RU2792933C2 - New quinoline derivatives - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions namely relates to quinoline derivatives of the general formula (I) as anthelmintic agents. Disclosed is a compound with general formula (I), where: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy and cyano, R_p is selected from the group consisting of from hydrogen, X is selected from the group consisting of CR⁷ R⁸, O and S, Y is CR⁷R⁸ or O, R¹ is hydrogen or C₁-C₄ alkyl, R² is selected from the group consisting of from tetrahydro-2H-pyran-4-yl, 3,6 dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R³ is hydrogen, R⁴ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl having from 1 to 5 halogen atoms, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, having from 1 up to 5 halogen atoms, preferably hydrogen, halogen and C₁ -C₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R⁵ is selected from the group consisting of hydrogen, R⁶ is selected from the group consisting of hydrogen, R⁷ selected from the group consisting of hydrogen and C₁-C₄-alkyl, R⁸ selected from the group consisting of hydrogen and C₁-C₄-alkyl, R¹⁰ is selected from the group consisting of hydrogen, R¹¹ is hydrogen, Q is 2,3,5-trifluorophenyl, or its stereoisomer, tautomer, or pharmaceutically or veterinarily acceptable salt, or mixture thereof Also disclosed is a process for preparing a compound with general formula (I), an intermediate compound with general formula (II), where the values of the radicals have the meanings indicated in the claims; a pharmaceutical composition based on a compound with formula (I); the use of a compound with formula (I); and a process for controlling helminth infections in humans and/or animals.

EFFECT: group of inventions provides effective treatment and control of helminth infections in humans and/or animals.

13 cl, 10 tbl, 7 ex

Description

The present invention covers novel quinoline derivatives of general formula (I) as described and defined in the specification of the present invention, processes for the preparation of said compounds, intermediates useful in the preparation of said compounds, pharmaceutical compositions and combinations containing said compounds, and the use of said compounds for the preparation of said compounds. pharmaceutical compositions for the control, treatment and / or prevention of diseases, in particular for the control, treatment and / or prevention of infections caused by helminths, in particular infections caused by gastrointestinal and extraintestinal nematodes, in animals and humans, formulations containing such compounds, and methods for the control, treatment and/or prevention of infections caused by helminths, in particular infections caused by gastrointestinal and extraintestinal nematodes, in animals and humans, in which these compounds are used as a single agent or in combination with other active ingredients.

State of the art

The emergence of resistance against all commercially available anthelmintic agents has proven to be an increasing problem in the field of veterinary medicine. The widespread use of anthelmintic agents to control nematode control has resulted in a significant selection of highly resistant helminth populations. Therefore, the spread of resistance against all classes of anthelminthic drugs threatens effective control of helminths in cattle, goats, sheep and horses. In addition, the successful prevention of heartworm disease in dogs, which currently relies solely on the use of macrocyclic lactones, is under threat, as a loss of efficacy for many macrocyclic lactones has been described in some areas of the United States of America - especially in areas where infection is a problem. heartworm is high. Finally, experimental infection studies with Dirofilaria immitis larvae from a suspected loss of potency area in the Lower Mississippi Delta confirmed the existence of macrocyclic lactone resistance in vivo.

Although resistance of human helminths to anthelminthic agents is currently rare, the spread of anthelminthic resistance in the veterinary field, as mentioned earlier, must be considered in the treatment of helminthiasis in humans. Long-term, regularly dosed therapies against filariasis can lead to highly resistant genotypes, and resistance has already been described for certain anthelmintic agents (eg, praziquantel, benzimidazole, and niclosamide).

Therefore, resistance-overcoming anthelmintic agents with new molecular modes of action are urgently needed.

The object of the present invention is to provide compounds that can be used as anthelminthic agents in medicine, especially veterinary medicine, having satisfactory or improved anthelmintic activity against a wide range of helminths, especially at relatively low doses, for the control, treatment and/or prevention of infections caused by helminths , in animals and humans, preferably without any adverse toxic effects on the organism to be treated.

Certain quinoline carboxamides are described in JP 2008-214323 A as agents suitable for the treatment and/or prevention of skin diseases such as acne vulgaris, dermatitis or the like.

WO 2017103851 describes quinoline-3-carboxamides as H-PGDS inhibitors useful in the treatment of atherosclerosis, psoriasis, sinusitis and Duchenne muscular dystrophy.

WO 2018087036 describes quinoline-3-carboxamides as anthelmintics in the medical, especially veterinary field.

However, the prior art does not describe the novel quinoline derivatives of the general formula (I) according to the present invention as described and defined in the specification of the present invention.

It has been found, and this forms the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.

In particular, the compounds of the present invention have been found to interact effectively with Slo-1 nematodes. This interaction is characterized by the achievement of paralysis/inhibition, in particular, of gastrointestinal nematodes, non-parasitic nematodes and filariae, for which data are given in the part of experiments on biological activity. Therefore, the compounds of the present invention can be used as anthelmintic agents for the control, treatment and/or prevention of infections caused by gastrointestinal and extraintestinal helminths, in particular gastrointestinal and extraintestinal infections caused by nematodes, including filariae.

Description of the invention

The first object of the present invention are the compounds of General formula (I):

wherein:

A is A1 or A2,

o is 0, 1, 2, 3 or 4,

R is selected from the group consisting of hydrogen, halogen, cyano, nitro, OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₃ -C ₆ -cycloalkyl, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -SC ₁ -C ₄ -alkyl, -S(O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -SC ₁ -C ₄ -haloalkyl, -S (O )-C ₁ -C ₄ -haloalkyl and -SO ₂ -C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O, S, and NR ⁹ , where at least one of X and Y is CR ⁷ R ⁸ , or

X, Y together form a ring member selected from the group consisting of -C(O)-O, -C(O)-NR ⁹ -, -S(O)-NR ⁹ -, -SO ₂ -NR ⁹ - and -SO ₂ -O-,

R ¹ is selected from the group consisting of hydrogen, cyano, -CHO, OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl having from 1 to 5 halogen atoms, C ₃ -C ₄ -alkenyl, C ₃ - C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl, cyano-C ₁ -C ₄ -alkyl, -NH- C ₁ -C ₄ -alkyl, -N (C ₁ -C ₄ -alkyl) ₂ , NH ₂ -C ₁ -C ₄ -alkyl-, C ₁ -C ₄ -alkyl-NH-C ₁ -C ₄ -alkyl -, (C ₁ -C ₄ -alkyl) ₂ N-C ₁ -C ₄ -alkyl-, C ₁ -C ₄ -alkyl-C (O) -, C ₁ -C ₄ -haloalkyl-C (O) - , having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy-C (O) -, benzyloxy- C (O) -, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl-C (O )-, -SO ₂ -C ₁ -C ₄ -alkyl and -SO ₂ -C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms;

phenyl-C ₁ -C ₄ -alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, OH, -NO ₂ , cyano, C ₁ -C ₄ -haloalkyl, having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -SC ₁ -C ₄ - alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -S-C ₁ - C ₄ haloalkyl having 1 to 5 halogen atoms, S(O)-C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, and -SO ₂ -C ₁ -C ₄ haloalkyl having 1 up to 5 halogen atoms;

heterocyclyl-C ₁ -C ₄ -alkyl, where the heterocyclyl substituent is selected from the group consisting of 4-10 membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents , independently selected from the group consisting of halogen, OH, -NO ₂ , cyano, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -S-C ₁ -C ₄ -alkyl, -S (O)-C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -SC ₁ -C ₄ - haloalkyl having from 1 to 5 halogen atoms, S (O) -C ₁ -C ₄ -haloalkyl having 1 to 5 halogen atoms, and -SO ₂ -C ₁ -C ₄ -haloalkyl having 1 to 5 halogen atoms,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl, and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or C ₁ -C ₄ -alkyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, OH, cyano, C ₁ -C ₄ - alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkyl-C (O) -, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -S-C ₁ -C ₄ -alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, halogen, OH, cyano, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkyl-C (O) -, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -S-C ₁ -C ₄ -alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl,

R ⁶ is selected from the group consisting of hydrogen, halogen, OH, cyano, C ₁ -C ₄ alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ haloalkyl having from 1 to 5 halogen atoms, C ₁ - C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkyl-C (O) - , -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -S-C ₁ -C ₄ -alkyl, -S (O) -C ₁ - C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl,

R ⁷ is selected from the group consisting of hydrogen, OH, fluorine, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ⁸ is selected from the group consisting of hydrogen, OH, fluorine, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

or R ⁷ and R ⁸ together form an oxo group (=O),

or R ⁷ and R ⁸ form together with the carbon atom to which they are attached, a 3-6 membered ring selected from the group consisting of C ₃ -C ₆ -nicloalkyl and 3-6 membered heterocycloalkyl,

R ⁹ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, and C ₁ -C ₄ alkoxy,

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

or R ¹⁰ and R ¹¹ form together with the carbon atom to which they are attached, a 3-6 membered ring selected from the group consisting of C ₃ -C ₆ -cycloalkyl and 3-6 membered heterocycloalkyl,

Q is 2,3,5-trifluorophenyl,

where when Y is O, S or NR ⁹ none of R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is —OH or C ₁ -C ₄ -alkoxy, and where when X is O, S or NR ⁹ , none of R ⁷ and R ⁸ is -OH or C ₁ -C ₄ -alkoxy;

and where is the formula compound

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, as well as mixtures of the above.

Definitions

The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced by a substituent selected from the specified group, provided that the normal valency of the designated atom under existing conditions will not be exceeded. Combinations of substituents and/or variables are allowed.

The term "optionally substituted" means that the number of substituents may be equal to or other than zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as may be attached by replacing a hydrogen atom with a non-hydrogen atom at any available carbon or nitrogen atom. Typically, the number of optional substituents, if present, may be 1, 2, 3, 4 or 5, in particular 1, 2 or 3.

As used in the description of the present invention, the term "one or more", for example, in the definition of substituents of compounds of general formula (I) according to the present invention, means "1, 2, 3, 4 or 5, especially 1, 2, 3 or 4, more specifically 1, 2 or 3, even more specifically 1 or 2".

As used herein, an oxo substituent is an oxygen atom that is bonded to a carbon atom or a sulfur atom via a double bond.

The term "ring substituent" means a substituent attached to an aromatic or non-aromatic ring that replaces an available atom of an atom in the ring.

If a complex substituent consists of more than one part, for example, (C ₁ -C ₄ -alkoxy)-(C ₁ -C ₄ -alkyl)-, the position of this part can be in any suitable position of the specified complex substituent, that is, C ₁ The -C ₄ -alkoxy portion may be attached to any carbon atom of the C ₁ -C ₄ -alkyl portion of said (C ₁ -C ₄ -alkoxy)-(C ₁ -C ₄ -alkyl) group. A hyphen at the beginning or end of such a complex substituent indicates the point of attachment of said complex substituent to the rest of the molecule. If a ring containing carbon atoms and optionally one or more heteroatoms such as a nitrogen atom, an oxygen atom or a sulfur atom, for example, is substituted with a substituent, optionally said substituent may be bonded at any suitable position of said ring, to a suitable carbon atom and/or suitable heteroatom.

As used herein, the position through which the respective substituent is connected to the rest of the molecule may in the structure shown be represented by a pound sign (#) or by a dotted line in said substituent.

The term "comprising" when used in the description of the present invention includes "consisting of".

If in the description of the present invention, any feature is accompanied by "as indicated in the description of the present invention", this means that it can be mentioned anywhere in the description of the present invention.

The terms used in the description of the present invention have the following meanings:

The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

The term "C ₁ -C ₆ -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C ₁ -C ₄ -alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl or tert-butyl group, or an isomer thereof. In particular, said group has 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl"), for example a methyl, ethyl, n-propyl or isopropyl group.

The term "C ₁ -C ₄ -hydroxyalkyl" means a linear or branched, saturated, monovalent carbon group, in which the term "C ₁ -C ₄ -alkyl" is defined above, and in which 1 or 2 hydrogen atoms are replaced by a hydroxy group, for example, hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan2-yl, 2-hydroxypropan2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan2 -yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.

The term "-NH(C ₁ -C ₄ -alkyl)" or "-N(C ₁ -C ₄ -alkyl) ₂ " means a linear or branched, saturated, monovalent group, in which the term "C ₁ -C ₄ -alkyl " is as defined above, for example, a methylamino, ethylamino, n-propylamino, isopropylamino, N,N-dimethylamino, N-methyl-N-ethylamino or N,N-diethylamino group.

The term "-SC ₁ -C ₄ -alkyl", "-S(O)-C ₁ -C ₄ -alkyl" or "-SO ₂ -C ₁ -C ₄ -alkyl" means a linear or branched, saturated group, in which the term "C ₁ -C ₄ -alkyl" has the meaning as defined above, for example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl or tert-butylsulfanyl group, methylsulfinyl, ethylsulfinyl, n -propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl group, or methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl or tert-butylsulfonyl group.

The term "C ₁ -C ₄ -haloalkyl" means a linear or branched, saturated, monovalent carbon group in which the term "C ₁ -C ₄ -alkyl" has the same meaning as above, and in which one or more of the hydrogen atoms are substituted , identical or different, to a halogen atom. In particular, said halogen atom is a fluorine atom. More specifically, all of these halogen atoms are fluorine atoms ("C ₁ -C ₄ -fluoroalkyl"). Said C ₁ -C ₄ haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1, 3-difluoropropan-2-yl.

The term "C ₁ -C ₄ -alkoxy" means a linear or branched, saturated, monovalent group of the formula (C ₁ -C ₄ -alkyl)-O-, in which the term "C ₁ -C ₄ -alkyl" has the meaning as indicated above, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy group, or an isomer thereof.

The term "C ₁ -C ₄ haloalkoxy" means a linear or branched, saturated, monovalent C ₁ -C ₄ alkoxy group as defined above in which one or more hydrogen atoms are replaced, identically or differently, by a halogen atom. In particular, said halogen atom is a fluorine atom.

Said C ₁ -C ₄ haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

The term "C ₂ -C ₄ alkenyl" means a linear or branched monovalent hydrocarbon group which contains one double bond and which has 2, 3 or 4 carbon atoms. Said C ₂ -C ₄ -alkenyl group is, for example, ethenyl (or "vinyl"), prop-2-enyl (or "allyl"), prop-1-enyl, but-3-enyl, but-2- enyl, but-1-enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl or 1-methylpropenyl group. In particular, said group is allyl.

The term "C ₂ -C ₄ alkynyl" means a linear monovalent hydrocarbon group which contains one triple bond and which contains 2, 3 or 4 carbon atoms. Said C ₂ -C ₄ alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl (or "propargyl"), but-1-ynyl, but-2-ynyl, but-3-ynyl or a 1-methylprop-2-ynyl group. In particular, said alkynyl group is prop-1-ynyl or prop-2-ynyl.

The term "C ₃ C ₆ cycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). Said C ₃ -C ₆ -cycloalkyl group is, for example, a monocyclic hydrocarbon ring, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term "C ₃ -C ₆ -halocycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring, in which the term "C ₃ -C ₆ -cycloalkyl" has the meaning as defined above, and in which one or more hydrogen atoms are substituted, equally or variously, a halogen atom. In particular, said halogen atom is a fluorine or chlorine atom. Said C ₃ -C ₆ halocycloalkyl group is, for example, a monocyclic hydrocarbon ring substituted with one or two fluorine or chlorine atoms, for example 1-fluoro-cyclopropyl, 2-fluoro-cyclopropyl, 2,2-difluoro-cyclopropyl, 2,3-difluoro-cyclopropyl , 1-chlorocyclopropyl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 2-fluoro-2-chlorocyclopropyl and 2-fluoro-3-chlorocyclopropyl group.

The term "benzo-C ₅ -C ₆ -cycloalkyl" means a monovalent, bicyclic hydrocarbon ring, where a saturated, monovalent, monocyclic hydrocarbon ring, which contains 5 or 6 carbon atoms ("C ₅ -C ₆ -cycloalkyl"), annelated with a phenyl ring. The specified benzo-C ₅ -C ₆ -cycloalkyl group is, for example, a bicyclic hydrocarbon ring, for example, indan (i.e. 2,3-dihydro-1H-indene) or tetralin (i.e. 1,2,3 ,4-tetrahydronaphthalene) group.

