methanol) to give the title compound. mS (m/z): 239.2 [M-H+].

Step C. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl )quinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione.

(S)-2-(1-(3-Chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione (34.3 mg, 97 μmol) was reacted with 2-methyl- 4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-ol (23.4 mg, 97 µmol) according to the procedure for the synthesis of (S)-2-(1-( 3-chloro-5-fluoro-2-((4-(4-fluoro-III-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione and obtained the desired compound. MS (m/z): 556.3 [MH ⁺ ].

Step D. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin- 8yloxy)methyl)phenyl)ethanamine.

U (S)-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin- 8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione (45.5 mg, 82 μmol) was deprotected according to the procedure for the synthesis of (S)-1-(3-chloro-5-fluoro-2 -((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethanamine and the desired compound was obtained. MS (m/z): 448.3 [M+Na ⁺ ].

Step E. Synthesis of (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl )quinolin-8yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

(S)-1-(3-Chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triαzol-5-ul)quinolin-8-uloxy) Methyl)phenyl)ethanamine (28.9 mg, 68 µmol) and 2-(difluoromethoxy)acetic acid (11.1 mg, 88 µmol) were reacted according to the procedure for the synthesis of (R)-N-((S)- 1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-ul)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide and obtained the desired 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-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl) ethyl)-2hydroxy-2-methylpropanamide.

Step A. Synthesis of (3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)methanol.

- 23 043330

LiBH ₄ (200 mg, 9.3 mmol), with stirring at RT for 3 hours, was added in several portions to a 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). After stirring at RT for 1 hour, the reaction mixture was partitioned between DCM (20 ml) and water (10 ml). The aqueous layer was extracted with DCM (2x15 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with EA/heptane) 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 the oxide was added manganese(IV) (9.96 g, 114.59 mmol). The reaction mixture was stirred at RT until the reaction was complete (TLC). After filtration through Celite, the filtrate was evaporated under reduced pressure to obtain the title compound.

Step C. Synthesis of (R,E)-N-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)-benzylidene)-2methylpropane-2-sulfinamide.

Under argon, 3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzaldehyde (317 mg, 1.08 mmol) and (R)-tBu-sulfinamide (143 μL, 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 completion of the reaction, the reaction was stopped with water. The aqueous layer was extracted 3 times with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to obtain 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)-2methylpropane-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 µmol) 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 RT overnight. Ice was carefully added, then the mixture was diluted with saturated aqueous NH ₄ Cl. The aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over Na ₂ SO ₄ and, after filtering, evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the desired 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)nropyl)-2-methylnpropane-2-sulfinamide (182 mg, 425 µmol ) was reacted with a 3 M methanol solution of HCl in accordance with the procedure for the synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to obtain the desired 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)isoindoline1,3-dione.

(S)-1-(3-Chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)propan-1-amine (95.4 mg, 295 μmol) was reacted with phthalic anhydride (48 mg , 324 µmol) in accordance with the procedure for the synthesis of (S)-2(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)isoindoline-1,3-dione and obtained the desired 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 μmol) was reacted with cerium(IV)-ammonium nitrate (308 mg, 562 µmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1, 3-dione and obtained the desired 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 μmol) was reacted with SOCl ₂ ( 22.06 μl, 304 μmol) in accordance with the procedure for the synthesis of (S)2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione and the desired compound was obtained. MS (m/z): 388.3 [M+Na].

Stage I. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl) phenyl)propyl)isoindoline-1,3-dione.

(S)-2-(1-(3-Chloro-2-(chloromethyl)-5-fluorophenyl)propyl)isoindoline-1,3-dione (53.3 mg, 146 μmol) was reacted with 4-(4 -fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-ol (35.4 mg, 146 µmol) according to the procedure for the synthesis of methyl-(S)-2-(1-(3-chloro-5 -fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione to obtain the desired compound. MS (m/z): 573.4 [M+H+].

Step J. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)propane -1-amine.

(S)-2-( 1 -(3-Chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1 -yl)-2-methylquinolin-8-yloxy)methyl)phenyl) propyl)iso- 24 043330 indoline-1,3-dione (80.8 mg, 141 µmol) was reacted with hydrazine hydrate (27.5 µl, 282 µmol) in accordance with the procedure for the synthesis of (S)-1-(3- chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethanamine to obtain the desired compound. MS (m/z): 444.1 [M+H+].

Step K. Synthesis of (S)-N-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)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 procedure for the synthesis of (R)-N-((S)-1-(3-chloro-5 -fluoro-2-((4-(4-fluoro-1H-pyrazol-1yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to obtain the desired compound. MS (m/z): 529.6 [M+H+].

Example 8. Preparation of compound No. 8

(R)-N-((S)-1 -(3-Chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1 H-pyrazol-1 -yl)-2-methylquinoline -8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide.

Stage A. Synthesis of 4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-8-methoxy-2-methylquinoline.

A mixture of 4-hydrazinyl-8-methoxy-2-methylquinoline (100 mg, 0.493 mmol) and 3-fluoro-4,4dimethoxybutan-2-one (110 mg, 0.739 mmol) [Funabiki, K. et al. J. Chem. Soc., Perkin Trans. 1 1997, 18, 2679-2680] in a 5 M aqueous solution of HCl (5.3 ml) was stirred at 90°C for 1.5 hours. The reaction mixture was concentrated in vacuum, subjected to distribution between a saturated aqueous solution

NaHCO ₃ (3 ml) and DCM (5 ml). The aqueous layer was extracted with DCM (2x5 ml), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with MeOH/DCM) to give the title compound. MS (m/z): 272.0 [M+H+].

Step B. Synthesis of 4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinolin-8-ol.

4-(4-Fluoro-5-methyl-1H-pyrazol-1-yl)-8-methoxy-2-methylquinoline (118 mg, 0.436 mmol) was demethylated according to the procedure for the synthesis of 4-(4-fluoro-1H-pyrazole -1-yl)-2-methylquinolin-8-ol and the desired compound was obtained. MS (m/z): 258.1 [M+H+].

Step C. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinoline8- yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione.

4-(4-Fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinolin-8-ol (21.0 mg, 82 μmol) was reacted with (S)-2-(1-( 3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione (28.8 mg, 82 µmol) according to the procedure for 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 and obtained the desired compound. MS (m/z): 573.1 [M+H+].

Step D. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl )phenyl)ethanamine.

U (S)-2-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy )Methyl)phenyl)ethyl)isoindoline-1,3-dione (31.1 mg, 54 μmol) was deprotected according to the procedure for the synthesis of (S)-1-(3-chloro-5-fluoro-2-(( 4-(4-fluoro-1 H-pyrazol-1 -yl)-2-methylquinolin-8 yloxy)methyl)phenyl)ethanamine and the desired compound was obtained. MS (m/z): 465.4 [M+Na ⁺ ].

Stage E. Synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1H-pyrazol-1-yl)- 2methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide.

(S)-1 -(3-Chloro-5-fluoro-2-((4-(4-fluoro-5-methyl-1 H-pyrazol-1 -yl)-2-methylquinolin-8-yloxy)methyl) Phenyl)ethanamine (20.5 mg, 46 μmol) was coupled with (R)-2-hydroxypropanoic acid (4.8 mg, 53 μmol) according to the procedure for 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 and obtained the desired compound. MS (m/z): 515.9 [M+H+].