The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and where said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10, or 11 carbon atoms, optionally said spirocycloalkyl the group is attached to the rest of the molecule through any one of the carbon atoms, with the exception of the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.

The term "heterocycloalkyl" means a monocyclic or bicyclic, saturated or partially saturated heterocycle with 4, 5, 6, 7, 8, 9 or 10 ring atoms in total ("4-10 membered heterocycloalkyl" group), in particular 4, 5 or 6 ring atoms ("4-6 membered heterocycloalkyl," group), which contains one or two identical or different ring heteroatoms from the series N, O and S, and, optionally, the specified heterocycloalkyl group is attached to the rest of the molecule through any one of carbon atoms, or, if present, a nitrogen atom.

Said heterocycloalkyl group may, without limitation, be a 4-membered ring such as, for example, azetidinyl, oxetanyl or thietanyl; or a 5-membered ring such as tetrahydrofuranyl, oxolanyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl or 1,2,4-triazolidinyl, for example; or a 6-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, itianyl, thiomorpholinyl, piperazinyl, oxanyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example; or a 7-membered ring such as azepanil, 1,4-diazepanil or 1,4-oxazepanil, for example; or a bicyclic 7-membered ring such as 6-oxa-3-azabicyclo[3.1.1]heptane, for example; or a bicyclic 8-membered ring such as 5,6-dihydro-4H-furo[2,3-c]pyrrole or 8-oxa-3-azabicyclo[3.2.1]octane, for example; or a bicyclic 9-membered ring such as octahydro-1H-pyrrolo[3,4-b]pyridine, 1,3-dihydro-isoindole, 2,3-dihydroindole or 3,9-dioxa-7-azabicyclo[3.3. 1]nonane, for example; or a bicyclic 10-membered ring such as decahydroquinoline or 3,4-dihydroisoquinoline, for example.

The term "heterospirocycloalkyl" means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common carbon atom, where "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from series: N, O, S; wherein optionally said heterospirocycloalkyl group is attached to the remainder of the molecule through any one of the carbon atoms except the spiro carbon atom, or, if present, a nitrogen atom.

Said heterospirocycloalkyl group is e.g. oxazaspiro[2.5]octyl, azaspiro[4.5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octitl, azaspiro[5.5]undecyl, or one of the other homologous variants such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro [4.6]-.

The term "6- or 10-membered aryl" means a monovalent, monocyclic or bicyclic aromatic ring having 6 or 10 ring carbon atoms, such as a phenyl or naphthyl group.

The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 9 or 10 ring atoms ("5 to 10 membered heteroaryl" group), in particular 5 or 6 ring atoms ("5 -6-membered heteroaryl" group), which contains at least one ring heteroatom and optionally one, two or three other ring heteroatoms from the series: N, O and/or S, and which is linked through a ring carbon atom or optionally through a ring nitrogen atom (if allowed by valency).

Said heteroaryl group may be a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as, for example, pyridinyl, dihydropyridinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl or triazinyl.

The term "heterocyclyl" means a heterocycle selected from the group consisting of heteroocycloalkyl and heteroaryl. In particular, the term "4-6 membered heterocyclyl" means a heterocycle selected from the group consisting of 4-6 membered heterocycloalkyl and 5-6 membered heteroaryl.

In general, and unless otherwise indicated, heteroaryl or heteroarylene groups include all their possible isomeric forms, eg tautomers and positional isomers relative to the point of attachment to the rest of the molecule. Thus, for some illustrative non-limiting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-l and thien-3-yl.

The term "C ₁ -C ₄ "as used in the description of the present invention, for example, in the context of the definition of "C ₁ -C ₄ -alkyl", "C ₁ -C ₄ haloalkyl", "C ₁ -C ₄ -hydroxyalkyl" , "C ₁ -C ₄ -alkoxy" or "C ₁ -C ₄ -haloalkoxy" means an alkyl group having a finite number of carbon atoms from 1 to 4, i.e. 1, 2, 3 or 4 carbons.

In addition, as used in this application, the term "C ₃ -C ₆ ", as used in the description of the present invention, for example, in the context of the definition of "C ₃ -C ₆ -cycloalkyl" or C ₃ -C ₆ -halocycloalkyl, means cycloalkyl a group having a finite number of carbon atoms from 3 to 6, i. e. 1, 2, 3, 4, 5 or 6 carbon atoms.

When a range of values is specified, the specified range spans every value and subrange in the specified range.

For example:

"C ₁ -C ₄ " includes C ₁ , C ₂ , C ₃ , C 4 , C 1 -C ₄ , C ₁ -C ₃ , C ₁ -C ₂ , C _{2 -C 4 ,} C _{2 -C 3} , and C ₃ -C ₄ ;

"C ₂ -C ₆ " includes C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₂ -C ₆ , C ₂ -C ₅ , C ₂ -C ₄ , C ₂ -C ₃ , C ₃ - C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₄ -C ₅ , and C ₅ -C ₆ ;

"C ₃ -C ₄ " encompasses C ₃ , C ₄ , and C ₃ -C ₄ ;

"C ₃ -C ₁₀ " includes C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₃ -C ₁₀ , C ₃ -C ₉ , C ₃ -C ₈ , C ₃ -C ₇ , C ₃ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₁₀ , C ₄ -C ₉ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₁₀ , C ₅ -C ₉ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ ;

"C ₃ -C ₈ " embraces C ₃ , C ₄ , C ₅ , C 6 _, C ₇ , C ₈ , C 3 -C ₈ , C ₃ -C ₇ , C ₃ -C ₆ , C _{3 -C 5} , C ₃ -C ₄ , C ₄ -C ₈ , C ₄ -C ₇ , C ₄ -C ₆ , C ₄ -C ₅ , C ₅ -C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ ;

"C ₃ -C ₆ " includes C ₃ , C ₄ , C ₅ , C 6 , C 3 -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C _{4 -C 6 ,} C _{4 -C 5} , and C ₅ -C ₆ ;

"C ₄ -C ₈ " includes C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C 4 -C 8 , C ₄ -C ₇ , C ₄ -C ₆ , C _{4 -C 5} , C _{5 -} C ₈ , C ₅ -C ₇ , C ₅ -C ₆ , C ₆ -C ₈ , C ₆ -C ₇ and C ₇ -C ₈ ;

"C ₄ -C ₇ " includes C ₄ , C ₅ , C ₆ , C ₇ , C ₄ -C 7 , C 4 -C ₆ , C ₄ -C ₅ , C ₅ -C ₇ , C _{5 -C 6 and} C ₆ -C ₇ ; "C ₄ -C ₆ " encompasses C ₄ , C ₅ , C ₆ , C ₄ -C ₆ , C ₄ -C ₅ and C ₅ -C ₆ ;

"C ₅ -C ₁₀ " includes C ₅ , C ₆ , C ₇ , C 8 , C ₉ , C ₁₀ , C _{5 -C 10 , C 5 -C 9} , C _{5 -C 8} , C _{5 -C 7} , C ₅ -C ₆ , C ₆ -C ₁₀ , C ₆ -C ₉ , C ₆ -C ₈ , C ₆ -C ₇ , C ₇ -C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ ;

"C ₆ -C ₁₀ " includes C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C 6 -C 10 , C ₆ -C ₉ , C ₆ -C ₈ , C _{6 -C 7} , C _{7 -} C ₁₀ , C ₇ -C ₉ , C ₇ -C ₈ , C ₈ -C ₁₀ , C ₈ -C ₉ and C ₉ -C ₁₀ .

As used in the description of the present invention, the term "leaving group" means an atom or group of atoms, which is replaced in the course of a chemical reaction in the form of a stable group, taken together with bonding electrons. In particular, such a leaving group is selected from the group consisting of: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy.

Oxo substituent in the context of the present invention means an oxygen atom which is bonded to a carbon atom via a double bond.

Compounds of general formula (I) may exist as isotopic variants. Therefore, the present invention includes one or more isotopic variants of the compounds of general formula (I), in particular deuterium-containing compounds of general formula (I).

The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits a non-naturally occurring proportion of one or more isotopes that make up that compound.

The term "isotopic variant of a compound of general formula (I)" is defined as a compound of general formula (I) exhibiting a non-naturally occurring proportion of one or more isotopes that constitute such a compound.

The term "non-naturally occurring proportion" means the proportion of such an isotope which is higher than its abundance in nature. Natural abundances of isotopes applicable in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C , ¹⁵ N, ¹⁷ O, ¹⁸ O ^{, 32} Р, 33 Р, ³³ S, ³⁴ S, 35 S, ³⁶ S, ¹⁸ F ^{, 36} Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I respectively.

With respect to the treatment and/or prevention of the disorders specified in this application, the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as ³ H or ¹⁴ C, are included are useful, for example, in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred because of their ease of incorporation and detection. Positron active isotopes such as ¹⁸ F or ¹¹ C may be included in the compound of general formula (I). These isotopic variants of the compound of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and ¹³ C-containing compounds of general formula (I) can be used in mass spectrometry analyzes in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can usually be obtained by methods known to the person skilled in the art, such as those described in the schemes and/or examples in the description of the present invention, by replacing the reagent with an isotopic variant of the specified reagent, preferably a deuterium-containing reagent. Depending on the deuteration sites desired, in some cases the deuterium from D ₂ O can be incorporated either directly into the compounds or into reagents that are useful in the synthesis of such compounds. Deuterium in the form of a gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetyl bonds is a fast way to incorporate deuterium. Metal-based catalysts (ie, Pd, Pt, and Rh) in the presence of gas deuterium can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. Various deiterated reagents and synthetic building blocks are commercially available from companies such as, for example, C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atoms are replaced by one or more deuterium atoms, and in which the content of deuterium in such a deuterated position of the compound of general formula (I) is higher than the deuterium content in nature, which is about 0.015%. In particular, in the deuterium-containing compound of general formula (I), the deuterium content in each deuterated position of the compound of general formula (I) is more than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% , preferably more than 90%, 95%, 96% or 97%, even more preferably more than 98% or 99% at the specified position(s). It is understood that the deuterium content of each deuterium position is independent of the deuterium content of the other deuterium position(s).

Selective incorporation of one or more deuterium atoms into a compound of general formula (I) may change the physicochemical properties (such as, for example, acidity [C.L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3 ), 271]) and/or the metabolic profile of the molecule and may lead to changes in the ratio of the parent compound and metabolites or the amounts of metabolites formed. Such changes may result in certain therapeutic benefits and may therefore be preferred in some applications. Decreased metabolic rates and metabolic shutdown, in which the ratio of metabolites changes, have been described (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes upon exposure to the parent drug and metabolites may have important implications for the pharmacodynamics, tolerability and efficacy of the deuterium-containing compound of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of an undesirable or toxic metabolite and enhances the formation of the desired metabolite (e.g., Nevirapine: A.M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A.E. Mutlib et al., Toxicol Appl Pharmacol 2000, 169, 102). In other cases, the main effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. Potential clinical benefits would include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This may lead to reduced side effects and improved efficacy, depending on the particular pharmacokinetic/pharmacodynamic relationship of the particular compound. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO 2012/112363) are examples of this deuterium effect. Other cases have also been reported in which reduced metabolic rates lead to increased drug exposure without altering the systemic clearance rate (eg, Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs exhibiting this effect may have reduced dosage requirements (eg, fewer doses or lower dose to achieve the desired effect) and/or may result in lower metabolic loads.

The compound of general formula (I) may have many potential sites of influence on metabolism. To optimize the above effects in terms of physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a specific pattern of one or more deuterium-hydrogen exchange(s) can be selected. In particular, the deuterium atom(s) of the deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located in those positions of the compound of general formula (I) that are sites of action on metabolizing enzymes, such as, for example, cytochrome P ₄₅₀ .

When the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like is used in the description of the present invention, it also means a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By "stable compound" or "stable structure" is meant a compound that is sufficiently stable to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The compounds of the present invention optionally contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms (R) or (S) are present in the configuration, which can lead to racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, it is possible that asymmetry is also present due to limited rotation about a given bond, for example, a central bond adjacent to two substituted aromatic rings of these compounds.

Preferred compounds are compounds that provide more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such materials can be performed by standard methods known in the art.

Preferred isomers are those that provide the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such materials can be performed by standard methods known in the art.

Optical isomers can be obtained by separating racemic mixtures according to conventional methods, for example by forming diastereomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers based on their physical and/or chemical differences by methods known in the art, for example by chromatography or fractional crystallization. Optically active bases or acids are then released from the separated diastereomeric salts. Various methods for separating optical isomers include the use of chiral chromatography (eg, HPLC columns using a chiral phase), with or without conventional derivatization, optionally chosen to maximize separation of enantiomers. Stable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, eg Chiracel OD and Chiracel OJ, for example, among many others, all of which are routinely available for selection. Enzymatic separations, with or without derivatization, also apply. Optically active compounds according to the present invention can similarly be obtained by chiral syntheses using optically active starting materials.

To distinguish the different types of isomers from each other, reference is made to the IUPAC Rules Part E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention, as individual stereoisomers, or as any mixture of said stereoisomers, eg (R)- or (S)-isomers in any ratio. Isolation of one stereoisomer, eg one enantiomer or one diastereomer of a compound of the present invention, is achieved by any suitable prior art method such as chromatography, especially chiral chromatography, for example.

The present invention includes all possible tautomers of the compounds of the present invention as individual tautomers, or as any mixture of said tautomers, in any ratio.

In addition, the compounds of the present invention may exist as N-oxides, which are defined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

The present invention also encompasses useful forms of the compounds of the present invention such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts and/or co-precipitates.

The compounds of the present invention may exist as a hydrate or as a solvate when the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol, for example, as a structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, can be in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

In addition, the compounds of the present invention may exist in free form, for example as a free base or as a free acid or as a zwitterion, or may exist as a salt. Said salt may be any salt, either an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt that is routinely used in the pharmaceutical industry, or that is used, for example, to isolate or purify the compounds of the present invention.

The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S.M. Berge, et al. "Pharmaceutical Salts," J. Pharm. sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid addition salt of a compound of the present invention bearing a nitrogen atom in the chain or ring, for example, which is sufficiently basic, such as an acid addition salt with an inorganic acid or "mineral acid ", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric or nitric acid, for example, or with an organic acid such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamon, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-fenapropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalenedisulfonic, camphorsulfonic, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic or thiocyanic acid, for example.

Furthermore, another suitable pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as calcium, magnesium or strontium, or an aluminum or zinc salt, or an ammonium salt, derivative from ammonia or from an organic primary, secondary or tertiary amine having from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane , procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine , sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion having from 1 to 20 atoms carbon, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

Those skilled in the art will also appreciate that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the alkali and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting the compounds of the present invention with an appropriate base by a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as individual salts, or as any mixture of said salts, in any ratio.

In the description of the present invention, in particular in the Experimental part, for the synthesis of intermediates and examples according to the present invention, when the compound is mentioned in the form of a salt with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the corresponding preparation method and/ or cleaning, in most cases is unknown.

Unless otherwise indicated, suffixes in chemical names or structural formulas referring to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF ₃ COOH", "x Na ⁺ ", for example, mean the form of the salt, where the stoichiometry of the form of the salt is not specified.

This applies similarly to cases where intermediates or exemplary compounds or salts thereof have been obtained by the described preparation and/or purification processes, in the form of solvates, such as hydrates, with (if determined) an unknown stoichiometric composition.

In addition, the present invention includes all possible crystalline forms, or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph, in any ratio.

In addition, the present invention also includes prodrugs of the compounds of the present invention. The term "prodrugs" in the context of the present invention means compounds which may or may not be biologically active or inactive in themselves, but are converted (eg metabolically or hydrolytically) to the compounds of the present invention during their stay in the body.