Example 9 Preparation of Compound No. 9 and Compound No. 10

(S)-N-(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-(difluoromethoxy)acetamide (9) and (S)-N-( 1 -(3 -chloro-5 -fluoro-2-((2-methyl-4-(3 -methyl-1H-1,2,4triazol-1-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (10).

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Stage A. Synthesis of 8-methoxy-2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinoline and 8-methoxy-2methyl-4-(3-methyl-1H- 1,2,4-triazol-1-yl)quinoline.

4-Chloro-8-methoxy-2-methylquinoline (100 mg, 0.481 mmol) was reacted with 3-methyl-1H-1,2,4triazole (46.0, 0.554 mmol) according to the procedure for the synthesis of 4-(4 -fluoro-1H-pyrazol-1-yl)-8methoxy-2-methylquinoline and a mixture of the desired compounds was obtained. MS (m/z): 255.3 [M+H+].

Step B. Synthesis of 2-methyl-4-(3-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-ol and 2-methyl-4-(5-methyl1H-1,2, 4-triazol-1-yl)quinolin-8-ol.

A mixture of 8-methoxy-2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinoline and 8-methoxy-2-methyl-4-(3methyl-1H-1,2 ,4-triazol-1-yl)quinoline (153 mg, 0.602 mmol) was demethylated according to the procedure for the synthesis of 4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-ol to obtain a mixture of the desired connections. MS (m/z): 241.1 [M+H+].

Step C. Synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl )quinolin-8yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione and (S)-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(3 - methyl-1H1,2,4-triazol-1-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione.

A mixture of 2-methyl-4-(3-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-ol and 2-methyl-4-(5-methyl-1H-1,2,4 -triazol-1yl)quinolin-8-ol (48.3 mg, 0.201 mmol) was reacted with (S)-2-(1-(3-chloro-2-(chloromethyl)-5fluorophenyl)ethyl)isoindoline-1 ,3-dione (70.7 mg, 0.201 mmol) according to the procedure for the synthesis of (S)-2-(1-(3chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol- 1 -yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione and a mixture of the desired compounds was obtained. MS (m/z): 556.4 [M+H+].

Step D. Synthesis of (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolin- 8yloxy)methyl)phenyl)ethanamine and (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(3-methyl-1H-1,2,4-triazol-1 yl )quinolin-8-yloxy)methyl)phenyl)ethanamine.

Contained in the mixture (S-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol-1yl)quinolin- 8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione and (S)-2-(1-(3-chloro-5-fluoro-2-((2-methyl-4(3-methyl- 1H-1,2,4-triazol-1-yl)quinolin-8-yloxy)methyl)phenyl)ethyl)isoindoline-1,3-dione (111 mg, 201 μmol) was deprotected according to the synthesis procedure (S )-1-(3-chloro-5-fluoro-2-((4-(4fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethanamine and obtained the desired compounds. MS (m/z): 448.3 [M+Na ⁺ ].

Step E. Synthesis of (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl )quinolin-8yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide and (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(3methyl- 1H-1,2,4-triazol-1-yl)-quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide.

Mixture of (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-yloxy )methyl)phenyl)ethanamine and (S)-1-(3-chloro-5-fluoro-2-((2-methyl-4-(3-methyl-1H-1,2,4-triazol-1-yl )quinolin-8yloxy)methyl)phenyl)ethanamine (19 mg, 43 μmol) was reacted with 2-(difluoromethoxy)acetic acid (7.2 mg, 56 μmol) in accordance with the procedure for the synthesis of (R)-N-(( S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide and purified by HPLC to give (S)-N-(1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazol- 1yl)quinolin-8-yloxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (MS (m/z): 534.2 [M+H+]) and (S)-N(1-(3 -chloro-5-fluoro-2-((2-methyl-4-(3-methyl-1H-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

(S)-N-(1-Deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl )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 a solution of deutero-b-selectride.

Anhydrous MeOH (0.591 ml, 14.6 mmol) was added to the LiAlD ₄ suspension (203 mg, 4.86 mmol) with stirring at 0°C for 10 min. The reaction mixture was allowed to warm to RT and then a solution of tri-sec-butylborane (1 M in THF, 3.6 mL, 3.6 mmol) was added. The deuterium-b-selectride solution was used after stirring for 15 min at RT.

Under argon, titanium(IV) ethoxide (1.02 mL, 4.86 mmol) was added dropwise to a solution of 1-(3chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanone (0.500 g, 1.62 mmol) and (R)-(+)-2-methyl-2propanesulfinamide (216 mg, 1.78 mmol) in anhydrous THF (1.7 ml). The mixture was refluxed until complete conversion (TLC) was achieved. Then the mixture was cooled to 0°C and a solution of deuterium-b-selectride was added dropwise. The mixture was stirred at this temperature until complete conversion (TLC) was achieved. Methanol (~10 ml) was then added until gas evolution ceased. The solution was poured into saturated aqueous NaCl solution (5 ml). The mixture was then filtered through a pad of celite and washed gently with DCM. The filtrate was washed with saturated aqueous NaCl solution. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The resulting residue was purified by flash chromatography on silica gel (eluting 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-2sulfinamide (323 mg, 779 µmol) was hydrolyzed according to the procedure for the synthesis of (S)-1-(3-chloro-5fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to obtain the desired 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 μmol) was coupled with 2-(difluoromethoxy )acetic acid (26.4 mg, 209 µmol) in accordance with the procedure for the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro- 1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to obtain the desired 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.

Y (S)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-(difluoromethoxy)acetamide (38 mg, 91 µmol ) the protecting group was removed in accordance with the procedure for the synthesis of (S)-2-(1(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione to obtain the desired 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 μmol) was chlorinated according to the procedure synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5fluorophenyl)ethyl)isoindoline-1,3-dione to obtain the desired 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-(1-methyl-1H-1,2,4-triazole -5yl)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 μmol) was reacted with 2- methyl 4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-ol (14 mg, 57 µmol) according to the procedure for 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 and obtained the desired connection. MS (m/z): 535.4 [M+H+].

Example 10A. Obtaining connection No. 11A /=h

N-[(1S)-1-[3-Chloro-5-fluoro-2-({[2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin- 8-yl]oxy}methyl)phenyl](1,2,2,2- ² H4)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-methylpropan-2sulfinamide (2.07 g, 17.1 mmol) in According to the procedure for the synthesis of (R,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide, the desired compound was obtained.

Step B. Synthesis of (S)-N-[(1S)-1-{3-chloro-5-fluoro-2-[(4-methoxyphenoxy)methyl]phenyl}(1,2,2,2 ² H ₄ ) 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- ² H ₄ )ethylidene]-2-methylpropane-2-sulfinamide (113 mg, 0.75 mmol) according to the procedure for the synthesis of (R)-N-((R)-2-(tert-butyldimethylsilyloxy) -1-(3-chloro-5-fluoro-2-((4methoxyphenoxy)methyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide to obtain the desired 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}( ^1,2,2,2-2H4 )ethyl]- 2-Methylpropane-2-sulfinamide (86.5 mg, 0.21 mmol), dissolved in methanol (1 ml), was reacted with 3 M methanolic HCl solution (207 μl, 0.62 mmol) according to the synthesis procedure (S)-1-(3-chloro-5fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine to obtain the desired compound. MS (m/z): 314.9 [M+H+].

Step D. Synthesis of N-[(1S)-1-{3-chloro-5 _- fluoro-2-[(4-methoxyphenoxy)methyl]-phenyl}( ^1,2,2,2-2H4 )ethyl] 2-(difluoromethoxy)acetamide.

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), RuAOP (70 mg, 0.13 mmol) and

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DIPEA (21 µl, 0.18 mmol), carried out in accordance with the procedure for the synthesis of (R)-N-((S)-1-(3-chloro-5fluoro-2-((4-(4-fluoro-III- pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide gave the crude title compound. This was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (m/z): 444.4 [M+Na+].

Step E. Synthesis of N-[(1S)-1-[3-chloro-5-fluoro-2-(hydroxymethyl)phenyl]-(1,2,2,2- ^2H4 )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 cerium(IV)-ammonium nitrate (95.7 mg, 0.175 mmol) according to the procedure for the synthesis of (S)-2-(1-(3-chloro-5-fluoro -2(hydroxymethyl)phenyl)ethyl)isoindoline-1,3-dione to obtain the desired compound.

Step F. Synthesis of N-[(1S)-1-[3-chloro-2-(chloromethyl)-5-fluorophenyl](1,2,2,2- ² H4)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 SOCl ₂ (17 μl, 0.23 mmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline -1,3-dione and obtained the desired compound.

Step G. Synthesis of N-[(1S)-1-[3-chloro-5-fluoro-2-({[2-methyl-4-(1-methyl-1H-1,2,4-triαzol-5yl) quinolin-8-yl]oxy}methyl)phenyl](1,2,2,2- ² H ₄ )ethyl]-2-(difluoromethoxy)acetamide.

N-[(1S)-1-[3-Chloro-2-(chloromethyl)-5-fluorophenyl]( ^1,2,2,2-2H4 )ethyl]-2-(difluoromethoxy)acetamide (14.3 mg , 43 µmol) was reacted with 2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl)quinolin-8-ol (11 mg, 47 µmol) in accordance with the synthesis procedure (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 obtain the title compound. MS (m/z): 539.2 [M+H+].

Example 10B. Obtaining connection No. 11B /=N

(R)-N-(1 -Deutero-1 -(3 -chloro-5-fluoro-2-((2-methyl-4-(1 -methyl- 1H-1,2,4-triazol-5-yl )quinolin-8-yloxy)methyl)phenyl)-2-hydroxyethyl)-2-(difluoromethoxy)acetamide.

Stage A. Synthesis of tert-butyldimethyl[2-oxo(2-2H)ethoxy]silane.

A solution of methyl 2-(tert-butyldimethylsilyloxy)acetate (2.0 g, 10 mmol) in anhydrous Et ₂ O (8.9 ml) was added dropwise to a suspension of LiAlD ₄ (0.49 g) with stirring at -78°C , 12 mmol) in anhydrous Et ₂ O (35 ml). After stirring at -78°C for 40 minutes, 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 allowed to warm to RT. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound.

Step B. Synthesis of (R)-N-[(1E)-2-[(tert-butyldimethylsilyl)oxy]( ^1-2H )ethylidene]-2-methylpropane-2sulfinamide.

A solution of titanium(iV) ethoxide (794 μl, 3.79 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (344 mg, 2.84 mmol) and tert-butyldimethyl[2-oxo(2 -2H)ethoxy]silane in anhydrous DCM (10 ml) was stirred under nitrogen at RT for 16 hours. After completion of the transformation (TLC), the reaction was stopped by adding water (20 ml) at 0°C and the resulting mixture was filtered through a pad celita. The filter was then washed gently with DCM (2x20 ml). The aqueous layer was extracted with DCM (20 ml) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (m/z): 279.2 [M+H+].

Step C. Synthesis of (R)-N-(2-(tert-butyldimethylsilyloxy)-1-deutero-1-(3-chloro-5-fluoro-2-((4methoxyphenoxy)methyl)phenyl)ethyl)pivalamide.

AlMe ₃ (2 M solution in toluene, 551 μl, 1.10 mmol) at -78°C was added to a solution of (R)-N-[(1E)-2[(tert-butyldimethylsilyl)oxy]( ^1-2H )ethylidene]-2-methylpropane-2-sulfinamide (279 mg, 1.00 mmol) in anhydrous toluene (1.6 ml) and the resulting solution was stirred at -78°C for 30 minutes. Then, in a second BuLi flask (2.5 M solution in hexanes, 508 µl, 1.27 mmol) at -78°C, 1 bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl) was added to the solution. -benzene (381 mg, 1.10 mmol) in anhydrous toluene (3.8 ml) and the resulting solution was stirred at -78°C for 15 minutes. Then the solution containing (R)-N-[(1E)-2[(tert-butyldimethylsilyl)oxy]( ^1-2H )ethylidene]-2-methylpropane-2-sulfinamide at -78°C was slowly added to the containing 1- bromo-3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)benzene solution. The reaction mixture was allowed to warm to RT over 4.5 hours and the reaction was stopped by adding a saturated aqueous NH4Cl solution. The mixture was extracted with EA and the combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with EA/heptane) to give the title compound. MS (m/z): 567.0 [M+Na+].

Step D. Synthesis of (R)-N-(1-deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(1-methyl-1H-1,2,4-triazole -5yl)quinolin-8-yloxy)methyl)phenyl)-2-hydroxyethyl)-2-(difluoromethoxy)acetamide.

Y (R)-N-(2-(tert-butyldimethylsilyloxy)-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)pivalamide (388 mg, 0.714 mmol) was deprotected according to the procedure for the synthesis of (R)-2-amino-2-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanol, then amidated using 2- (difluoromethoxy)acetic acid in accordance with the procedure for the synthesis of (S)-N-((R)-1(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)-2-hydroxyethyl)-2 -hydroxy-3-methylbutanamide, then benzoylated, the 4-methoxyphenol group removed and chlorinated according to the procedure for the synthesis of (S)-1-((R)-2-(benzoyloxy)-1-(3-chloro-5-fluoro- 2-(hydroxymethyl)phenyl)ethylamino)-3-methyl-1oxobutan-2-ylbenzoate was then reacted with 2-methyl-4-(1-methyl-1H-1,2,4-triazol-5-yl) quinolin8-ol and then debenzoylated according to the procedure for 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 obtain the desired compound. MS (m/z): 551.3 [M+H+].

Example 10C. Obtaining compound No. 11C

(R)-N-((S)-1-Deutero-1-(3-chloro-5-fluoro-2-((2-methyl-4-(5-methyl-1H-1,2,4-triazole -1 -yl)quinolin-8yloxy)methyl)phenyl)ethyl)-2-fluoropropanamide.

Stage A. Synthesis of 8-methoxy-2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolinol.