According to a second embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is A1 or A2,

o is 0, 1, 2, 3 or 4,

R is selected from the group consisting of hydrogen, halogen, cyano, nitro, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₃ -C ₆ -cycloalkyl, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -SC ₁ -C ₄ -alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -S-C ₁ -C ₄ -haloalkyl, -S (O)-C ₁ -C ₄ -haloalkyl and SO ₂ -C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O, S, and NR ⁹ , where at least one of X and Y is CR ⁷ R ⁸ , or

X, Y together form a ring member selected from the group consisting of -C(O)-O-, -C(O)-NR ⁹ -, -S(O)-NR ⁹ -, -SO ₂ -NR ⁹ - and -SO ₂ -O-,

R ¹ is selected from the group consisting of hydrogen, cyano, -CHO, OH, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl having from 1 to 5 halogen atoms, C ₃ -C ₄ -alkenyl, C ₃ - C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl, cyano-C ₁ -C ₄ -alkyl, -NH- C ₁ -C ₄ -alkyl, N (C ₁ -C ₄ -alkyl) ₂ , NH ₂ -C ₁ -C ₄ -alkyl-, C ₁ -C ₄ -alkyl-NH-C ₁ -C ₄ -alkyl- , (C ₁ -C ₄ -alkyl) ₂ N-C ₁ -C ₄ -alkyl-, C ₁ -C ₄ -alkyl-C (O) -, C ₁ -C ₄ -haloalkyl-C (O) -, having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy-C (O) -, benzyloxy - C (O) -, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl-C (O) -, -SO ₂ -C ₁ -C ₄ -alkyl and -SO ₂ -C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms;

phenyl-C ₁ -C ₄ -alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, OH, -NO ₂ , cyano, C ₁ -C ₄ -haloalkyl, having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -SC ₁ -C ₄ - alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -S-C ₁ - C ₄ -haloalkyl having 1 to 5 halogen atoms, -S(O)-C ₁ -C ₄ -haloalkyl having 1 to 5 halogen atoms, and -SO ₂ -C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms;

heterocyclyl-C ₁ -C ₄ -alkyl, where the heterocyclyl substituent is selected from the group consisting of 4-10 membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is optionally substituted with 1, 2 or 3 substituents , independently selected from the group consisting of halogen, OH, -NO ₂ , cyano, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ , -S-C ₁ -C ₄ -alkyl, -S (O)-C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, -SC ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, S (O) -C ₁ -C ₄ -haloalkyl having 1 to 5 halogen atoms, and -SO ₂ -C ₁ -C ₄ -haloalkyl having 1 to 5 halogen atoms,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl, and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or C ₁ -C ₄ -alkyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH(C ₁ -C ₄ -alkyl), -N(C ₁ -C ₄ -alkyl) ₂ , preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ ,

R ⁶ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ ,

R ⁷ is selected from the group consisting of hydrogen, OH, fluorine, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ⁸ is selected from the group consisting of hydrogen, OH, fluorine, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

or R ⁷ and R ⁸ together form an oxo group (=O),

R ⁹ is selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, and C ₁ -C ₄ alkoxy,

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ¹¹ is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

Q is 2,3,5-trifluorophenyl,

where when Y is O, S or NR ⁹ none of R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ is -OH or C ₁ -C ₄ -alkoxy, and

where when X is O, S or NR ⁹ none of R ⁷ and R ⁸ is —OH or C ₁ -C ₄ -alkoxy;

and where is the formula compound

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a third embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is A1 or A2,

o is 0, 1 or 2,

R is selected from the group consisting of halogen, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, piano, C ₁ -C ₄ -haloalkyl having from 1 to 5 halogen atoms,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ where at least one of X and Y is CR ⁷ R ⁸ ,

R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl, C ₃ -C ₄ alkynyl, C ₁ -C ₄ -alkoxy- C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl, cyano-C ₁ -C ₄ -alkyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or C ₁ -C ₄ -alkyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH(C ₁ -C ₄ -alkyl), -N(C ₁ -C ₄ -alkyl) ₂ , preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ ,

R ⁶ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) ₂ ,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

or R ⁷ and R ⁸ together form an oxo group (=O),

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,

R ¹¹ is hydrogen,

Q is 2,3,5-trifluorophenyl,

where when Y is O, S or NR ⁹ , R ¹⁰ is not -OH or C ₁ -C ₄ -alkoxy;

and where is the formula compound

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a fourth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is A1 or A2,

o is 0, 1 or 2,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and piano,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X is selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ ,

Y is CR ⁷ R ⁸ or O,

R ¹ is hydrogen or C ₁ -C ₄ -alkyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or C ₁ -C ₄ -alkyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, piano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, -NH ₂ , preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, piano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy,

R ⁶ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

or R ⁷ and R ⁸ together form an oxo group (=O),

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH and C ₁ -C ₄ -alkyl,

R ¹¹ is hydrogen,

Q is 2,3,5-trifluorophenyl,

where is the compound formula

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a fifth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is selected from the group consisting of

R ¹ is hydrogen or methyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or methyl,

R ⁴ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl, methoxy, trifluoromethyl, trifluoromethoxy and NH ₂ , preferably hydrogen, fluorine, chlorine and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine , methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl, methoxy and trifluoromethyl,

R ⁶ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl and methoxy,

Q is 2,3,5-trifluorophenyl,

where is the compound formula

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a sixth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is selected from the group consisting of

R ¹ is hydrogen or methyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or methyl,

R ⁴ is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy, isopropoxy and trifluoromethyl, preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, piano, methyl, trifluoromethoxy and NH ₂ ,

R ⁶ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl and methoxy,

Q is 2,3,5-trifluorophenyl,

where is the compound formula

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a seventh embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is selected from the group consisting of

R ¹ is hydrogen or methyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or methyl,

R ⁴ is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, piano, methyl, methoxy, trifluoromethyl, trifluoromethoxy and NH ₂ , preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, piano, methyl, methoxy and trifluoromethyl,

R ⁶ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl and methoxy,

Q is 2,3,5-trifluorophenyl,

where is the compound formula

исключено;

excluded;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to an eighth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) above, wherein:

A is A3 or A4

o represents 0 or 1,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and cyano,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X is selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ ,

Y is CR ⁷ R ⁸ or O,

R ¹ is hydrogen or C ₁ -C ₄ -alkyl,

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

R ³ is hydrogen or C ₁ -C ₄ -alkyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, NH ₂ , preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms,

R ⁶ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, or R ⁷ and R ⁸ together form an oxo group (=O) ,

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH and C ₁ -C ₄ -alkyl,

R ¹¹ is hydrogen,

Q is 2,3,5-trifluorophenyl,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

Other embodiments of the first aspect of the present invention:

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0, 1 or 1,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, piano, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms,

_Rp is hydrogen,

X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ , where at least one of X and Y is CR ⁷ R ⁸ ,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, and

R ¹¹ is hydrogen,

where when Y is O, S or NR ⁹ , R ¹⁰ is not -OH or C ₁ -C ₄ -alkoxy,

and where is the formula compound

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0, 1 or 2,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, piano, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl,

X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ , where at least one of X and Y is CR ⁷ R ⁸ ,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, or R ⁷ and R ⁸ together form an oxo group (=O),

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, and

R ¹¹ is hydrogen,

where when Y is O, S or NR ⁹ , R ¹⁰ is not -OH or C ₁ -C ₄ -alkoxy,

and where is the formula compound

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0, 1 or 2,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, piano, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms,

R _p is hydrogen, X, Y are independently selected from the group consisting of CR ⁷ R ⁸ , O and S,

where at least one of X and Y is CR ⁷ R ⁸ ,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, or R ⁷ and R ⁸ together form an oxo group (=O),

R ¹⁰ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy, and

R ¹¹ is hydrogen,

where when Y is O, S or NR ⁹ , R ¹⁰ is not -OH,

and where is the formula compound

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0 or 1,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and piano,

_Rp is hydrogen,

X is selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ ,

Y is CR ⁷ R ⁸ ,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH and C ₁ -C ₄ -alkyl, and

R ¹¹ represents hydrogen, and where the compound of formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0 or 1,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and piano,

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl, X is selected from the group consisting of CR ⁷ R ⁸ , O, S and NR ⁹ ,

Y is CR7R ⁸ or O,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

or R ⁷ and R ⁸ together form an oxo group (=O),

R ⁹ is C ₁ -C ₄ -alkyl,

R ¹⁰ is selected from the group consisting of hydrogen, OH and C ₁ -C ₄ -alkyl, and

R ¹¹ is hydrogen,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is A1 or A2,

○ represents 0 or 1,

R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and piano,

_Rp is hydrogen,

X is selected from the group consisting of CR ⁷ R ⁸ , O and S,

Y is CR ⁷ R ⁸ or O,

R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl,

or R ⁷ and R ⁸ together form an oxo group (=O),

R ¹⁰ is selected from the group consisting of hydrogen, OH and C ₁ -C ₄ -alkyl, and

R ¹¹ is hydrogen,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is selected from the group consisting of

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is selected from the group consisting of

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is selected from the group consisting of

preferably

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

A is selected from the group A ¹ as defined elsewhere herein above;

;preferably A is

;

.with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R _p is hydrogen or C ₁ -C ₄ -alkyl, where the compound of formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R _p is hydrogen or methyl, where the compound of formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ³ represents hydrogen or C ₁ -C ₄ -alkyl, where the compound of formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ³ is hydrogen or methyl,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, piano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, NH ₂ , preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁴ is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, piano, methyl, methoxy, isopropoxy, trifluoromethyl, trifluoromethoxy and NH ₂ , preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁵ is selected from the group consisting of hydrogen, halogen, -OH, piano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁵ is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, piano, methyl, methoxy and trifluoromethyl,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁶ is selected from the group consisting of hydrogen, halogen, -OH, piano, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ⁶ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, piano, methyl and methoxy,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ² is tetrahydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl,

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ² is 3,6-dihydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl,

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ² is ethyl,

R ⁴ is selected from the group consisting of hydrogen, halogen, OH, cyano, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, C ₁ -C ₄ -alkyl-C (O) -, -NH ₂ , -NH (C ₁ -C ₄ -alkyl), -N (C ₁ -C ₄ -alkyl) 2, -SC ₁ -C ₄ -alkyl, -S (O) -C ₁ -C ₄ -alkyl, -SO ₂ -C ₁ -C ₄ -alkyl, preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy,

;Q is 2,3,5-trifluorophenyl provided that R ⁴ is not hydrogen when A is

;

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein:

R ² is 3-fluoroazetidin-1-yl,

Q is 2,3,5-trifluorophenyl,

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another embodiment of the first aspect, the present invention encompasses compounds of formula (I) above, wherein

A is A3 or A4

Where

R _p is selected from the group consisting of hydrogen, C ₁ -C ₄ -alkyl; preferably hydrogen,

where is the compound formula

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to another aspect of the present invention, in any or all of the embodiments described anywhere in this document, in the definition of X and/or Y "NR ⁹ "as defined above, is excluded.

According to another aspect, the present invention encompasses compounds of formula (I) as defined in any of the embodiments herein, wherein:

.R ⁴ is as defined elsewhere herein, provided that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

.

In addition, the compound of the formula

excluded from the present invention.

In a specific other embodiment of the first aspect, the present invention encompasses combinations of two or more of the above embodiments of the present invention, referred to as "other embodiments of the first aspect of the present invention".

The present invention embraces any subcombination within any embodiment of the present invention or subject matter of the present invention of the compounds of general formula (I) above.

The present invention covers compounds of general formula (I) which are disclosed in the Examples part of the description of the present invention, below.

Compounds according to the present invention of general formula (I) can be obtained according to schemes 1-5, as shown in the Experimental part of the present invention (General methods). The described schemes and procedures illustrate the ways of synthesis of compounds of General formula (I) according to the present invention and are not intended to be limiting. One skilled in the art will appreciate that the order of transformations as shown in Figures 1-5 can be modified in various ways. Therefore, the order of transformations exemplified in these diagrams is not limiting. In addition, the interconversion of any of the substituents Q, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ can be achieved before and/or after the examples of transformations. These modifications may be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metalation, substitution, or other reactions known to the person skilled in the art. These transformations include those that introduce a functional group that allows further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, ^3rd edition, Wiley 1999). Specific examples are described in the following paragraphs.

According to a second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula 1N:

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compound of general formula (I), as defined above, and Hal represents a halogen, in particular chlorine and bromine, in reaction with a compound of general formula 1F:

in which R ² is 3-fluoroazetidine, thus obtaining a compound of general formula (I):

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q are as defined above, and R ² is 3-fluoroazetidine,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to an alternative embodiment of the second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula 1T:

in which A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compound of general formula (I) as defined above, and in which Hal represents a halogen, in particular chlorine, bromine or iodine

;with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

;

in reaction with a compound of general formula 1H:

in which Q is 2,3,5-trifluorophenyl and each R can individually be H or Me, or both R are pinacolate,

thus obtaining a compound of general formula (I):

wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above and Q is 2,3,5-trifluorophenyl,

,with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to an alternative embodiment of the second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula 1W:

in which Q, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compound of General formula (I), as defined above,

;with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

;

in reaction with a compound of general formula 1M:

in which R ¹ and A have the meanings as defined for the compounds of General formula (I), as defined above,

thus obtaining a compound of general formula (I):

in which A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Q are as defined above,

,with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to an alternative embodiment of the second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula 1N:

in which Q, A, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compound of general formula (I), as defined above, and Hal represents a halogen, in particular chlorine and bromine,

in reaction with a compound of general formula 2A:

in which R ² is ethyl or 3,6-dihydro-2H-pyran-4-yl, Met is magnesium or zinc, and X is chlorine, bromine or iodine,

;with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

;

thus obtaining a compound of general formula (I):

,in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q are as defined above, and R ² is ethyl or 3,6-dihydro-2H-pyran-4-yl, provided that R ⁴ is not hydrogen when R ² is ethyl and when A is

,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to an alternative embodiment of the second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula 1N:

in which Q, A, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compound of general formula (I), as defined above, and Hal represents a halogen, in particular chlorine and bromine,

in reaction with a compound of general formula 2P:

in which R ² is ethyl or 3,6-dihydro-2H-pyran-4-yl, and each R can individually be H or Me, or both R are pinacolate,

;with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

;

thus obtaining a compound of general formula (I):

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ m Q have the meanings as defined above, and R ² represents ethyl or 3,6-dihydro-2H-pyran-4-yl,

,with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to an alternative embodiment of the second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, said methods comprising the step of introducing an intermediate compound of general formula I-b1:

in which Q, A, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compound of General formula (I), as defined above,

in reaction with hydrogen (H ₂ ) in the presence of catalysts such as palladium on activated carbon,

thus obtaining a compound of general formula (I):

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and Q are as defined above, and R ² is tetrahydropyran-4-yl,

then optionally converting said compounds into solvates, salts and/or solvates of such salts using appropriate (i) solvents and/or (ii) bases or acids.

According to a third aspect, the present invention encompasses intermediates which are useful in the preparation of compounds of general formula (I) above.

In particular, the present invention covers intermediate compounds of general formula (II):

wherein

R ² is OH or is as defined for the compound of general formula (I) above,

R ³ , R ⁴ , R ⁵ , R ⁶ , and Q are as defined for the compound of general formula (I) above, and

R ^A is H or C ₁ -C ₄ -alkyl,

and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

According to a fourth aspect, the present invention encompasses the use of said intermediates for the preparation of a compound of general formula (I) as defined above.

In particular, the present invention covers the use of these intermediates of general formula (II):

wherein

R ² is OH or is as defined for the compound of general formula (I) above,

R ³ , R ⁴ , R ⁵ , R ⁶ , and Q are as defined for the compound of general formula (I) above, and

R ^A is H or C ₁ -C ₄ -alkyl, to obtain a compound of general formula (I) as above.

The present invention covers the intermediates which are disclosed in the Experimental section of the description of the present invention, below.

The compounds of general formula (I) according to the present invention can be converted into any salt, preferably pharmaceutically acceptable salts, as described in this application, by any method known to a person skilled in the art. Similarly, any salt of a compound of general formula (I) according to the present invention may be converted to the free compound by any method known to the person skilled in the art.

The compounds of general formula (I) according to the present invention have shown a valuable pharmacological spectrum of activity that could not be predicted. Compounds according to the present invention were surprisingly found to interact effectively with Slo-1 and therefore said compounds can be used for the treatment or prevention of diseases, especially helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections. with nematodes in humans and animals.