Acetic anhydride (0.645 mL, 0.692 g, 6.78 mmol) was added to a mixture of formamidine acetate (0.705 g, 6.78 mmol) in anhydrous DMF (23.1 mL) with stirring at RT. After stirring at RT for 5 min, Et ₃ N (1.56 mL, 1.14 g, 11.3 mmol) was added. After stirring at RT for 5 min, the reaction mixture was heated to 80°C and stirred until the reaction mixture became a clear solution. The reaction mixture was then allowed to cool to RT before acetic acid (3.10 mL, 3.25 g, 54.2 mmol) and 4-hydrazinyl-8-methoxy-2-methylquinoline were added [AA Avetisyan et al. Russ. J. of Org. Chem. 2010 46(3), 427-431] (0.918 g, 4.52 mmol). After stirring at 80°C for 17 hours, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with DCM/MeOH) to give the title compound. MS (m/z): 255.2 [M+H+].

Step B. Synthesis of 2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-ol.

2-Methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-ol (0.750 g, 2.95 mmol) was demethylated using AlCl ₃ (1.18 g, 8.85 mmol) in accordance with the procedure for the synthesis of 4-(4-fluoro-1H-pyrazol-1yl)-2-methylquinolin-8-ol and the desired compound was obtained. MS (m/z): 240.8 [M+H+].

Step C. Synthesis of (S)-N-((S)-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)2-hydroxypropanamide.

(S)-1-Deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethanamine (250 mg, 0.804 mmol) was reacted with L-(+)lactic acid (76 μl, 76 mg, 0.85 mmol) according to the procedure for the synthesis of (R)-N-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro- 1H-pyrazol-1-yl)-2-methylquinolin-8yloxy)methyl)phenyl)ethyl)-2-hydroxypropanamide to obtain the desired compound. MS (m/z): 383.7 [M+H+].

Step D. Synthesis of (R)-N-((S)-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)2-fluoropropanamide.

1,8-Diazabicyclo[5.4.0]undec-7-ene (170 µl, 173 mg, 1.14 mmol) and perfluoro-1-butanesulfonyl fluoride (200 µl, 343 mg, 1.14 mmol) with stirring at 0° C was sequentially added to a solution of (S)-N-((S)-1-deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-hydroxypropanamide ( 290 mg, 0.758 mmol) in anhydrous toluene (8 ml). After stirring at 0°C for 30 min, the reaction mixture was allowed to warm to RT and was stirred at RT overnight. The reaction mixture was then poured into ice/water and extracted with DCM (3x20 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluting with EA/heptane) 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)-2fluoropropanamide.

(R)-N-((S)-1-Deutero-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethyl)-2-fluoropropanamide (96 mg, 0. 25 mmol) was reacted with cerium(IV)-ammonium nitrate (342 mg, 0.624 mmol) in accordance with the procedure for the synthesis of (S)-2-(1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl )ethyl)isoindoline-1,3- 29 043330 dione and the desired compound was obtained. MS (m/z): 276.8 [M-H ⁺ ].

Step F. Synthesis of (R)-N-((S)-1-deutero-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2fluoropropanamide.

(R)-N-((S)-1-Deutero-1-(3-chloro-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-2-fluoropropanamide (47 mg, 0.17 mmol) was added to reaction with SOCl ₂ (49 μl, 0.68 mmol) in accordance with the procedure for the synthesis of (S)-2(1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)isoindoline-1,3-dione and the desired compound was obtained. MS (m/z): 294.8 [M-H ⁺ ].

Step G. Synthesis of (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.

(R)-N-((S)-1-Deutero-1-(3-chloro-2-(chloromethyl)-5-fluorophenyl)ethyl)-2-fluoropropanamide (29 mg, 0.10 mmol) was reacted with 2-methyl-4-(5-methyl-1H-1,2,4-triazol-1-yl)quinolin-8-ol (26 mg, 0.11 mmol) according to the procedure for 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 and obtained the desired compound. MS (m/z): 501.8 [M+H ⁺ ].

Example 11. Compounds No. 12-213.

Compounds No. 12-213, shown in the table below. 1 are further representative examples of compounds of general formula (I) provided by the present invention. These compounds were synthesized according to the methods described above, as well as using synthetic procedures disclosed in the publications cited in the present invention or known in the field of synthetic organic chemistry, and modifications thereof obvious to those skilled in the art. All publications cited in the present invention related to the synthetic routes described in Examples 1-10C are incorporated herein by reference in their entirety. In any case, for specialists in the field of organic synthesis, the starting materials and reaction conditions, including their modifications, to obtain compounds are obvious.

Table 1

Connections of examples No. 12-213

Connection No. Structure Weight 12 / O 501.1 13 O 501.0

- 30 043330

- 31 043330

19 O 527.1 20 Ό/ZI .....< o 528.0 21 id ^nV·· F 516.5 22 d ^F N (Л γ n ^c sX^^V^ UJ ^H OH F 530.1 23 And N CCX JN ^· ^α ^Λ ^οΗ F 516.1

- 32 043330

24 515.2 25 Cl- 516.1 26 Cl- I N 516.1 27 Cl- Cl- ^Ν^ΟΗ I 7λ A F 516.1 28 Cl- /GL Ν, ,Ν Ν ^Γί γ'Ν^ ^χ ___Ε__________________________ 499.1

- 33 043330

29 /GA N, ,N N (XX Y N F 498.6 thirty /Гь V o\ γ N °> = 0 ^Cl ψό ^Α Ο F 511.0 31 /ch Ns ,N A »Ύν F 485.0 32 /GL Ns ,NN (XX YN ^CI ^V ^H F 484.5 33 /GL Ns ,NN OCX γ^ N Oax- Έγ/ ^H 0H F 499.1

- 34 043330

34 O 499.1 35 V ^th o o 537.5 36 CHA ° t 531.1 37 o / ^zx ν>γΑ.....< ^Z 529.6 38 About A? uAa g ’ o I 501.5

- 35 043330

39 Η V y N F ¹ 556.3 40 OO. 7° O 1 541.5 41 О < ,Ν Ν OD γ^ Ν % = 0 ^α ψν·ο F 510.2 42 η Ν Od γΉ F 498.2 43 Ο.....A 498.2

- 36 043330

44 Г'' < ,Ν Ν Οχ F 498.2 45 nX ^F Ν Οχ F 517.1 46 ъ Ν Οχ °> - F 543.3 47 b F 543.3 48 ъ ό “φΆ ⁰ ' ¹ F 567.1

- 37 043330

49 ъ ссх ^с| ^L ^he F 487.1 50 th LJ ⁿ OH F 529.2 51 5 o o 555.3 52 F. n Ν dl ζΐ] ⁿ /on F 569.2 53 R__ On N схх F 569.1

- 38 043330

54 R On N 553.5 ω 55 F. On N F 499.1 56 513.4 57 513.4 58 ъ A F 527.1

- 39 043330

59 ъ 515.2 N n ^С| ^йУ° F 60 T o / / ZI GYYA.....L o 529.3 61 about τι IZ/ 557.5 62 557.2 63 , ^N =\ -NyN φάθ F 498.2

- 40 043330

64 ..... ρΗ-ί ΞΕΖ / ABOUT I 512.1 65 / 526.1 66 A A “A ^L “k~ ^,g kJ ⁿ OH F 530.3 67 •V oA ^s| ^m F 529.1 68 ъ N Ol γ N Ts1| n V-NH F 512.0

- 41 043330

69 ъ Ctf °> = 0 OH ο'ψΑΑΤγκ F 559.1 70 YΟΥ °> - oh he F 559.1 71 ъ tf Al? F 531.2 72 tf tf CJ ⁿ he F 558.4 73 / ζτ £\nI _g .....C 537.5