The compounds according to the present invention can be used for the control, treatment and/or prevention of helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis. The method comprises administering to a mammal in need thereof a small amount of a compound of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; that are effective in treating the disorder.

Alternatively, this method comprises administering to birds, namely caged birds, or in particular poultry in need thereof, an amount of a compound of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; that are effective in treating the disorder.

In particular, in the field of veterinary medicine, the compounds of the present invention are suitable, with favorable toxicity in warm-blooded animals, for the control of parasites, in particular helminths, which occur in animal husbandry, animal breeding, zoo, laboratory, experimental and domestic animals. They are active against all or specific stages of development of parasites, in particular helminths.

Farm animals include, for example, mammals such as sheep, goats, horses, donkeys, camels, buffaloes, rabbits, deer, fallow deer, and in particular cattle and pigs; or birds such as turkeys, ducks, geese and in particular chickens; or fish or crustaceans, for example in aquaculture.

Pets include, for example, mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, or in particular dogs, cats; cage birds; reptiles; amphibians or aquarium fish.

The present invention also provides methods for the treatment of helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal nematode infections.

These disorders are well characterized in animals and can be treated by administering the pharmaceutical compositions of the present invention.

The term "treat" or "treatment" as used in the description of the present invention is conventionally used, such as controlling or caring for a subject to combat, alleviate, reduce, relieve, ameliorate a disease or disorder such as a hookworm infection. In particular, and especially in the field of animal health or the veterinary field, the term "treat" or "treatment" includes prophylactic, metaphylactic or therapeutic treatment.

Helminths pathogenic to humans or animals include, for example, acanthocephalans, nematodes, pentastomes, and flatworms (eg, monogeneans, cestodes, and flukes).

Exemplary helminths include, without any limitation:

Monogeneans: for example: Dactylogyrus spp., Gyrodactylus spp., Microbothrium spp., Polystoma spp., Troglocephalus spp.

Cestodes: from the order Pseudophyllidea, for example: Bothridium spp., Diphyllobothrium spp., Diplogonoporus spp., Ichthyobothrium spp., Ligula spp., Schistocephalus spp., Spirometra spp.

from the order Cyclophyllids, for example: Andyra spp., Anoplocephala spp., Avitellina spp., Bertiella spp., Cittotaenia spp., Davainea spp., Diorchis spp., Diplopylidium spp., Dipylidium spp., Echinococcus spp., Echinocotyle spp., Echinolepis spp., Hydatigera spp., Hymenolepis spp., Joyeuxiella spp., Mesocestoides spp., Moniezia spp., Paranoplocephala spp., Raillietina spp., Stilesia spp., Taenia spp., Thysaniezia spp., Thysanosoma spp.

Trematodes: from the class of digenetic flukes, for example: Austrobilharzia spp., Brachylaima spp., Calicophoron spp., Catatropis spp., Clonorchis spp. Collyriclum spp., Cotylophoron spp., Cyclocoelum spp., Dicrocoelium spp., Diplostomum spp., Echinochasmus spp ., Echinoparyphium spp., Echinostoma spp., Eurytrema spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Fischoederius spp., Gastrothylacus spp., Gigantobilharzia spp., Gigantocotyle spp., Heterophyes spp., Hypoderaeum spp., Leucochloridium spp., Metagonimus spp., Metorchis spp., Nanophyetus spp., Notocotylus spp., Opisthorchis spp., Omithobilharzia spp., Paragonimus spp., Paramphistomum spp., Plagiorchis spp., Posthodiplostomum spp., Prostpphogonimus spps., Schistosoma ., Trichobilharzia spp., Troglotrema spp., Typhlocoelum spp.

Nematodes: from the order Trichinellida, for example: Capillaria spp., Eucoleus spp., Paracapillaria spp., Trichmella spp., Trichomosoides spp., Trichuris spp.

from the Tylenchida order, for example: Micronema spp., Parastrongyloides spp., Strongyloides spp.

from the order Rhabditina, for example: Aelurostrongylus spp., Amidostomum spp., Ancylostoma spp., Angiostrongylus spp., Bronchonema spp., Bunostomum spp., Chabertia spp., Cooperiaspp., Cooperioides spp., Crenosomaspp., Cyathostomum spp., Cyclococercus spp ., Cyclodontostomum spp., Cylicocyclus spp., Cylicostephanus spp., Cylindropharynx spp., Cystocaulus spp., Dictyocaulus spp., Elaphostrongylus spp., Filaroides spp., Globocephalus spp., Graphidium spp., Gyalocephalus spp., Haemonchus spp., Heligmosomoides spp., Hyostrongylus spp., Marshallagia spp., Metastrongylus spp., Muellerius spp., Necator spp., Nematodirus spp., Neostrongylus spp., Nippostrongylus spp., Obeliscoides spp., Oesophagodontus spp., Oesophagostomum spps., Ollulanus .; Omithostrongylus spp., Oslems spp., Ostertagia spp., Paracooperia spp., Paracrenosoma spp., Parafilaroides spp., Parelaphostrongylus spp., Pneumocaulus spp., Pneumostrongylus spp., Poteriostomum spp. ., Strongylus spp., Syngamus spp., Teladorsagia spp., Trichonema spp., Trichostrongylus spp., Triodontophorus spp., Troglostrongylus spp., Uncinaria spp.

from the order Spirurida, for example: Acanthocheilonema spp., Anisatds spp., Ascaridia spp.; Ascaris spp., Ascarops spp., Aspiculuris spp., Baylisascaris spp., Bmgia spp., Cercopithifilaria spp., Crassicauda spp., Dipetalonema spp., Dirofilaria spp., Dracunculus spp.; Draschia spp., Enterobius spp., Filaria spp., Gnathostoma spp., Gongylonema spp., Habronema spp., Heterakis spp.; Litomosoides spp., Loa spp., Onchocerca spp., Oxiuris spp., Parabronema spp., Parafilaria spp., Parascaris spp., Passalurus spp., Physaloptera spp., Probstmayria spp., Pseudofilaria spp., Setaria spp., Skjrabmema spp ., Spirocerca spp., Stephanofilaria spp., Strongyluris spp., Syphacia spp., Thelazia spp., Toxascaris spp., Toxocara spp., Wuchereria spp.

Acanthocephalans: from the order Oligacanthorhynchida, for example: Macracanthorhynchus spp., Prosthenorchis spp.; from the order Moniliformida, for example: Moniliformis spp. from the order Polymorphida, for example: Filicollis spp.; from the order Echinorhynchida, for example: Acanthocephalus spp., Echinorhynchus spp., Leptorhynchoides spp.

Pentastomes: from the order Porocephalida, for example: Linguatulaspp.

The compounds according to the present invention can be used in particular for the treatment and prevention, i. prevention, helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes.

By using the compounds of the present invention to control animal parasites, in particular helminths, it is intended to reduce or prevent disease, death and loss of productivity (in the case of meat, milk, wool, hides, eggs, honey, and the like), so that it becomes possible more economical and easier animal breeding and better animal welfare.

The term "control" or "control", as used in the description of the present invention in relation to the field of animal welfare, means that the compounds according to the present invention are effective in reducing the incidence of the corresponding parasite in an animal infected with such parasites to innocuous levels. More specifically, "control", as used in the description of the present invention, means that the compounds according to the present invention are effective in killing the corresponding parasite, inhibiting its growth or inhibiting its proliferation.

According to another object, the present invention covers compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, for use in treatment or prevention of diseases, in particular helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes.

The pharmaceutical activity of the compounds of the present invention can be elucidated by their interaction with the Slo-1 ion channel.

According to another object, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and in particular their pharmaceutically acceptable salts, or mixtures thereof, for treatment or prevention of diseases, in particular helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes.

According to another object, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and in particular their pharmaceutically acceptable salts, or mixtures thereof, in a method for the treatment or prevention of diseases, in particular helminthiasis, especially gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes.

According to another object, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, and in particular their pharmaceutically acceptable salts, or mixtures thereof, for obtaining a pharmaceutical composition, preferably a drug, for the prevention or treatment of diseases, in particular helminthiasis, especially gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes.

According to another object, the present invention covers a method for the treatment or prevention of diseases, in particular helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and non-intestinal infections caused by nematodes, using an effective amount of a compound of general formula (I ) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts or mixtures thereof.

According to another object, the present invention covers compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, for use in as an anti-endoparasite agent.

According to another object, the present invention covers compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, for use in as an anthelmintic agent, in particular for use as a nematicidal agent, platyhelminthicidal agent, acanthocephalicidal agent or pentastomycidal agent

In accordance with another object, the present invention covers pharmaceutical compositions, in particular a veterinary composition containing a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydroxide, solvate, salt, in particular a pharmaceutically acceptable salt , or a mixture thereof, and one or more excipients, in particular one or more pharmaceutically acceptable excipients. You can use the usual techniques for the preparation of such pharmaceutical compositions in appropriate dosage forms.

In accordance with another object, the present invention covers a method for preparing a pharmaceutical composition, in particular a veterinary composition, comprising the step of mixing a compound of general formula (I) as described above, or its stereoisomer, tautomer, N-oxide, hydroxide, solvate, salt, in in particular a pharmaceutically acceptable salt, or mixtures thereof, with one or more excipients, in particular one or more pharmaceutically acceptable excipients.

According to another object, the present invention covers a method for the treatment or prevention of diseases, in particular helminthiasis, in particular gastrointestinal and extraintestinal helminthiasis, more specifically gastrointestinal and extraintestinal infections caused by nematodes, using a pharmaceutical composition, in particular a veterinary composition, containing an effective amount of a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof.

In addition, the present invention relates to pharmaceutical compositions, in particular veterinary compositions, which contain at least one compound according to the invention, usually together with one or more pharmaceutically acceptable excipients, and their use for the above-mentioned purposes.

Compounds according to the present invention may have systemic and/or local activity. To this end, they can be administered in a suitable manner, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, auricular route, or as an implant or stent. Such administration may be carried out prophylactically, metaphylactically or therapeutically.

For these routes of administration, the compounds of the present invention may be administered in suitable administration forms.

For oral administration, the compounds of the present invention can be prepared in dosage forms known in the art that deliver the compounds of the present invention rapidly and/or in a modified manner, such as, for example, tablets (tablets (uncoated tablets or coated tablets, for example with enteric coatings or controlled release coatings that are delayed or insoluble), orally disintegrating tablets, films/plates, films/lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, chewing gums (eg soft chewing gums), powders, emulsions, suspensions, aerosols or solutions. You can include the compounds according to the present invention in crystalline and/or amorphous and/or dissolved form in these dosage forms.

Parenteral administration may be by preventing the absorption step (eg, intravenously, intraarterially, intracardiac, intraspinally, or endolumbally) or by including absorption (eg, intramuscularly, subcutaneously, intradermally, transdermally, or intraperitoneally). Administration forms suitable for parenteral administration include, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples suitable for other routes of administration are pharmaceutical forms for inhalation (including powder inhalers, nebulizers), nasal drops, nasal solutions, nasal sprays; tablets/films/lozenges/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, lenses, ear drops, ear sprays, ear powders, ear rubs, ear swabs; vaginal capsules, aqueous suspensions (lotions, shaking potions), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milks, pastes, foams, topical preparations, powders, implants or stents.

Compounds according to the present invention can be included in these forms of administration. This can be done in a known manner by mixing with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, among others,

наполнители и носители (например, целлюлоза, микрокристаллическая целлюлоза (например, Avicel®), лактоза, маннит, крахмал, фосфат кальция (такой как, например, Di-Cafos^®)),

fillers and carriers (eg cellulose, microcrystalline cellulose (eg Avicel®), lactose, mannitol, starch, calcium phosphate (such as eg Di-Cafos ^® )),

основания мази (например, вазелин, парафины, триглицериды, воски, шерстный воск, спирты шерстного воска, ланолин, гидрофильная мазь, полиэтиленгликоли),

ointment bases (eg petrolatum, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),

основания для суппозиторий (например, полиэтиленгликоль, кокосовое масло, твердый жир),

suppository bases (eg polyethylene glycol, coconut oil, tallow),

растворители (например, вода, этанол, изопропанол, глицерин, пропиленгликоль, жирные масла триглицеридов средней длины цепи, жидкие полиэтиленгликоли, парафины),

solvents (e.g. water, ethanol, isopropanol, glycerin, propylene glycol, medium chain triglyceride fatty oils, liquid polyethylene glycols, paraffins),

поверхностно-активные вещества, эмульгаторы, диспергирующие средства или смачивающие средства (например, натрия додецилсульфат), лецитин, фосфолипиды, жирные спирты (такие как, например, Lanette^®), сложные эфиры сорбитана и жирной кислоты (такие как, например, Span^®), полиоксиэтиленовые сложные эфиры сорбитана и жирной кислоты (такие как, например, Tween^®), полиоксиэтиленовые глицериды жирной кислоты (такие как, например, Cremophor^®), полиоксиэтиленовые сложные эфиры жирной кислоты, полиоксиэтиленовые сложные эфиры жирного спирта, глицериновые сложные эфиры жирной кислоты, полоксамеры (такие как, например, Pluronic^®),

surfactants, emulsifiers, dispersants or wetting agents (eg sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, ^Lanette® ), sorbitan fatty acid esters (such as, for example, ^Span® ) , polyoxyethylene fatty acid esters of sorbitan (such as, for example, ^Tween® ), polyoxyethylene fatty acid glycerides (such as, for example, ^Cremophor® ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol esters, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic ^® ),

буферы, кислоты и основания (например, фосфаты, карбонаты, лимонная кислота, уксусная кислота, соляная кислота, раствор гидроксида натрия, аммония карбонат, трометамол, триэтаноламин),

buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

изотонические средства (например, глюкоза, хлорид натрия),

isotonic agents (eg glucose, sodium chloride),

адсорбенты (например, высоко диспергированные диоксиды кремния),

adsorbents (e.g. highly dispersed silicas),

повышающие вязкость средства, гелеобразоатели, загустители и/или связующие вещества (например, поливинилпирролидон, метилцеллюлоза, гидроксипропилметилцеллюлоза, гидроксипропилцеллюлоза, карбоксиметилцеллюлоза-натрий, крахмал, карбомеры, полиакриловые кислоты (такие как, например, Carbopol^®); альгинаты, желатин),

viscosity-increasing agents, gelling agents, thickeners and/or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (such as e.g. Carbopol ^® ); alginates, gelatin),

дезинтегрирующие средства (например, модифицированный крахмал, карбоксиметилцеллюлоза-натрий, натрия крахмала гликолят (как например, Explotab^®), поперечно-сшитый поливинилпирролидон, кроскармеллоза-натрий (как например, AcDiSol^®)),

disintegrants (eg modified starch, sodium carboxymethylcellulose, sodium starch glycolate (eg ^Explotab® ), cross-linked polyvinylpyrrolidone, croscarmellose sodium (eg ^AcDiSol® )),

регуляторы скорости потока, смазывающие вещества, вещества, способствующие скольжению и смазки, облегчающие выемке изделий из форм (например, стеарат магния, стеариновая кислота, тальк, высоко диспергированные диоксиды кремния (как например, Aerosil^®)),

flow regulators, lubricants, glidants and demolding agents (eg magnesium stearate, stearic acid, talc, highly dispersed silicas (eg Aerosil ^® )),

покрывающие вещества (например, сахара, шеллак) и пленкообразователи для пленок или диффузионные мембраны, которые растворяются быстро или модифицированным образом (например поливинипирролидоны (такие как, например,

coating agents (e.g. sugars, shellac) and film formers or diffusion membranes which dissolve rapidly or in a modified manner (e.g. polyvinipyrrolidones (such as e.g.

Kollidon ^® ), polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ^® )),

материалы капсулы (например, желатин, гидроксипропилметилцеллюлоза),

capsule materials (e.g. gelatin, hydroxypropyl methylcellulose),

синтетические полимеры (например, полилактиды, полигликолиды, полиакрилаты, полиметакрилаты (такие как, например, Eudragit^®), поливинипирролидоны (такие как, например, Kollidon^®), поливиниловые спирты, поливинилацетаты, полиэтиленоксиды, полиэтиленгликоли и их сополимеры и блок-сополимеры),

synthetic polymers (eg polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, ^Eudragit® ), polyvinipyrrolidones (such as, for example, ^Kollidon® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers),

пластификаторы (например полиэтиленгликоли, пропиленгликоль, глицерин, триацетин, триацетилцитрат, дибутилфталат),

plasticizers (e.g. polyethylene glycols, propylene glycol, glycerin, triacetin, triacetyl citrate, dibutyl phthalate),

усилители проникновения,

penetration enhancers,

стабилизаторы (например, антиоксиданты, такие как, например, аскорбиновая кислота, аскорбилпальмитат, натрия аскорбат, бутилгидроксианизол, бутилгидрокситолуол, пропилгаллат),

stabilizers (for example, antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propylgallate),

консерванты (например, парабены, сорбиновая кислота, тиомерзал, бензалкония хлорид, хлоргексидина ацетат, натрия бензоат),

preservatives (eg parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

красители (например, неорганические пигменты, такие как, например, оксиды железа, диоксид титана),

dyes (for example, inorganic pigments, such as, for example, iron oxides, titanium dioxide),

ароматизаторы, подсластители, ароматизаторы и/или средства против запаха.

flavors, sweeteners, flavors and/or anti-odor agents.

In addition, the present invention relates to a pharmaceutical composition that contains at least one compound according to the present invention, usually together with one or more pharmaceutically acceptable excipients and their use according to the present invention.

According to another object, the present invention covers pharmaceutical combinations, in particular drugs containing at least one compound of general formula (I) according to the present invention and at least one or more additional active ingredients, in particular for the treatment and/or prevention of endo - and/or ectoparasitic infection.

The term "endoparasite" in the present invention is used as known to experts in this field, and refers in particular to helminths. The term "ectoparasite" in the present invention is used as known to those skilled in the art, and refers in particular to arthropods, in particular insects or acarids.

In particular, the present invention covers a pharmaceutical combination, in particular a veterinary combination, which contains:

one or more first active ingredients, in particular compounds of general formula (I) as above, and

one or more additional active ingredients, in particular one or more endo- and/or ectoparasiticides.

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

"Fixed combination" in the present invention is used as known to those skilled in the art and is defined as a combination in which, for example, a first active ingredient, such as one or more compounds of general formula (I) according to the present invention, and an additional active ingredient are present. together in one single dosage or in one dosage form. One example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the additional active ingredient are present in a mixture for simultaneous administration, for example in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the other active ingredient are present in the same unit without mixing.

The loose combination or "set of parts" in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the additional active ingredient are present in more than one unit. One example of a non-fixed combination or set of parts is a combination in which the first active ingredient and the additional active ingredient are present separately. The components of a non-fixed combination or set of parts can be administered separately, sequentially, simultaneously, at the same time, or in chronological order

Compounds according to the present view can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients, where the combination does not cause unacceptable side effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention may be combined with known ectoparasiticides and/or endoparasiticides.

Other or additional active ingredients referred to in this application under their "common name" are known and described, for example, in the pesticide manual ("The Pesticide Manual" 16th Ed., British Crop Protection Council 2012) or can be found on the Internet (for example , http://www.alanwood.net/pesticides). The classification is based on the principle of the IRAC system in force at the time the patent application was filed.

Examples of ectoparasiticides and/or endoparasiticides are insecticides, acaricides and nematicides and include, in particular:

(1) Acetylcholinesterase (AChE) inhibitors, such as carbamates, such as alanicarb, aldicarb, Bendiocarb, Benfuracarb, Butocarboxym, Butoxycarboxym, Carbaryl, Carbofuran, Carbosulfan, Ethiophencarb, Phenobucarb, Formethanate, Furatiocarb, Isoprocarb, Methiocarb, Methomyl, Metholcarb, Oxamyl, pyrimicarb, propoxur, thiodicarb, thiophanox, triazamate, trimetacarb, CMS, and Xylylcarb; or organophosphorus compounds, e.g. acephate, azamethifos, azinphos-ethyl, azinphos-methyl, Caduzaphos, chlorethoxyphos, chlorfenvinphos, chlormephos, chlorpyrifos, chlorpyrifos-methyl, Coumaphos, cyanophos, demeton-v-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfotone, EPN, Ethion, Etoprofos, Famfur, Fenamiphos, Fenitrothion, Fenthion, Fostiazate, Heptenophos, Imiciaphos, Isofenphos, Isopropyl-O-(methoxyaminothio-phosphoryl) salicylate, Isoxathion, Malathion, Mecarbam, Metamidophos, Metidathione, Mevinphos , Monocrotophosphos, Naled, Ometoate, Oxydometon-methyl, Parathion, Parathion-methyl, Fentoate, Forate, Phosalon, Phosmet, Phosfamidone, Phoxim, Pirimiphos-methyl, Profenophos, Propetamphos, Prothiophos, Pyraclophos, Pyridafenthion, Quinalphos, Sulfotep, Tebupyrimphos, Temephos , Terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon, and vamidothion.

(2) GABA-dependent chloride channel antagonists, eg cyclodiene organochlorines, eg chlordane and Endosulfan; or phenylpyrazoles (fiprols) such as Etiprol and Fipronil.

(3) Sodium channel modulators/Voltage-gated sodium channel blockers, e.g. pyrethroids e.g. , cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyfenotrin [(1R)-trans-isomers], deltamethrin, empentrin [(EZ)-(1R) isomers), Esfenvalerate, Ethofenprox, Fenpropatrin, Fenvalerate, Flucitrinate, Flumethrin, Tau-Fluvalinate, Halfenprox, Imiprothrin, Cadetrin, Permethrin, Phenothrin [(1R)-trans-isomer), Pralletrin, pyrethrin ( feverfew), Resmethrin, Silafluofen, Tefluthrin, tetramethrin, tetramethrin [(1R) isomers)], tralometrin, and transfluthrin; or DCT; or methoxychlor.

(4) Nicotinic acetylcholine receptor (nAChR) agonists, eg neonicotinoids, eg acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam; or nicotine; or Sulfoxachlor or flupyradifuron.

(5) Allosteric modulators of the nicotinic acetylcholine receptor (nAChR), such as spinosyns, eg Spinetoram and Spinosad.

(6) Glutamate dependent chloride channel (GluCl) allosteric modulators, eg avermectins/milbemycins, eg abamectin, Emamectin benzoate, Lepimectin and Milbemectin.

(7) Juvenile hormone mimetics, eg juvenile hormone analogs, eg hydroprene, kinoprene and methoprene; or fenoxycarb; or pyriproxyfen.

(9) Insect hearing modulators, eg pymetrosine; or flonicamid.

(10) Mite growth inhibitors, such as Clofentezin, Hexythiazox, and Difluvidazine; or etoxazole.

(12) inhibitors of mitochondrial ATP synthesis, such as ATP disintegrators, such as, for example; diafenthiuron or organotin miticides such as azocyclotin, cyhexatin, and fenbutatin oxide; or Propargit; or tetradiphone.

(13) Agents that uncouple oxidative phosphorylation by disrupting the proton gradient, such as chlorfenapyr, DNOC, and Sulfluramide.

(14) Nicotinergic acetylcholine receptor blockers such as, for example, Bensultap, Cartap hydrochloride, thiocyclam and Thiosultap sodium.

(15) Type 0 chitin biosynthesis inhibitors such as Bistrifluron, Chlofluazuron, Diflubenzuron, Flucycloxuron, Flufenoxuron, Hexaflumuron, Lufenuron, Novaluron, Noviflumuron, Teflubenzuron and Triflumuron.

(16) Inhibitors of chitin biosynthesis, type 1, eg Buprofezin.

(17) Moulting inhibitors (particularly for Diptera, ie flies), such as, for example, cyromazine.

(18) Ecdysone receptor agonists, eg Chromafenoside, Halofenoside, Methoxyfenoside and Tebufenoside.

(19) Octopaminergic agonists such as, for example, amitraz.

(20) Mitochondrial complex III electron transport inhibitors, eg Hydramethylnon; or Acechinocil; or fluacripyrim.

(21) Mitochondrial complex I electron transport inhibitors, eg from the METI group of acaricides, eg Phenazakhine, Fenpyroximate, pyrimidifen, pyridaben, Tebufenpyrad and Tolfenpyrad; or Rotenon (Derris).

(22) Voltage-gated sodium channel blockers, eg Indoxacarb; or Metaflumizone.

(23) Acetyl-CoA carboxylase inhibitors, for example, tetronic and tetramic acid derivatives, for example, Spirodiclofen, Spiromesifen and Spirotetramat.

(25) Mitochondrial complex II electron transport inhibitors, eg beta-ketonitrile derivative, eg cyenopyraphene and cyflumethofen, and carboxanilide, eg Piflubumide.

(28) Ryanodine receptor modulators such as, for example, diamides, such as chlorantraniliprole, cyantranilipol and flubendiamide,

Other active ingredients with an unknown or unproven mechanism of action, such as, for example, afidopyropene, afoxolaner, azadirachtin, benclothiaz, benzoximate, biphenazate, bromoflanilide, bromopropylate, quinomethionate, cryolite, cyclaniliprol, cycloxapride, cyhalodiamide, dicloromesothiaz, dicofol, diflovidazine, flumethoquinidazole , флуенсульфон, флуфенерим, флуфеноксистробин, флуфипрол, флугексафон, флуопирам, флураланер, флуксаметамид, фуфенозид, гуадипир, гептафлутрин, имидаклотиз, ипродион, лотиланер, меперфлутрин, паичонгдинг, пифлубумид, пиридалил, пирифлуквиназон, пириминостробин, сароланер, тетраметилфлутрин, тетранилипрол, тетрахлорантранилипрол, тиоксазафен , triflumesopyrim and iodomethane; in addition, preparations based on Bacillus firmus (I-1582, BioNeem, Votivo), as well as the following active compounds: 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfinyl]phenyl }-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (known from WO 2006/043635) (CAS 885026-50-6), {1'-[(2E)-3-( 4-chlorophenyl)prop-2-en-1-yl]-5-fluorospiro[indol-3,4'-piperidin]-1(2H)-yl}(2-chloropyridin-4-yl)methanone (known from WO 2003 /106457) (CAS 637360-23-7), 2-chloro-N-[2-{1-[(2E)-3-(4-chlorophenyl)prop-2-en-1-yl]piperidin-4- yl}-4-(trifluoromethyl)phenyl]isonicotinamide (known from WO 2006/003494) (CAS 872999-66-1), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy- 1,8-diazaspiro[4.5]dec-3-en-2-one (known from WO 2010052161) (CAS 1225292-17-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy- 2-oxo-1,8-diazaspiro[4.5]dec-3-en-4-yl-ethyl carbonate (known from EP 2647626) (CAS-1440516-42-6), 4-(but-2-yn-1- yloxy)-6-(3,5-dimethylpiperidin-1-yl)-5-fluoropyrimidine (known from WO 2004/099160) (CAS 792914-58-0), PF1364 (known from JP 2010/018586) (CAS-Reg .No. 1204776-60-2), N-[(2E)-1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (known from WO 2012 /029672) (CAS 1363400-41-2), (3E)-3-[1-[(6-chloro-3-pyridyl)methyl]-2-pyridylidene]-1,1,1-trifluoropropan-2-one (known from WO 2013/144213) (CAS 1461743-15-6), N-[3-(benzylcarbamoyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole -5-carboxamide (known from WO 2010/051926) (CAS 1226889-14-0), 5-bromo-4-chloro-N-[4-chloro-2-methyl-6-(methylcarbamoyl)phenyl]-2- (3-chloro-2-pyridyl)pyrazole-3-carboxamide (known from CN 103232431) (CAS 1449220-44-3), 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)benzamide, 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-( trifluoromethyl)-3-isoxazolyl]-2-methyl-Н-(trans-1-oxido-3-thietanyl)benzamide and 4-[(5S)-5-(3,5-dichlorophenyl)-4,5-dihydro- 5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(cis-1-oxido-3-thietanyl)benzamide (known from WO 2013/050317 A1) (CAS 1332628-83-7), N-[ 3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-H-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]propanamide, (+)-N-[3 -chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]propanamide and (-)-N-[3-chloro -1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)sulfinyl]propanamide (known from WO 2013/162715 A2, WO 2013/162716 A2, US 2014/0213448 A1) (CAS 1477923-37-7), 5-[[(2E)-3-chloro-2-propen-1-yl]amino]-1-[2,6-dichloro-4 -(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile (known from CN 101337937 A) (CAS 1105672-77-2), 3-bromo-N-[4-chloro- 2-methyl-6-[(methylamino)thiochomethyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, (Liudaibenjiaxuanan, known from CN 103109816 A) (CAS 1232543-85- 9); N-[4-chloro-2-[[(1,1-dimethylethyl)amino]carbonyl]-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-3-(fluoromethoxy)-1H-pyrazole- 5-carboxamide (known from WO 2012/034403 A1) (CAS 1268277-22-0), N-[2-(5-amino-1,3,4-thiadiazol-2-yl)-4-chloro-6- methylphenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known from WO 2011/085575 A1) (CAS 1233882-22-8), 4-[3-[ 2,6-dichloro-4-[(3,3-dichloro-2-propen-1-yl)oxy]phenoxy]propoxy]-2-methoxy-6-(trifluoromethyl)pyrimidine (known from CN 101337940 A) (CAS 1108184-52-6); (2E)- and 2(Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(difluoromethoxy)phenyl]hydrazinecarboxamide (known from CN 101715774 A) (CAS 1232543-85-9); cyclopropanecarboxylic acid-3-(2,2-dichloroethenyl)-2,2-dimethyl-4-(1H-benzimidazol-2-yl)phenyl ester (known from CN 103524422 A) (CAS 1542271-46-4); (4a8)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-[(trifluoromethyl)thio]phenyl]amino]carbonyl]indeno[1,2-e][1,3,4 ]oxadiazine-4a(3H)-carboxylic acid methyl ester (known from CN 102391261 A) (CAS 1370358-69-2); 6-deoxy-3-O-ethyl-2,4-di-O-methyl-1-[N-[4-[1-[4-(1,1,2,2,2-pentafluoroethoxy)phenyl]- 1H-1,2,4-triazol-3-yl]phenyl]carbamate]-α-L-mannopyranose (known from US 2014/0275503 A1) (CAS 1181213-14-8); 8-(2-cyclopropylmethoxy-4-trifluoromethylphenoxy)-3-(6-trifluoromethylpyridazin-3-yl)-3-azabicyclo[3.2.1]octane (CAS 1253850-56-4), (8-anti)-8- (2-cyclopropylmethoxy-4-trifluoromethylphenoxy)-3-(6-trifluoromethylpyridazin-3-yl)-3-azabicyclo[3.2.1]octane (CAS 933798-27-7), (8-syn)-8-(2 and N -[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-H-ethyl-3-[(3,3,3-trifluoropropyl)thio]-propanamide (known from WO 2015/058021 A1, WO 2015/058028 A1) (CAS 1477919-27-9) and N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3 ,3,3-trifluoropropyl)thio]-propanamide (known from WO 2015/058021 A1, WO 2015/058028 A1) (CAS 1477919-27-9) and N-[3-chloro-1-(3-pyridinyl)- 1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)hyo]-propanamide (known from WO 2015/058021 A1, WO 2015/058028 A1) (CAS 1477919-27- 9) and N-[4-(aminothioxomethyl)-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known from CN 103265527 A) (CAS 1452877-50-7), 5-(1,3-dioxan-2-yl)-4-[[4-(trifluoromethyl)phenyl]methoxy]pyrimidine (known from WO 2013 /115391 A1)(CAS 1449021-97-9), 3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diazaspiro[4.5]dec-3 -en-2-one (known from WO 2010/066780 A1, WO 2011/151146 A1) (CAS 1229023-34-0), 3-(4-chloro-2,6-dimethylphenyl)-8-methoxy-1- methyl-1,8-diazaspiro[4.5](decane-2,4-dione (known from WO 2014/187846 A1) (CAS 1638765-58-8), 3-(4-chloro-2,6-dimethylphenyl)- 8-methoxy-1-methyl-2-oxo-1,8-diazaspiro[4.5]dec-3-en-4-yl-carboxylic acid ethyl ester (known from WO 2010/066780 A1, WO 2011151146 A1) (CAS 1229023-00-0), N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylidene]-2,2,2-trifluoroacetamide (known from DE 3639877 A1, WO 2012029672 A1) (CAS 1363400-41-2), [N(E]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylidene]-2,2,2- trifluoroacetamide, (known from WO 2016005276 A1) (CAS 1689566-03-7), [N(Z)]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)- pyridinylidene]-2,2,2-trifluoroacetamide, (CAS 1702305-40-5), 3-endo-3-[2-propoxy-4-(trifluoromethyl)phenoxy]-9-[[5-(trifluoromethyl) -2-pyridinyl]oxy]-9-azabicyclo[3.3.1]nonane (known from WO 2011/105506 A1, WO 2016/133011 A1) (CAS 1332838-17-1).