- 42 043330

74 TO On N Qa F 524.1 75 / Qa YN °> ^H0 - ₀ Mo F 517.1 76 T z T M °\o 544.1 77 N Qa γ n “^jCb^A” ² F 544.1 78 A /ZI fzJA.....C O 524.1

- 43 043330

79 ъ N gX F 537.1 80 ъ gk °> η ^Cl ψΓ0' ^ΟΗ F 515.2 81 Ε Ον η °\ / F 501.2 82 ъ Ν Qi F 524.1 83 .4 / / 7^ .....R ^ζ 498.5

- 44 043330

84 \U~O )..... )—< z IZ/1 U o 512.4 85 /=^ NyN^ gk °> = ⁰ О ^h J F 548.3 86 F A °> = O Ck J\A h ^N ii % L Η h ' / %/ n- _n 1 \ F 551.2 87 O UA ^o= \ ^x / ZI r\-TN .....A “ УУ <гу}~ o 552.1 88 F. On N ccx ______E___________________________ 538.1

- 45 043330

89 7 .....ν (ξ-уУ ABOUT 538.1 90 ζΓ 540.1 91 ν ^ο= \ / ^ζτ rw4.....с 538.1 92 JX / ^ζτ HzV .....% - Α-ΜΑ ο 538.5 93 ο -1 ν □ΞΖ / Ο ν “Π 551.5

- 46 043330

- 47 043330

99 gAdX .....C A ^0^2 512.3 100 ν-^ V SSk γ ν F 512.4 101 o\ HA F 529.3 102 That 501.1 103 Ν OCX F 533.1

- 48 043330

104 nV F 545.2 105 nV N 9a F 531.1 106 nV N eV °> A ^H O F 553.1 107 V J ο ZT IL ___/ \ 1.../ >=\ ' ^z ' o 531.2 108 nV N oV γ n °> W F 537.1

- 49 043330

109 L Ν cA γ Ν °> - F 555.2 110 O ..... ^z p ^z Λ 541.2 111 'A..... ^ζ ρ ^ζ Λ IZ l^ 542.2 112 O . aG ^oh O ..... p V IZ 0^0 542.1 FROM "L N o\ ci hdam^·^ Г Τ ΰ f ΝΗ ΗΝ^ 541.2

- 50 043330

114 N(XX F 540.2 115 nA Ncd F 540.2 116 AZ ΞΕΖ / 1 -n O :χ “P 552.0 117 id about 5 538.3 118 /=N (XX Y N ______E___________________________ 552.4

- 51 043330

119 /=N ΝγΝ^. OH YEAH F 538.4 120 /=Ν СО ^С| ^O> F 521.3 121 R__ On D DL-u, F 555.1 122 /=N NyN^ d D»A F 521.3 123 534.4

- 52 043330

124 N (XX Y N F 534.4 125 d ^F N Y (¾ F 534.4 126 /=N ςά ^ci xd^ F 535.9 127 /=N γ χν F 535.8 128 /=N NyN^ F 522.2

- 53 043330

129 A \=z // 549.3 130 /=Ν ΝγΝ^ <?λ F 536.2 131 Ο and ^ζ 0^0 ω 549.2 132 R Η Ν сО °> - F 542.1 133 ° / ° \ / / 7 ^Χ .....C ^Ζ QhoO> ^L 538.2

- 54 043330

134 O//ZI hHCh.....X ABOUT 549.3 135 U'N Ns X N ccx Y N Xa F 536.2 136 y^ Ns Xs. N Ox Y N Xx F 550.2 137 X ex.....c ω 550.3 138 XX <χ _ο χχ о 527.4

- 55 043330

139 Μ ίν ω 567.3 140 ο ΙΖ / ο “Π 548.9 141 ο Α Υηι ΙΖ ' 4 ν° ο^ 536.0 142 , A ry^ _z .....С ^ζ «Н^сГ^ о 549.0 143 ,^ρΟΎ^ ¹ n уА ¹ ΤΖ / / 5=0 ⁷ ο I 527.0

- 56 043330

144 '“S ⁿ SgA ...... )—' z > ! 537.4 145 Y YYZz Y=\ ^z ω 566.8 146 R__ On tf /SU F 507.4 147 /=N NyN^ AA ^! 7' F 504.4 148 /=N NyN-. ςά F 518.0

- 57 043330

149 /=N ΝγΝ^ A F 549.5 150 A ¹ Z \n../ ^{ZT z} Ar o 535.5 151 nA A y ®v F 521.1 152 nA A °> F 552.4 153 538.4

- 58 043330

- 59 043330

159 X u с.....с с W С /=\ о 521.9 160 ΞΕ / / ΐΐ сС Х=\ ^н χΟΟΧ 512.9 161 7° Ή^-π 553.2 162 ^=Г Шз ΞΕΖ / / WITH 531.0 163 s / / 7 ^T 531.0

- 60 043330

164 /=N A °4Vo F 531.0 165 N F 535.4 166 N, A N A 'Α^τ F 549.3 167 A ^with| ^Л°л F 566.9 168 О ^rL· ⁰ ^) A Ar V о Ά “Π 535.4

- 61 043330

169 V ^th o J. A ..... c o 549.2 170 o -cWb, OQ 536.2 171 That 4 n°-g o 527.2 172 N QCX Vv F 514.9 173 ^T VVо 518.1

- 62 043330

- 63 043330

179 N (XX γ n “^И^С F 536.1 180 0=^ I A .....Г L, Ά / /=\ ’ “HhoAW O 518.0 181 sSh T] ⁴¹ 537.8 182 /=N NyN^ X Xu F 519.8 183 LL / , Q ^ZT ϊΜ$ L=% O 505.8

- 64 043330

184 // U tH>Ον O 512.3 185 o s about nuclear weapons “d o I “P” 533.9 186 /=Ν NH O -Yes F 504.2 187 /=N ΟγΝΗ CO at N YES F 520.8 188 05 od t / U AO ^g Ον l _{u o} ug O 497.9

- 65 043330

189 About χ: Ο*ι ΙΖ ^Ζ / ^τ τ 511.9 190 ο y..„/° νΗ=ι ΙΖ ^Ζ / / ?° ο “Π 549.9 191 =? ^ζ / / / ^{ζτ ζ} 537.1 192 07 Ο<ϊ ιζ' / / \=° °\ 497.9 193 Ν, Ν CCX 0* F 500.0

- 66 043330

194 ABOUT \=/ / \—Οι )..... iz' / / O T 483.9 195 5 ⁿ he F 498.2 196 / _J 7^ ΐΜ O Οοχη about 521.2 197 ^=with LED >'>i| )----' Z IZ ⁷ 7 / “P 518.1 198 Ν, X, N QX γ n ______E___________________________ 523.2

- 67 043330

199 // ^Q v ^ZT iaaS HA. ^z ^guU^ 523.2 200 ί A - G J=v o 525.1 201 /tku-Gt / / ά 526.2 202 o / / “ / ^{ZT Z} ' ^Z \ /HA °1__ IL 7 /=4 ^z o 538.0 203 / / CHO ² .....A ^z ^уУ- о 500.2

- 68 043330

204 o=^ / / / ^ζτ ϊ;><>.....С ^ζ Ο 500.3 205 ΙΖ / / ζ “Π 559.2 206 Ο , ζ 'Υ ^z w41 ιζ' / / § “Π ⁴¹ 561.2 207 __^CN γν F 525.2 208 ο 538.1

- 69 043330

209 GC N (XX ν °> _h D O F sk D(D^ Il ^N F L 1] n F 520.1 210 /=Ν °> D Ο F N F Ll| h F 519.7 211 /=N ΝγΝ^ X °> 4 D О ckXx DE ΊΓ II ^N I U ⁿ ί F 501.2 212 ABOUT \=< / λ—z *1 χ y z o ' ' G 501.7 213 /=N ΝγΝ-. X °> o sk D\ES Dk/ g G Ν U ^N F F 501.7

#"<_.._.