Active ingredients with unknown or non-specific mechanisms of action, eg fentrifanil, phenoxacrim, cycloprene, chlorbenzilate, chlordimeform, flubenzimine, dicyclanil, amidoflumet, quinomethionate, triarathene, clothiazoben, tetrazul, potassium oleate, kerosene, methoxadiazon, gossyplure, flutensin, bromopropylate, cryolite;

Active ingredients from other classes, e.g. butacarb, dimethylan, cloetocarb, phosphocarb, pyrimiphos(-ethyl), parathion(-ethyl), methacryphos, isopropyl-o-salicylate, trichlorfon, sulprofos, propafos, sebuphos, pyridathione, protoate, dichlofenthion, demeton-8-methylsulfone, isazophos, cyanofenphos, dialifos, carbophenotion, autathiophos, aromfenvinphos(-methyl), azinphos(-ethyl), chlorpyrifos(-ethyl), phosmethylan, iodophenphos, dioxabenzophos, formotion, phonophos, flupyrazophos, fensulfothion, etrymphos;

Organochlorines, eg camphechlor, lindane, heptachlor; or Phenylpyrazoles, eg acetoprol, pyrafluprol, pyriprole, vaniliprole, sisapronil; or isoxazoline, eg sarolaner, afoxolaner, lotilaner, fluralaner;

Pyrethroids, e.g. (cis-, trans-)methofluthrin, profluthrin, flufenprox, flubrocitrinate, flubfenprox, fenfluthrin, protrifenbut, pyrezmethrin, RU15525, teralletrin, cis-resmethrin, heptafluthrin, bioethanometrin, biopermethrin, fenpyrythrin, cis-cyper methin, cis -permethrin, clocitrin, cyhalothrin (lambda), chlovaportrin, or halogenated hydrocarbon compounds (HCH);

neonicotinoids, such as nithiazine; dichlormesothiasis, triflumesopyrim;

macrocyclic lactones, eg nemadectin, ivermectin, latidectin, moxidectin, selamectin, eprinomectin, doramectin, emamectin benzoate; milbemycinoxime;

Tryfen, Epofenonan, diofenolan;

Biological substances, hormones, pheromones, eg natural products, eg thuringiensin, codlemon or neem components of Codlemon or Neem;

dinitrophenols, eg dinocap, dinobuton, binapacryl;

benzoylureas, e.g. fluazuron, penfluron,

Amidine derivatives, eg Chlormebuform, simiazole, demiditraz;

Acaricides to protect bees from Varroa mites, eg organic acids, eg formic acid, oxalic acid.

Non-limiting examples of insecticides and acaricides of particular interest for use in animal health are and include in particular [i.e. Mehlhorn et al Encyclpaedic Reference of Parasitology ^4th edition (ISBN 978-3-662-43978-4)]:

Effectors on arthropod ligand-gated chloride channels: chlordane, heptachlor, endocoulfan. Dieldrin, bromocyclene, toxaphene, lindane, fipronil, pyriprol, sisapronil, afoxolaner, fluralaner, sarolaner, lotilaner, fluxamethamide, bromflanilide, avermectin, doramectin, eprinomectin, ivermectin, milbemycin, moxidectin, selamectin;

Arthropod octopamine receptor modulators: amitraz, BTS27271, cimiazole, demiditraz;

Voltage dependent arthropod sodium channel effectors: DDT, methoxychlor, metaflumizone, indoxacarb, cynerin I, cynerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, allethrin, alphacypermethrin, bioallethrin, betacisfluthrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin , etofenprox, fenvalerate, flucitrinate, flumethrin, halfenprox, permethrin, phenothrin, resmethrin, tau-fluvalinate, tetramethrin;

Effectors of arthropod nicotinic cholinergic synapses (acetylcholine esterase, acetylcholine receptors): brompripilate, bendiocarb, carbaryl, methomyl, promacyl, propoxur, azamethifos, chlorfenvinphos, chlorpyrifos, coumaphos, cythioate, diazinon, dichlorvos, dicrotophos, fenthenion, fenthoate, ethno , heptenophos, malathion, naled, phosmet, phoxim, phthalophos, propetamphos, temephos, tetrachlorvinphos, trichlorfon, imidacloprid, nitenpyram, dinotefuran, spinosad, spinetoram;

Effectors of arthropod development processes: cyromazine, dicyclanil, diflubenzuron, fluazuron, lufenuron, triflumuron, fenoxycarb, hydroprene, methoprene, pyriproxyfen, fenoxycarb, hydroprene, S-methoprene, pyriproxyfen.

Exemplary active ingredients from the group of endoparasiticides as an additional or other active ingredient according to the present invention include, without limitation, anthelmintic active compounds and antiprotozoal active compounds.

Anthelmintic agents include, for example, the following active substances against nematodes, flukes and/or cestodes:

from the class of macrocyclic lactones, for example: eprinomectin, abamectin, nemadectin, moxidectin, doramectin, selamectin, lepimectin, latidectin, milbemectin, emamectin, milbemycin;

from the class of benzimidazoles and probenzimidazoles, for example: oxibendazole, mebendazole, triclabendazole, thiophanate, parbendazole, oxfendazole, netobimine, fenbendazole, febantel, thiabendazole, cyclobendazole, cambendazole, albendazole sulfoxide, albendazole, flubendazole;

from the class of depsipetides, preferably cyclic depsipetides, especially 24-membered cyclic depsipetides, for example: emodepside, PF1022A;

from the class of tetrahydropyrimidines, for example: morantel, pyrantel, oxanthel;

from the class of imidazothiazoles, for example: butamisole, levamisole, tetramizole;

from the class of aminophenylamidines, for example: amidantel, diacylated amidantel (dAMD), tribendimidine;

from the class of aminoacetonitriles, for example: monepantel;

from the class of paraherquiamides, for example: paraherquiamide, derquiantel;

from the class of salicylanilides, for example: tribromsalan, bromxanide, brotianide, clioxanide, closantel, niclosamide, oxyclozanide, rafoxanide;

from the class of substituted phenols, for example: nitroxinil, bitionol, dicophenol, hexachlorphen, niclofolan, meniclofolan;

from the class of organophosphates, for example: trichlorfon, naftalofos, dichlorvos/DDVP, krufomat, koumaphos, haloxon;

from the class of piperazines/quinolines, for example: praziquantel, epsiprantel; from the class of piperazines, for example: piperazine, hydroxyzine;

from the class of tetracyclines, for example: tetracycline, chlortetracycline, doxycycline, oxytetracycline, rolitetracycline;

from various other classes, for example: Bunamidine, Niridazole, Resorantel, Omphalothin, Oltipraz, Nitroscanate, Nitroxinil, Oxamniquin, Mirazan, Miracil, Lucanthone, Gikanthone, Getolin, Emetine, Diethylcarbamazine, Dichlorphen, Diamphenetide, Clonazepam, Befenium, Amoscanate, Clorsulon;

The antiprotozoan active ingredients of the present invention include, but are not limited to, the following active ingredients:

from the class of triazines, for example: diclazuril, ponazuril, letrazuril, toltrazuril;

from the class of polyester ionophores, for example: monensin, salinomycin, maduramycin, narasin;

from the class of macrocyclic lactones, for example: milbemycin, erythromycin;

from the class of quinolones, for example: enrofloxacin, pradofloxacin;

from the class of quinolones, for example: enrofloxacin, pradofloxacin;

from the class of quinines, for example: chloroquine;

from the class of pyrimidines, for example: pyrimethamine;

from the class of sulfonamides, for example: sulfakhinoksalin, trimethoprim, sulfaklozin;

from the class of thiamines, for example: amprolium;

from the class of lincosamides, for example: clindamycin;

from the class of carbanilides, for example: imidocarb;

from the class of nitrofurans, for example: nifurtimox;

from the class of quinazolinone alkaloids, for example: halofuginone;

from other classes, for example: oxamniquin, paromomycin,

from the vaccine class or antigens of microorganisms, for example: Babesia canis rossi, Eimeria tenella, Eimeria praecox, Eimeria necatrix, Eimeria mitis, Eimeria maxima, Eimeria brunetti, Eimeria acervulina, Babesia canis vogeli, Leishmania infantum, Babesia canis, Dictyocaulus viviparus.

All of the aforementioned mixing partners may, if they are capable on the basis of their functional groups, optionally form salts with suitable bases or acids.

Based on standard laboratory methods known to evaluate compounds useful in the treatment of helminthiasis, standard toxicity tests and standard pharmacological assays to determine treatment for the conditions mentioned above in animals, and by comparing these results with those for known active ingredients or medicaments that are used to treatment of these conditions, an effective dose of the compounds according to the present description can be easily determined for the treatment of each desired indication. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely according to conditions such as the particular compound and dosage unit employed, the route of administration, the period of treatment, the age and sex of the subject to be treated, and the nature and extent of the subject to be treated. states.

The total amount of active ingredient administered will typically be from about 0.001 mg/kg to about 200 mg/kg of body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg of body weight per day. Clinically useful dosing regimens will range from once to three times a day to dosing once every four weeks. In addition, "drug rest" is possible, in which the subject does not receive a dose of drug for a certain period of time, which is beneficial for the overall balance between pharmacological effect and tolerability. In addition, it is possible to carry out long-term treatment, when the subject receives treatment once for more than four weeks. A dosage unit may contain from about 0.5 mg to about 1500 mg of the active ingredient and may be administered one or more times per day, or less than once per day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion methods will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosing regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosing regimen will preferably be from 0.1 to 200 mg administered 1 to 4 times a day. The transdermal concentration will preferably be such as is necessary to maintain a daily dose of 0.01 to 200 mg/kg. The average daily dosage regimen by inhalation will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course, the specific initial and ongoing dosing regimen for each subject will vary depending on the nature and severity of the condition as determined by the treating diagnostician, the activity of the particular compound used, the age and general condition of the subject, the time of administration, the route of administration, the rate of drug excretion, the combination of drugs and the like. The desired method of treatment and the number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional treatment tests.

experimental part

Abbreviations and abbreviations

water. - water

atm - standard atmosphere

DAD - diode array detector

DMF - dimethylformamide

DMSO - dimethyl sulfoxide

ELSD - Evaporative Light Scattering Detector

ESI - electrospray ionization

h - hour (hours)

LC-MS - Liquid Chromatography with Mass Spectrometry

min - minute (minutes)

MTBE - methyl tert-butyl ether

NMR - nuclear magnetic resonance spectrometry

R. - page(s)

R _t - retention time

THF - tetrahydrofuran

TLC - thin layer chromatography

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the present invention in any way.

The example testing experiments described in this application serve to illustrate the present invention, and the present invention is not limited to the examples given.

Experimental part - general part

All reagents for which the synthesis is not described in the experimental part are either commercially available or known compounds, or can be obtained from known compounds by known methods by a person skilled in the art.

Compounds and intermediates prepared according to the methods of the present invention may require purification. Purification of organic compounds is well known to the person skilled in the art, and there may be several ways to purify the same compound. In some cases, cleaning is not required. In some cases, compounds can be purified by crystallization. In some cases, impurities can be eliminated using a suitable solvent. In some cases, compounds can be purified by chromatography, in particular flash column chromatography, using, for example, pre-filled silica gel cartridges, such as Biotage SNAP KP- ^Sil® or KP- ^NH® cartridges, in combination with the Biotage autopurifier system ( ^SP4® or Isolera ^Four® ) and eluents such as hexane/ethyl acetate or dichloromethane/methanol gradients. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or a real-time sputter ionization mass spectrometer, in combination with a suitable prepacked reverse phase column and eluents such as a water gradient and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia.

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

Analytical and chromatographic methods

Analytical and preparative liquid chromatography

Analytical (UP) LC-MS was performed using various equipment as described below. Masses (m/z) are based on electrospray ionization from electrospray ionization of positively charged ions unless negative mode (ESI-) is specified.

LC-MS way 0:

LogP values were measured according to EEC Directive 79/831 Appendix V.A8 by HPLC (High Performance Liquid Chromatography) on reverse phase columns in the following ways:

Device(s): Agilent 1100 LC system, Agilent MSD system, HTS PAL; Waters IClass Acquity UPLC, SQD2 (MS), PDA (UV).

[a] logP value is determined by measuring LC-UV, in the acid range, with 0.1% formic acid in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile).

[b] logP value is determined by measuring LC-UV, in the neutral range, with 0.001 molar ammonium acetate in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile).

Calibration was performed using straight chain alkan-2-ones (from 3 to 16 carbon atoms) with known logP values (measurement of logP values using retention times with linear interpolation between successive alkanones). Maximum lambda values were determined using UV spectra from 200 nm to 400 nm and peak chromatographic signals.

M+1 (or M+H) means a molecular ion peak plus or minus 1 amu. (atomic mass unit), respectively, as observed in mass spectroscopy with electrospray ionization (ESI+ or -).

LC-MS method 1:

MS device type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC device type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 30x2.1mm, 3.5mkm); flow: 1 ml/min; column temperature: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; linear gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow 1.2 ml/min, gas temperature: 70°C, probe: 50°C.

LC-MS method 2:

Device type: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T3 1.8 µm 50 × 1 mm; eluent A: 1 l water + 0.25 ml formic acid, eluent B: 1 l acetonitrile + 0.25 ml formic acid; gradient: 0.0 min 90% A 1.2 min 5% A 2.0 min 5% A oven: 50°C; flow: 0.40 ml/min; UV detection: 210 nm.

LC-MS method 3:

MS device type: Agilent Technologies LC/MSD SL; HPLC device type: Agilent Technologies 1100 Series; column: Waters XSelect (C18, 30×2.1 mm, 3.5 µm); flow: 1 ml/min; column temperature: 25°C, eluent A: 95% acetonitrile + 5% 10 mM ammonium bicarbonate in water, eluent B: 10 mM ammonium bicarbonate in water pH=9.0; linear gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800.

LC-MS method 4:

Device type: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 µm 50 × 1 mm; eluent A: 1 l water + 0.25 ml 99% formic acid, eluent B: 1 l acetonitrile + 0.25 ml 99% formic acid; gradient: 0.0 min 95% A→6.0 min 5% A→7.5 min 5% A oven: 50°C; flow: 0.35 ml/min; UV detection: 210 nm.

LC-MS method 5:

Device type: UPLC with SQD2 and Waters Sample Manager, column: Zorbax Eclipse Plus C18, 50 mm × 2.1 mm, 1.8 µm, eluent A: 1 L acetonitrile + 1 ml formic acid, eluent B: 1 L water + 0.9 ml formic acid; gradient 0.0 min 90% B→1.7 min 5% B→2.4 min 5% B

DAD A: 210 ± 4 nm, control 360 ± 50 nm, DAD A: 270 ± 2 nm, control 550 ± 50 nm (ketones only), MSD, 100-1000 Amu, ES ionization, positive or negative.