Mass: Mass spectrometry data (based on spectra obtained by liquid chromatography-mass spectrometry) (m/z) are given and represent values for protonated molecular ions [M+H+].

Example 12. Determination of the antagonistic activity of the test compounds towards human B2R.

The following cell-based human bradykinin B2 receptor calcium mobilization (hB2RCaM) assay was used to determine the antagonistic activity of compounds selected from Examples 1-168 towards the human bradykinin B2 receptor (hB2R). This assay is defined herein as a standard in vitro B2 receptor activity assay that can be used to determine the IC ₅₀ values of compounds of the present invention, such as those described in Examples 1-11.

The antagonist activity of the compounds of the present invention was determined using the hB2R-CaM assay using the bradykinin B2 receptor stable cell line, HTS041C (Eurofins, St. Charles MO) and the FLIPR Calcium 6 assay kit (Molecular Devices, Wokingham, UK). in accordance with the manufacturer's instructions. The CaM assay was performed using a Flexstation 3 system (Molecular Devices), which allows precise addition of compounds (B2R antagonists) and bradykinin (B2R agonist) to cells and simultaneous continuous recording of time-dependent signals in the CaM assay.

Cell culture, seeding in plates and growing in minimal medium.

HTS041C cells were cultured in high glucose cell culture medium MDSI (Lonza) supplemented with 10% heat-inactivated FBS (PAN Biotech), 10 mM HEPES (N2-hydroxyethylpiperazine-N -2-ethanesulfonic acid), penicillin/streptomycin mixtures (200 IU/ml, 200 μg/ml, IU), 1x essential amino acids (Lonza), and 250 μg/ml G418 (Invivogen) in a cell incubator at 37° C and in an atmosphere containing 5% CO ₂ .

- 70 043330

The day before the experiments for CaM studies, cells were seeded in 200 μl of MDSI cell culture medium with a reduced content of FBS (5%) and without the addition of G418, in black 96-well plates with a transparent bottom (ThermoFisher #165305). Cells were grown in minimal media by incubating (37°C, 5% CO ₂ ) at a density of 70,000 cells/well for 24 to 28 hours. Immediately before calcium dye was added, the media was gently aspirated and the cells were washed with balanced salt solution. Hanks (SCPX, Gibco) containing Ca ²⁺ , Mg ²⁺ and 20 mM HEPES, the pH value of which was set to 7.4 (SCPX+).

Introduction of calcium dye into the cages.

For calcium dye administration, an aliquot of FLIPR 6 assay was dissolved in 20 ml of CCPX+. 150 μl of dye solution was added to the cell plate and incubated at 37°C and 5% CO2 for 120 min. After dye injection, the cell plate was immediately transferred to a prewarmed (37°C) Flexstation 3 system for CaM assay.

Study of intracellular calcium mobilization (CaM study).

Shortly before the experiment, serial dilutions of freshly prepared compound (B2 receptor antagonists) (8 spots, n=2) and bradykinin solution (B2 receptor agonist) were transferred from non-binding surface plates (Costar) to the Flexstation system (source plate). Bradykinin was added at the EC80 concentration determined in n>3 preliminary experiments using 8-point concentration-response relationships (n=8). The CaM study was carried out using the Flexstation 3 system, starting with recording the fluorescence intensity of the calcium-sensitive dye in Flex bottom reading mode at excitation/emission wavelength = 485 nm/525 nm, threshold (emission) = 515 nm. After 20 s, 50 μl of 4-fold dilutions of concentrated compounds were added to the cells to obtain a final concentration of DMSO (dimethyl sulfoxide, Sigma) in the cell plate of 0.1%. CaM signals were detected for 80 s after additions to detect possible agonistic activities. Before adding stimulus-bradykinin, compound- and vehicle-treated cells were incubated in a Flexstation system at 37°C for 25 minutes. Then, 50 μl of a 5-fold dilution of concentrated bradykinin solution (CCBX+, 0.1% DMSO) was added to initiate CaM signals (readout: max.min value), which were detected within 80 s after the addition of the bradykinin stimulus.

The determination of IC ₅₀ values was carried out by approximating the compound concentration-response relationships plotted over 8 points (n=2) using a 4-parameter logistic model using XLFIT (IDBS) software.

Results of the study.

Connections of examples No. 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 and 213 had an _IC50 value for the human bradykinin B2 receptor (hB2R) less than or equal to 50 nM.

Compounds of examples No. 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 had IC ₅₀ values for the human bradykinin B2 receptor (hB2R) of between 51 and 250 nM.

Compounds of Examples Nos. 3, 13, 21, 47, 52, 53, 55, 65, 72, 98 and 100 had IC ₅₀ values for human bradykinin B2 receptor (hB2R) of 251 to 1000 nM.

In the cell system studied, none of the compounds tested had any toxic effects.

Example 13: Determination of biological activity, permeability and metabolic stability.

To study in more detail the possibility of therapeutic effects of the compounds of examples Nos. 1, 6, 11 and 13 proposed in the present invention, their hB2R antagonistic activity, their permeability and their metabolic activity were studied.

The prior art patent applications cited above or other publications do not disclose structurally similar compounds. The prior art document WO 2008/116620 discloses heteroarylquinolin-8-yloxymethylpyridines which contain similar substituents on the pyridine ring. However, WO 2008/116620 does not provide any description of the pharmacokinetic characteristics of these compounds, eg permeability and metabolic stability. WO 2010/031589 discloses second generation compounds developed from the compounds described in WO 2008/116620, which, as disclosed in WO 2014/159637, have low metabolic stability, low bioavailability, form adducts with glutathione and are prone to bioactivation ( toxic).

Due to the lack of known structurally related compounds and to demonstrate the beneficial effects of the new structural elements proposed in the present invention, such

- 71 043330 similarly examined the hB2R antagonistic activity, permeability and metabolic activity of model reference compounds containing the elements proposed in WO 2008/116620 and WO 2010/031589, respectively. Comparative compounds Nos. 169, 170, 171, 172, 173 and 174, presented in the table below, were used as model comparative compounds. 2. Comparative compounds Nos. 169, 170 and 171 are based on the structural elements proposed in WO 2008/116620. Comparative compounds Nos. 172, 173 and 174 actually combine the structural elements proposed in WO 2008/116620, with the pyridine ring moiety structurally modified (replaced with a phenyl ring) as proposed in WO 2010/031589 and WO 2014/159637. However, in this regard, it should be noted that neither WO 2010/031589 nor WO 2014/159637 makes any description or suggestion regarding the claimed substituents being in the meta position with respect to the chlorine atom in the phenyl ring moiety. In fact, WO 2010/031589 and WO 2014/159637 do not describe a fluorine substituent in the meta position with respect to the chlorine atom in the phenyl ring moiety, and additionally propose other substituents in the 2-position, meta position with respect to to the chlorine atom in the phenyl ring.