¹ H-NMR data

¹ H-NMR data were determined with a Bruker Avance 400 (equipped with a flow cell (volume 60 µl), or with a Bruker AVIII 400 equipped with a 1.7 mm cryo CPTCI probe, or with a Bruker AVIII 400 (400.13 MHz) equipped with a 5 mm probe , or with a Bruker AVIII 600 (600.13 MHz) equipped with a 5 mm cryo TCI probe, or with a Bruker AVIII 600 (601.6 MHz) equipped with a 5 mm cryo CPMNP probe, or with a Bruker AVIII 500 (500.13 MHz) equipped with a 5 broadband probe or 5 mm Prodigy™ probe, or Bruker Avance NEO 600 MHz (5 mm TCI cryoprobe), with tetramethylsilane as a control (0.0) and CD ₃ CN, CDCl ₃ or D ₆ -DMSO solvents Alternative ¹ H- and ¹³ C-NMR device types: Bruker DMX300 ¹ H-NMR: 300 MHz; ¹³ C NMR: 75 MHz), Bruker Avance III 400 ( ¹ H-NMR: 400 MHz; ¹³ C NMR: 100 MHz) or Bruker 400 Ultrashield ¹ H-NMR: 400 MHz; ¹³ NMR: 100 MHz).

Chemical shifts (δ) are shown in parts per million [ppm]; the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. =extended; coupling constants are given in Hertz [Hz].

Experimental part - general methods

The synthesis of compounds of formula (I) can be carried out similarly to the following schemes (scheme 1, scheme 2, scheme 3, scheme 4 and scheme 5).

Scheme 1:

2-Halogenated anilines 1A (Hal=iodine, bromine, chlorine) are commercially available and can be readily converted with (alkoxymethylene)malonates 1B dissolved in an appropriate alcoholic solvent, preferably under reflux conditions, to (anilinomethylene)malonates 1C as described in Monatshefte flier Chemie, 2015, 146(2), 291-302, or without any solvent as described in WO 2002004444. Ring closure is performed in high boiling solvents, preferably diphenyl ether or xylene, to give hydroxyquinolines ID, as described in WO 2013118071. Hydroxyquinolines 1D can be readily converted to the corresponding chlorine compounds 1E with a chlorination reagent, preferably by refluxing POCl ₃ as described in WO 2013118071.

Depending on the nature of the nucleophile R ² H 1F, chloroquinolines 1E react with 1F in the presence of a base, such as sodium ethoxide, sodium methoxide, potassium tert-butoxide, N,N-diisopropylethylamine triethylamine, diazabicycloundecane, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate or the like, to give ester intermediates 1G.

Depending on the organometallic reagent 2A and the halogen, haloquinolines 1E are reacted with zinc reagents, if necessary in the presence of a catalyst, e.g. cobalt salts, as described in Tetrahedron Letters 39 (1998), p.6163-6166, or Grignard reagents, or boronic acids, or their 2P esters (R=H; R=Me or R, R=pinacolate) in the presence of palladium catalysts as described in Angew. Chem., 2014, vol. 126, p. 12975-12978 or European Journal of Medicinal Chemistry; vol. 147; (2018); p. 238-252 to give 1G intermediates.

The 1G ester intermediates can be easily hydrolyzed to the corresponding 1S acids using, for example, aqueous sodium hydroxide or lithium hydroxide in suitable solvents such as alcohols or cyclic ethers. 1S acids can react with commercially available amines 1M via amide formation and dehydrating reagents such as N-(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) or 2,4,6-tripropyl-1,3,5, 2,4,6-trioxatrifosfinan 2,4,6-trioxide, to obtain amides I-a. Similar syntheses are described in the Journal of Medicinal Chemistry 2012, 55, p. 3563-3567 or Chem. commun. 1999, p. 1847 1848, for example.

Suzuki coupling reaction of carboxamide intermediates I-a with boronic acids or boronic acid esters 1H QB(OR) ₂ (R=H; R=Me or R,R=pinacolate) as described in Chem. soc. Rev. 2014, 43, p. 412-443 or in Tetrahedron 2002, 58 (48), p. 9633-9695 leads to the final products of formula (I).

Acids 1R can react with commercially available amines 1M via amide formation and dehydrating reagents such as N(3-dimethylaminoisopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) or 2,4,6-tripropyl-1,3,5,2 ,4,6-trioxatrifosfinan 2,4,6-trioxide, to give amides 1N. Similar syntheses are described in Journal of Medicinal Chemistry 2012, 55, p. 3 563-3567 or Chem. commun. 1999, p.1847 1848, for example. The halo re but intermediates 1N can be coupled with olefinic boronic esters 2P (R=Me or R,R=pinacolate) in the presence of palladium catalysts, such as disclosed in WO 200537826. Olefin residues can be hydrated under standard conditions, for example , hydrogen over palladium on activated carbon to give (I). If further reduction takes place in the quinoline core, such reduction products, e.g. dihydroquinoline intermediates, can be re-oxidized to quinoline with e.g. cerium(IV) salts in suitable solvents, e.g. a mixture of DMSO and water or acetonitrile and water to give ( I).

Suzuki coupling reaction of ester intermediates 1G with boronic acids or boronic acid esters 1H QB(OR) ₂ (R=H; R=Me or R,R=pinacolate) as described in Chem. soc. Rev. 2014, 43, p. 412-443, or in Tetrahedron 2002, 58 (48), p. 9633-9695 leads to ester intermediates 1T, which can then be hydrolyzed to the corresponding acids 1R using, for example, aqueous sodium hydroxide or lithium hydroxide, in suitable solvents such as alcohols or cyclic ethers.

Scheme 2:

Alternatively, Suzuki coupling reaction of intermediates II) with boronic acids or boronic acid esters 1H QB(OR) ₂ (R=H; R=Me or R,R=pinacolate) as described in Chem. So s. Rev. 2014, 43, p. 412443 or in Tetrahedron 2002, 58 (48), p. 9633-9695 to ester intermediates 1I. The false ester intermediates 1I can then be mildly saponified, for example using sodium hydroxide or lithium hydroxide, to give the corresponding car 6 o new acids 1J, which can be readily converted to the corresponding chlorocarboxylic acid chlorides 1K using a halogenating reagent , for example, POCl ₃ or POBr ₃ , preferably POCl ₃ , as described in WO 2013096151. The 1K intermediates are reacted under hydrolytic conditions to give quinolinecarboxylic acids 1L, which are reacted with commercially available amines 1M via amide formation and dehydrating reagents, eg N -(3-dimethyl amino isopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) or 2,4,b-tripropyl-1,3,5,2,4,6-trioxatrifosfinan 2,4,6-trioxide with obtaining amides 1N. Similar syntheses are described in the Journal of Medicinal Chemistry 2012, 55, p. 3563-3567 or Chem. commun. 1999, p. 1847-1848, for example. 1K intermediates can directly form 1N amides when 1K carboxylic acid chlorides are reacted with 1M amines under basic conditions, such as pyridine, triethylamine, or N,N-diisopropylethylamine, as described in Chemical Biology & Drug Design 2015, 85(5), p . 549-564.

Depending on the nature of the nucleophile R ² H 1F, chloroquinolines 1N react with 1F in the presence of a base, such as sodium ethoxide, sodium methoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, diazabicycloundecane, sodium hydride, lithium hydroxide, sodium hydroxide , potassium hydroxide, potassium carbonate, cesium carbonate, or the like, to obtain the target compounds of formula (I).

Scheme 3:

The 1Q ester intermediates can be readily hydrolyzed to the corresponding 1R acids using, for example, aqueous sodium hydroxide or lithium hydroxide in suitable solvents such as alcohols or cyclic ethers. Acids 1R can react with commercially available amines 1M via amide formation and dehydrating reagents, e.g. ,4,6-trioxatrifosfinan 2,4,6-trioxide, to give amides 1N. Similar syntheses are described in the Journal of Medicinal Chemistry 2012, 55, p. 3563-3567 or Chem. Cornmun. 1999, p. 1847-1848, for example. Halogen intermediates 1N can be coupled with olefinic boronic esters 1P (R=Me or R,R=pinacolate; R ²¹ , R ²² , R ²³ are C ₁ -C ₃ alkyl or form a dihydropyranyl ring) in the presence of a palladium catalyst, as for example disclosed in WO 200537826. Olefin residues can be hydrated under standard conditions, eg hydrogen over palladium on activated carbon, to (I). If further reduction occurs in the quinoline core, such reduction products, e.g. dihydroquinoline intermediates, can be re-oxidized to quinoline, e.g. with cerium(IV) salts, in suitable solvents, e.g. a mixture of DMSO and water or acetonitrile and water to give (I).

Scheme 4:

Alternatively, chloroquinolines IE can be substituted in the presence of a base, such as lithium hexamethylsilazane, sodium hydride or potassium tert-butoxide, with WR ² groups if R ² carries at least one hydrogen atom and W is a CH-activating pike group , for example, with a false ester or cyano group, resulting in 1G. similar reactions are described, for example, in Org. Proc. Res. and Dev. 2001, 5, p. 28-36 or in WO 2013174780. During the saponification of the 1G esters, the W group can be cleaved off by saponification and decarboxylation, resulting in acids IX. From the acids IX, the amide intermediates I-a can be readily prepared via amide formation reactions as described above.

Scheme 5:

Alternatively, 7-fluoroquinolines 1G (R ⁴ ═F) can be converted to 7-alkoxyquinoline carboxylic acids 1S (R ⁴ ═C ₁ -C ₄ -alkoxy) by treatment with alcohol, base and some water at elevated temperatures.

End products (I) can be synthesized by the same reactions as described above.

In Schemes 1-5 above, Q, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above unless specifically noted otherwise.

List of NMR peaks

1H-NMR data of selected examples are recorded as 1H-NMR signal lists. For each signal, the d-value in ppm and signal strength are listed in parentheses. The pairs of d-values and intensity values are separated by a semicolon as separators.

An example of a list of signals is therefore:

d ₁ (intensity ₁ ), d ₂ (intensity ₂ ), …; di (intensity _i ), …, d _n (intensity _n )

The intensity of the narrow signals correlates with the height of the signals in the printed example of the NMR spectrum in cm and shows the actual ratios of the signal intensities. From wide signals, several peaks or the middle of the signal and their relative intensity compared to the most intense signal can be displayed.

To calibrate the chemical shift for the 1H spectra, we used tetramethylsilane and/or the chemical shift of the solvent used, in particular, in the case of spectra measured in DMSO. Therefore, the lists of NMR signals may include the peak of tetramethylsilane, but not necessarily.

The lists of 1H-NMR signals are similar to the classical 1H-NMR and therefore generally contain all the peaks that are listed in the classical NMR interpretation.

In addition, they can show similar to classical 1H-NMR signals of solvents, stereoisomers of target compounds, which are also the object of the present invention, and/or impurity peaks.

In order to show signals in the delta range of solvents and/or water, common solvent peaks, e.g. DMSO peaks in DMSO-D ₆ and water peak are shown in our 1H-NMR signal lists and are typically of high intensity on average. .

Peaks of stereo isomers of the target compounds and/or peaks of impurities usually have an average lower intensity than the peaks of the target compounds (eg >90% purity).

Such stereoisomers and/or impurities may be typical of a particular production process. Therefore, their peaks can help identify the reproducibility of our production process using "by-product fingerprints".

An expert who calculates target compound peaks using known methods (MestreC, ACD modeling, but also from empirically estimated averages) can highlight the target compound peaks, if necessary, using additional intensity filters. Such a selection will be similar to the corresponding peak of the classical 1H-NMR interpretation.

Further details of the description of NMR peak list data can be found in "Citation of NMR Peaklist Data within Patent Applications" in Research Disclosure Database Number 564025.

Intermediates

Intermediate 1A

4-Hydroxy-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid

Ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate mixture (5.00 g, 16.89 mmol) (Zask, al. Bioorganic and Medicinal Chemistry Letters, 2003, 1487-1490; Gharat, al. WO/2013/118071), (2 ,3,5-trifluorophenyl)boronic acid (3.56 g, 20.26 mmol) and potassium fluoride (2.94 g, 50.70 mmol) in tetrahydrofuran (50 ml) and water (5 ml) were purged with nitrogen for 10 min. After adding tris(dibenzylideneacetone)dipalladium(0) (0.77 g, 0.84 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.49 g, 1.69 mmol), the reaction mixture was purged with nitrogen for 10 min and stirred at 75°C for 18 h Then water (25 ml) and lithium hydroxide monohydrate (3.54 g, 84 mmol) were added and the reaction mixture was stirred at 90°C for 4 h. ), stirring at 90°C was continued for 18 hours, the Reaction mixture was left to cool to room temperature. Activated charcoal (2 g) was added and the mixture was stirred for 1 hour. The solids were filtered through a pad of diatomaceous earth. The filter cake was washed with aqueous sodium hydroxide (1 M; 3×30 ml) and tetrahydrofuran (3×30 ml). The filtrate was slowly added to hydrochloric acid (1 M; 300 ml). The resulting suspension was stirred for 30 minutes. The precipitate was filtered off, washed with water and diethyl ether and dried in air. 5.33 g (99% of theoretical yield) of the title compound was obtained.

LC-MS (method 1): R _t =1.92 min; m/z=320 (M+H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 15.11 (s, 1H), 12.35 (s, 1H), 8.58 (s, 1H), 8.46 (dd, 1H), 7.91 (dd, 1H), 7.86 -7.77 (m, 1H), 7.73 (t, 1H), 7.44-7.36 (m, 1H).

Intermediate 2A

4-Chloro-8-(2,3,5-trifluorophenyl)quinoline-3-carbonyl chloride

Under a nitrogen atmosphere, 4-hydroxy-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (5.33 g, 17 mmol) was added to phosphorus oxychloride (8.0 ml, 86 mmol) at room temperature. The suspension was stirred at 110°С for 2.5 h. The reaction mixture was left to cool to room temperature. Volatile compounds were removed in vacuum at 40°C. The remaining black oil was stored under argon and used as such.

LC-MS (method 1): R _t =2.24 min; m/z=352 (M+H) ⁺ [for the corresponding methyl ester]

Intermediate 3A

4-Chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

In an argon atmosphere at 0°C, N,N-diisopropylethylamine (15 ml, 84 mmol). The mixture was stirred for 10 min and (S)-chroman-4-amine hydrochloride (3.13 g, 17 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 74 hours. Activated charcoal (2 g) was added and the mixture was stirred for 30 minutes. Solids were filtered through a pad of diatomaceous earth. The filter cake was washed with tetrahydrofuran (3×30 ml). At 0°C, the filtrate was slowly added to hydrochloric acid (1 M; 150 ml). The resulting suspension was stirred for 30 minutes. The solids were filtered off, washed with water, diisopropyl ether and methyl t-butyl ether and air dried. 5.41 g (69% of theoretical yield) of the title compound were obtained.

LC-MS (method 3): R _t =2.21 min; m/z=469/471 (M+H) ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (d, 1H), 8.93 (s, 1H), 8.45 (dd, 1H), 8.02-7.91 (m, 2H), 7.74-7.56 (m, 1H ), 7.38 (dd, 1H), 7.34-7.26 (m, 1H), 7.18 (td, 1H), 6.93 (td, 1H), 6.80 (dd, 1H), 5.28 (dt, 1H), 4.33-4.20 ( m, 2H), 2.27-2.17 (m, 1H), 2.12-2.02 (m, 1H).

Intermediate 4A

Ethyl 8-bromo-4-[4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]quinoline-3-carboxylate

Under argon, a solution of methyl tetrahydro-2H-pyran-4-carboxylate (3.2 ml, 24 mmol) in THF (32 ml) was treated at -5°C with bis-(trimethylsilyl)-lithium amide (29 ml, 1.0 M solution in THF, 29 mmol) and stirred at -5 to 0°C for 10 minutes. Then solid ethyl 8-bromo-4-chloroquinoline-3-carboxylate (5.0 g, 15.9 mmol) (Zask, al. Bioorganic and Medicinal Chemistry Letters, 2003, 1487-1490; Gharat, al. WO/2013/118071) was added at parts at this temperature and stirring was continued at -5°C for 30 minutes. The reaction mixture was allowed to warm to room temperature. After 45 min the mixture was added in portions to a stirred mixture of water (250 ml) and acetic acid (3.3 ml, 58 mmol). THF was removed by evaporation under reduced pressure and the aqueous mixture was extracted with ethyl acetate. The organic phase was dried and evaporated. The residue was purified by flash chromatography on silica (100 g) with cyclohexane/ethyl acetate (12-17%).