A. Preparation of comparative compounds Nos. 169-174.

The compounds of comparative examples Nos. 169-174, presented in the table below. 2 was prepared in accordance with the methods described above and the methods described in WO 2010/031589 and WO 2008/116620, using their respective modifications to prepare the compounds, obvious and known to specialists in the field of synthetic organic chemistry.

B. Antagonistic activity of the test compounds towards hB2R.

The relative IC ₅₀ values for the test compounds were determined using the same hB2R-CaM assay as described in Example 12. The results are shown in the table below. 2.

C. Permeability of the compounds under study.

The permeability of the test compounds was determined using a permeability assay using Caco-2 cells according to the publication (Hubatsch I. et al. Nat. Protoc. 2007, 2 (9), 2111-2119).

The Caco-2 cell line is a continuous layer of heterogeneous human colorectal adenocarcinoma cells. When cells are grown as a confluent monolayer on a permeable support, such as a cell culture insert filter, they differentiate to form a polarized layer of epithelial cells that provides a physical and biochemical barrier to the entry of ions and small molecules. Caco-2 cells in the form of a confluent monolayer are useful in the pharmaceutical industry, and also as a common in vitro model of the small intestinal mucosa for predicting the adsorption of orally administered drugs. Examining transport in both directions (apical to basolateral (A-B) and basolateral to apical (B-A)) across a cell monolayer allows the efflux ratio to be determined, which is an indication of whether the compound is actively effluxing. If a compound has a higher efflux ratio, this indicates that the compound is more susceptible to active efflux. It is clear that active efflux significantly impairs oral bioavailability.

The results of the determined efflux ratio values are given in the table below. 2.

D. Metabolic stability of the test compounds.

Hepatic clearance is the most important mechanism for drug elimination from the body, and many commercially available compounds are eliminated via hepatic cytochrome P450-mediated metabolism. The release or excretion characteristics of the test compounds were determined using a metabolic stability study according to the publication (Obach RS Drug Metab. Dispos. 1999, 27(11), 1350-1359).

The study was performed in 96-well deep well plates using liver microsomes obtained from male Wistar rats (Corning). Rat liver microsome incubation experiments were performed in duplicate, and the incubation mixtures contained liver microsomes (0.5 (mg microsomal protein)/ml), test compound (1 μM), MgCl ₂ (2 mM), and NADP (nicotinamide adenine dinucleotide phosphate, 1 mM). with a total volume of sodium phosphate buffer (100 mM, pH 7.4) equal to 0.7 ml. Reactions were initiated by adding NADP and the mixtures were shaken using a horizontal shaker equipped with a heating device at 37°C. At time t=0 min and at time points: 10 min, 30 min and 60 min; Aliquots (70 μL) were taken from the incubated mixture and added to 140 μL mixtures to stop the reaction. Stop mixtures contained acetonitrile with diazepam, diclofenac, and griseofulvin added as internal analytical standards. Samples in which the reaction was stopped were processed by mixing and centrifugation (2,200xg, 5 min). The particle-free supernatant was diluted with deionized water (1+1) and then LC-MS (liquid chromatography

- 72 043330 graphy - mass spectrometry) a quantitative bioanalysis was performed to determine the reduction in the amount of the test compound (pump flow rate: 600 μl/min; Kinetex Phenyl-Hexyl analytical column, 2.6 μm, 50x2.1 mm (Phenomenex, Germany) ). Incubated mixtures containing verapamil at a concentration of 1 μM were used as a high-clearance positive control (PC; n=2), and incubated mixtures containing no NADP (70 μl phosphate solution) were used as a negative control (NC; n=2). buffer (with the addition of 2 mM MgCl ₂ ) instead of 70 μl of NADP solution) to confirm that no apparent metabolic loss of the test compound occurred during the incubation study.

In this metabolic stability study, the rate of disappearance of the test compound over time in liver microsomes is determined and these results are used to calculate intrinsic clearance (Cl _int ) in vitro. Cl _int values predict in vivo hepatic clearance or, in other words, they can be used as an indicator of the in vivo half-life of a compound and its oral bioavailability. Compounds that have high clearance are generally considered unfavorable because they are cleared rapidly in vivo and this results in short-lasting effects. In other words, a lower intrinsic clearance in vitro generally indicates a longer half-life in vivo and better oral bioavailability.

The results obtained for Cl _int are presented in the table below. 2.

Table 2 Biological activity, permeability and metabolic stability

Comparative compound No. 169 Comparative compound No. 172 Example Compound #13 ъ xUU ъ оУ ъ ςά Relative IC50* 57 29 7.6 Clint (µl/min/(mg protein))** 427 56 13 Caco-2 BA/AB*** 3.4 1.6 0.6 Comparative compound No. 170 Comparative compound No. 173 Example Compound #1 ъ ъ У 1 ^{0 cl} viAV U ⁿ it ъ 0, “хУА Relative IC50* 37 34 8.0 Cl i _n t (µl/min/(mg protein))** 329 132 56 Saso-2 VA/AV*** 2.9 1.1 0.7

Comparative compound No. 171 Comparative compound No. 174 Example Compound #6 G Relative IC50* 4.3 2.6 1.0 Clint (µl/min/(mg protein))** 497 135 28 Saso-2 VA/AV*** 7.7 1.3 1.0

Example connection no. 11 Relative IC50* 1.1 Clint (µl/min/(mg protein))** 20 Saso-2 VA/AV*** 1.3

*IC ₅₀ /(IC ₅₀ of compound No. 6) **Metabolic stability in liver microsomes of male Wistar rats according to Obach RS Drug Metab. Dispos. 1999, 11, 1350-1359.

***Caco-2 BA/AB: P _rel . (from B to A)/P _rel . (from A to B) (P _rel . - relative permeability), obtained in a study of a monolayer of differentiated Caco-2 cells according to the publication of Hubatsch I. et al. Nat. Protoc. 2007, 2, 2111-2119.

- 73 043330

As can be seen from the table above. 2, the compounds of general formula (I) proposed in the present invention have a number of important advantages, the existence of which could not be predicted. In contrast to compounds containing structural elements proposed in the prior art, the compounds proposed in the present invention have high antagonistic activity towards hB2R;

significantly improved efflux ratio and significantly improved metabolic stability. More precisely, typical compounds of general formula (I) proposed in the present invention, i.e. compounds of Examples Nos. 1, 6 and 13 have improved hB2R antagonistic activity. For example, Example No. 13 has a relative IC ₅₀ value of 7.6, which is 7.5 times and 3.8 times less than the relative IC ₅₀ values of Comparative Compound No. 169 and Comparative Compound No. 172, respectively, which have there are no structural elements proposed in the present invention, namely, a fluorine atom located in a meta position with respect to the chlorine atom, in combination with a specific stereochemical configuration of the stereocenter of the benzyl ring.

Typical compounds of general formula (I) proposed in the present invention, i.e. compounds of Examples Nos. 1, 6 and 13 also have a better efflux ratio than the corresponding comparative compounds. In fact, all compounds of the examples have an extremely favorable efflux ratio value of less than 1.5, while comparative compounds Nos. 169-171 have an unfavorable high efflux ratio value of greater than 2, which indicates that the compounds are subject to active efflux.

Typical compounds of general formula (I) proposed in the present invention, i.e. the compounds of Examples Nos. 1, 6 and 13 also have better metabolic stability than the corresponding comparative compounds. In fact, all compounds of the examples have extremely low intrinsic clearance compared to the intrinsic clearance of comparative compounds that lack the structural elements proposed in the present invention. For example, Example No. 6 has a Cl _int value of 28, which is 17.8 times and 4.8 times less than the Cl _int values of Comparative Compound No. 171 and Comparative Compound No. 174, respectively.

In addition, a compound having the stereochemical configuration of the benzyl ring stereocenter proposed in the present invention has more predictable pharmacokinetic characteristics, safety, toxicity and tolerability, since all compounds are metabolized in a similar manner, in contrast to compounds having different stereochemical configurations, which may undergo metabolism in different ways or at different rates.

Overall, the results show that the compounds of general formula (I) provided by the present invention are superior to compounds lacking the combination of structural elements provided by the present invention (e.g., a fluorine atom in a meta position relative to the chlorine atom in the phenyl fragment, in combination with the stereochemical configuration of the alkyl-containing substituent of the stereocenter of the benzyl ring proposed in the present invention), in terms of activity and pharmacokinetic characteristics, such as absorption and excretion. In addition, these results show that the compounds of general formula (I) proposed in the present invention are suitable for use as active agents in oral drugs.

The features of the present invention disclosed in the description and/or in the claims, individually or in any combination thereof, may provide material for the implementation of the present invention in its various forms.

Claims (13)

1. Compound of general formula (I) or a pharmacologically acceptable salt thereof, wherein A represents the group And ¹ represents N or CH; A ² stands for N or CR ^A2 ; And ³ is N or C-RA3; - 74 043330 And ⁵ denotes N-RA ⁵ ; R ^a1 represents a hydrogen atom or a methyl group; R ^A2 and R ^A3 each independently represent a hydrogen atom, a halogen atom, CN, NH ₂ or (C ₁ -C ₃ )alkyl; R ^A5 represents a hydrogen atom or a (C ₁ -C ₃ )alkyl group; R ¹ denotes a (C ₁ -C ₃ )alkyl group, where the alkyl group may be substituted by one or more identical or different groups selected from deuterium atom and OH; R ² represents a hydrogen atom or a deuterium atom; R ³ represents a hydrogen atom or a methyl group; E is CR ^e1 R ^e2 R ^e3 or Hce; Hce denotes a monocyclic aromatic heterocycle containing from 3 to 10 C atoms and from 1 to 4 heteroatoms, each of which is independently selected from N, O or S, where the heterocycle is unsubstituted or may be mono-, di- or tri-substituted in in each case independently G; G denotes a (C ₁ -C ₆ )alkyl group, in which from 1 to 7 H atoms in each case can independently be replaced by a halogen atom, OR ^g1 , CN, NR ^G2 R ^G3 or (C ₃ -C ₆ )cycloalkyl, and/or in which one CH ₂ group or two non-adjacent CH ₂ groups can be replaced by C(O)O or C(O)NH; R ^g1 , RG ² and RG ³ each independently represent a hydrogen atom or a (C ₁ -C ₄ )alkyl group; R ^e1 and R ^e2 each independently represent a hydrogen atom, a halogen atom or G; or R ^e1 and R ^e2 taken together form =O or Cyc; R ^e3 represents a hydrogen atom, a halogen atom, G, OG or OH and Cys denotes a mono- or bicyclic, saturated or partially unsaturated 3-10 membered cycloalkyl group or 4-10 membered heterocycloalkyl group containing from 1 to 3 heteroatoms, each of which is independently selected from N, O or S, where cycloalkyl or the heterocycloalkyl group is unsubstituted or may be mono-, di-, tri- or tetra-substituted, in each case independently of G and/or =O. 2. A compound or pharmacologically acceptable salt according to claim 1, wherein R ¹ denotes a (C ₁ -C ₂ )alkyl group, where the alkyl group may be replaced by one or more identical or different groups selected from a deuterium atom and OH. 3. A compound or pharmacologically acceptable salt according to claim 1 or 2, where E is CR ^e1 R ^e2 R ^e3 ; R ^e1 represents a hydrogen atom, a fluorine atom, methyl or ethyl; and each of R ^E2 and R ^E3 is as defined in claim 1. 4. A compound or pharmacologically acceptable salt according to any one of claims 1 to 3, where R ^E2 denotes a hydrogen atom, a fluorine atom, a (C1-C6) alkyl group, preferably a (C1-C3) alkyl group, in which from 1 to 4 atoms H in each case can independently be replaced by a fluorine atom, OH or NR ^c1 R ^C2 ; and R ^c1 and R ^C2 each independently represent a hydrogen atom or a (C1- _C3 )alkyl group. 5. A compound or pharmacologically acceptable salt according to any one of claims 1 to 4, where R ^E3 denotes a hydrogen atom, a fluorine atom, OH, a (C1-C6)alkyl group, preferably a (C1-C3)alkyl group, in which from 1 to The 5 H atoms in each case can independently be replaced by a fluorine atom, OH or NR ^C1 R ^C2 ; (C1-C ₆ )alkoxy group, in which from 1 to 5 H atoms in each case can independently be replaced by a fluorine atom, OH or cyclopropyl; and each of ^RC1 and ^RC2 independently represents a hydrogen atom or a (C ₁ -C ₃ )alkyl group. 6. A compound or pharmacologically acceptable salt according to claim 1 or 2, where E is CR ^e1 R ^e2 R ^e3 ; and R ^e1 and R ^e2 are linked together to form =O or Cyc, where Cyc is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,3-dioxolanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , (imidazolidin-2-on)yl and (oxazolidin-2-on)yl, and is unsubstituted or may be mono-, di- or tri-substituted in each case independently of G and/or =O; and R ^E3 is as defined in claim 1. 7. A compound or pharmacologically acceptable salt according to claim 6, where R ^E3 denotes a hydrogen atom, a fluorine atom, OH or a (C ₁ -C ₃ )alkyl group. 8. A compound or pharmacologically acceptable salt according to claim 1 or 2, where E is Hce and Hce is a monocyclic aromatic heterocycle containing from 3 to 5 C atoms and from 1 to 3 N atoms; from 3 to 5 C atoms, 1-2 N atoms and 1 O atom or from 3 to 5 C atoms, 1-2 N atoms and 1 S atom; where the heterocycle is unsubstituted or may be mono-, di- or tri-substituted, in each case independently (C ₁ -C ₃ )alkyl. - 75 043330 9. A compound or pharmacologically acceptable salt according to any one of claims 1, 2, 3-5 and 8, where E denotes a group 10. A compound or pharmacologically acceptable salt according to any one of claims 1 to 9, where the compound is selected from the group 11. A pharmaceutical composition which contains one or more compounds or pharmacologically acceptable salts according to any one of claims 1 to 10 and at least one carrier, excipient and/or excipient. 12. The pharmaceutical composition according to claim 11, where the pharmaceutical composition is prepared in the form of an aerosol, cream, gel, pill, capsule, syrup or solution. 13. Use of a compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 10 as a medicament for the treatment and/or prevention of a pathological condition or disease that responds to modulation of the BK B2 receptor.