Yield: 5.44 g (98% pure, 79% theoretical)

LC-MS (method 2): R _t =1.07 min; MS (ESIpos): m/z=422 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.357 (6.88), 1.375 (14.95), 1.393 (7.58), 1.397 (4.39), 2.179 (0.88), 2.200 (1.86), 2.213 ( 1.51), 2.220 (1.36), 2.233 (2.39), 2.254 (1.26), 2.414 (3.29), 2.447 (2.46), 3.310 (16.00), 3.820 (6.73), 3.838 (6.62), 3.966 (0.97), 1.06), 4.431 (2.21), 4.449 (6.96), 4.467 (6.93), 4.485 (2.15), 5.755 (2.36) 3.11), 8.205 (2.76), 8.206 (2.77), 8.224 (3.20), 8.242 (3.07), 8.911 (7.68).

Intermediate 5A

8-Bromo-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid

Ethyl 8-bromo-4-[4-(methoxycarbonyl)tetrascro-2H-pyran-4-yl]quinoline-3-carboxylate (845 mg, 2.0 mmol) was refluxed for 2 days in isopropanol (8 ml) containing aqueous hydroxide sodium (2.4 ml, 5 M, 12 mmol). Water (15 ml) was added and hydrochloric acid (3 ml, 5 M, 15 mmol) was added dropwise at 50°C. The resulting suspension was stirred for 3 hours at ambient temperature, the precipitate was filtered off, washed with water/isopropanol (2:1) and dried in vacuo.

Yield: 691 mg (>100% theoretical yield, crude)

LC-MS (method 4): R _t = 1.88 min; MS (ESIpos): m/z = 336 [M+H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: -0.007 (1.50), 0.006 (1.00), 1.034 (1.53), 1.046 (1.51), 1.678 (4.44), 1.699 (4.80), 2.348 ( 1.15), 2.357 (1.43), 2.373 (3.28), 2.381 (3.40), 2.398 (3.41), 2.406 (3.20), 2.423 (1.35), 2.431 (1.19), 3.526 (3.52), 3.547 (6.66), 3.67), 3.906 (0.86), 3.913 (1.53), 3.920 (1.03), 3.931 (1.74), 3.938 (2.90), 3.945 (1.68), 3.955 (1.01), 3.962 (1.46), 3.970 (0.81) 4.92), 4.006 (5.13), 4.021 (4.63), 4.029 (4.38), 7.606 (4.83), 7.621 (6.26), 7.623 (5.84), 7.638 (5.05), 8.223 (7.00), 8.225 (6.80), 7.01), 8.525 (5.52), 8.542 (5.36), 8.685 (0.47), 8.987 (16.00), 13.845 (0.91).

Intermediate 6A

8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxamide

A solution of 8-bromo-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid (690 mg, 2.05 mmol) in DMF/THF (1:3 mixture, 14 mL) was placed in an oil bath at 55 °C and treated with (48)-chroman-4-amine hydrochloride (457 mg, 2.46 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.2 mmol). The heating was stopped and a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifosfinan 2,4,6-trioxide in ethyl acetate (1.9 ml, 50% content, 3.3 mmol) was added dropwise, and the mixture was stirred overnight at ambient temperature. The reaction mixture was again heated to 55°C, (4S)-chroman-4-amine hydrochloride (152 mg, 0.82 mmol), N,N-diisopropylethylamine (0.5 ml, 2.87 mmol) was added and after heating was stopped, a solution of 2.4, 6-tripropyl-1,3,5,2,4,6-trioxatrifosfinan 2,4,6-trioxide in ethyl acetate (0.6 ml, 50% content, 1.03 mmol) and stirring was continued at ambient temperature for 3.5 h. Then water (80 ml) was added and the mixture was stirred at 60° for 20 min. THF was removed under reduced pressure and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and dried in a vacuum.

Yield: 748 mg (78% of theoretical yield)

LC-MS (method 2): R _t = 0.97 min; MS (ESIneg): m/z = 465 [M] ^-

¹ H-NMR (500 Mi4,DMSO-d6) δ [ppm]: 1.351 (0.58), 1.644(3.27), 1.670(3.71), 1.686 (3.38), 1.713 (3.35), 1.755 (1.16), 1.988 (0.44 ), 2.060 (2.11), 2.070 (2.36), 2.084 (2.76), 2.229 (2.51), 2.240 (2.55), 2.246 (2.47), 2.257 (1.85), 2.377 (4.33), 2.401 (4.40), 2.632 (0.47 ), 3.296 (0.44), 3.393 (1.42), 3.440 (1.96), 3.461 (3.53), 3.495 (2.87), 3.519 (4.15), 3.541 (2.36), 3.598 (1.27), 3.697 (2.22), 3.988 (5.45 ), 4.000 (6.33), 4.011 (5.09), 4.212 (1.89), 4.229 (4.40), 4.247 (3.20), 4.290 (3.49), 4.297 (3.31), 4.303 (3.60), 5.299 (1.82), 5.310 (4.00 ), 5.325 (3.85), 5.336 (1.78), 6.793 (7.02), 6.810 (7.60), 6.933 (3.49), 6.948 (7.16), 6.963 (4.07), 7.168 (3.75), 7.184 (6.29), 7.199 (3.09 ), 7.414 (6.47), 7.429 (6.04), 7.577 (4.11), 7.593 (7.05), 7.609 (4.36), 8.185 (7.96), 8.200 (7.64), 8.465 (6.55), 8.482 (6.18), 8.856 (16.00 ), 9.192 (5.85), 9.208 (5.71).

Intermediate 7A

Ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate

A mixture of 2-bromo-3-fluoroaniline (24.89 g, 131 mmol) and diethylethoxymethylenemalonate (28.33 g, 131 mmol, 26 mL) was stirred at room temperature for 16 h. Stirring was continued at 250°C under vacuum (60 mbar) for 6 hours The reaction mixture was left to cool to room temperature. The solid residue was stirred under reflux of ethyl acetate (400 ml). The precipitate was filtered off and washed with ethyl acetate. The solid was stirred in a reflux mixture of ethanol (400 ml) and methanol (40 ml). The hot suspension was filtered. The solid was washed with ethanol and air dried.

Yield: 28.60 g (83 mmol, 63% of theoretical yield)

LC-MS (method 1): R _t = 1.73 min, m/z = 314/316 (M+H) ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.45 (s, 1H), 8.22 (m, 1H), 7.50-7.39 (m, 1H), 4.23 (d, J=7.1 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).

Intermediate 8A

Ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate

To stirred phosphorus oxychloride (38.4 g, 250 mmol, 23 ml) was added ethyl 8-bromo-7-fluoro-4-hydroxyquinoline-3-carboxylate (step 1) (23.6 g, 75 mmol). The resulting suspension was stirred at 80°C for 1 hour. The mixture was left to cool to room temperature and poured into vigorously stirred ice water (100 ml). The resulting mixture was allowed to stand for two days at room temperature. The precipitate was collected by filtration and washed with water until the filtrate was neutralized. The solids were triturated with a mixture of diethyl ether and diisopropyl ether (1:1; 1 L). Solids were filtered off. The filtrate was concentrated in vacuo at 25°C. After coevaporation of the residue with toluene, 21.3 g (64 mmol, 85% of theoretical yield) of the title compound was obtained.

Yield: 21.3 g (64 mmol, 85% of theoretical yield)

LC-MS (method 1): R _t = 2.18MHH, m/z = 332/334 (M+H) ⁺

Intermediate 9A

Ethyl 4,8-dibromo-7-fluoroquinoline-3-carboxylate

DMF (6.0 ml, 6.0 ml, catalytic amount), and then phosphoryl bromide (77.9 g, 271.8 mmol) in parts and stirring was continued at 0°C to ambient temperature for 5 hours. The reaction mass was poured into ice water and neutralized with solid sodium bicarbonate to pH 7. The mixture was stirred within 30 min and the organic phase was separated. The aqueous phase was extracted with DCM. The combined organic phase was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10:1) to give 53.32 g (77% of theory) of product.

LC-MS (method 2): R _t = 1.19 min; MS (ESIpos): m/z = 376 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.375 (7.47), 1.393 (16.00), 1.411 (7.67), 2.524 (0.74), 4.426 (2.42), 4.444 (7.47), 4.461 (7.34 ), 4.479 (2.33), 7.897 (1.80), 7.920 (2.69), 7.941 (2.06), 8.443 (1.83), 8.457 (1.91), 8.466 (1.82), 8.481 (1.75), 9.179 (4.99).

Intermediate 10A

Ethyl 8-bromo-4-ethyl-7-fluoroquinoline-3-carboxylate

Ethylboronic acid (10.6 g, 143 mmol), 1.1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.22 g, 5.17 mmol) and cesium fluoride (26.0 g, 171 mmol) and the mixture was stirred at a bath temperature of 70° C. overnight. Water and ethyl acetate were added to dissolve the reaction mixture, and the organic solvents were evaporated under reduced pressure. The aqueous phase was extracted with DCM several times, the combined organic phases were dried and evaporated. The residue (28 g) was purified in several parts by flash chromatography on silica using cyclohexane/ethyl acetate (4-18%) to give pure (17.56 g) and a mixed fraction (4.79 g). The mixed fraction was chromatographed under the same conditions to give pure material (1.44 g) and a mixed fraction (1.99 g). The latter was purified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile) to give a purer material (1.33 g).

Total yield: 20.33 g (78% of theoretical yield)

LC-MS (method 4): R _t = 3.55 min; MS (ESIpos): m/z = 326 [M+H] ⁺

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.275 (4.81), 1.288 (10.56), 1.300 (4.53), 1.376 (7.45), 1.388 (16.00), 1.395 (0.68), 1.400 (7.58 ), 3.389 (1.35), 3.402 (4.01), 3.414 (3.89), 3.427 (1.17), 4.405 (2.31), 4.417 (7.12), 4.428 (7.00), 4.440 (2.15), 7.776 (1.85), 7.790 (2.36 ), 7.791 (2.28), 7.805 (1.87), 8.451 (1.74), 8.461 (1.80), 8.467 (1.72), 8.476 (1.60), 9.219 (7.16).

Intermediate 11A

8-Bromo-4-ethyl-7-fluoroquinoline-3-carboxylic acid

A mixture of ethyl 8-bromo-4-ethyl-7-fluoroquinoline-3-carboxylate (19.0 g, 58.3 mmol) in ethanol (80 ml) and THF (80 ml) was treated dropwise with aqueous sodium hydroxide (35 ml, 5.0 M, 175 mmol) and stirred for 30 min at 80°С. The reaction mixture was slowly added at t 40° with stirring to water (200 ml) and formic acid (13.2 ml). To complete the precipitation, the organic solvents were mostly evaporated and hydrochloric acid (15 ml, 5.0 M) (pH 2) was added. The precipitate was filtered off, washed in several parts with water and dried in a vacuum.

Yield: 17.27 g (95% pure, 95% theoretical)

LC-MS (method 2): R _t = 0.87 min; MS (ESIpos): m/z = 298 [M+H] ⁺

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.267 (7.94), 1.279 (16.00), 1.291 (7.47), 1.447 (0.45), 3.447 (2.52), 3.459 (6.78), 3.472 (6.52 ), 3.484 (2.11), 7.759 (2.54), 7.774 (4.56), 7.788 (2.55), 8.439 (2.58), 8.449 (2.82), 8.454 (2.85), 8.464 (2.37), 9.244 (10.71), 13.665 (1.91 ).

Intermediate 12A

8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-ethyl-7-fluoroquinoline-3-carboxamide

A suspension of 8-bromo-4-ethyl-7-fluoroquinoline-3-carboxylic acid (17.3 g, 57.9 mmol) in THF (300 ml) was heated to 60°C and treated with (4S)-chroman-4-amine hydrochloride (14.0 g , 75.3 mmol), N,N-diisopropylethylamine (40 ml, 230 mmol). With stirring, a solution of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifosfinan 2,4,6-trioxide in ethyl acetate (55 ml, 50% content, 93 mmol) was added dropwise, heating temporarily stopped to maintain the temperature from 60 to 65°C. After the addition was complete, the mixture was stirred at 60°C for 1 hour. Water (300 ml) was added, THF was largely removed under reduced pressure, and the mixture was stirred at 60°C for 45 minutes. The precipitate was filtered off, washed with water, and dried in vacuum at 50°C.

Yield: 24.0 g (97% of theoretical yield)

LC-MS (method 4): R _t = 3.37 min; MS (ESIpos): m/z = 429 [M+H] ⁺

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.265 (7.90), 1.278 (16.00), 1.290 (7.22), 2.050 (1.41), 2.055 (1.44), 2.062 (1.53), 2.067 (1.48 ), 2.073 (1.72), 2.084 (0.99), 2.215 (1.72), 2.223 (1.65), 2.229 (1.65), 2.238 (1.21), 2.386 (0.41), 2.425 (0.80), 2.653 (0.58), 3.223 (2.36 ), 3.235 (6.25), 3.248 (6.02), 3.260 (2.17), 4.231 (1.22), 4.245 (2.98), 4.250 (2.22), 4.258 (2.47), 4.263 (2.12), 4.271 (2.13), 4.276 (2.43 ), 4.282 (2.20), 4.288 (2.44), 4.295 (1.01), 4.301 (1.01), 5.297 (1.25), 5.306 (2.53), 5.320 (2.44), 5.330 (1.08), 6.794 (4.46), 6.807 (4.69 ), 6.928 (2.32), 6.939 (4.56), 6.951 (2.53), 7.166 (2.29), 7.177 (3.74), 7.189 (1.85), 7.357 (4.02), 7.370 (3.65), 7.736 (3.06), 7.751 (4.60 ), 7.766 (3.06), 8.364 (2.91), 8.374 (3.11), 8.380 (3.01), 8.390 (2.77), 8.939 (12.93), 9.149 (3.67), 9.163 (3.55).

Intermediate 13A

8-Bromo-4-chloro-7-fluoroquinoline-3-carboxylic acid

A mixture of ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (Example 8A) (11.9 g, 35.7 mmol) in THF (82 ml) was treated dropwise with aqueous sodium hydroxide (14 ml of 45% sodium hydroxide, diluted with 0.8 ml of water) at room temperature, followed by dilution with 15 ml of water. The resulting precipitate was filtered off and slowly added to water (200 ml, Т = 40°С) with stirring. The resulting mixture was treated with formic acid (59 ml) at 60°C. The precipitate was filtered off, washed in several parts with water, and dried in air.

Yield: 9.4 g (88% pure, 76% theoretical)

LC-MS (method 5): R _t = 0.774 min; m/z = 305.9 (M+H) ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ 14.14 (bs), 9.29 (s, 1H), 8.51-8.47 (dd, 1H), 7.93-7.88 (t, 1H).

Intermediate 14A

8-Bromo-4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoroquinolin-3-carboxamide

To a suspension of 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylic acid (8.56 g, 24.41 mmol) in dry toluene (180 ml) was added 3 drops of DMF. Then thionyl chloride (4.35 g, 36.62 mmol) was added dropwise over 10 minutes. After stirring for 2 hours at 90° C., the mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was dissolved in dry tetrahydrofuran (200 ml) and after adding (4S)-chroman-4-amine hydrochloride (4.53 g, 24.41 mmol) and N,N-diisopropylethylamine (24.47 g, 189 mmol), stirring was continued for 18 h at room temperature. temperature. The solvents were removed under reduced pressure and the residue was partitioned between water (150 ml) and dichloromethane (150 ml). The precipitate was filtered off, washed with several parts of water, and dried in air.

Yield: 10.16 g (96% of theoretical yield)

LC-MS (method 5): R _t = 1.26 min; m/z = 435 (M+H) ⁺

logP(HCOOH) (method 0) = 3.18

¹ H-NMR (400 MHz, DMSO-d6) δ 9.30-9.28 (m, 1H), 9.08 (s, 1H), 8.43-8.39 (m, 1H), 7.92-7.88 (m, 1H), 7.40-7.38 (m, 1H), 7.21-7.16 (m, 1H), 6.96-6.92 (m, 1H), 6.82-6.79 (m, 1H), 5.29 (m, 1H), 4.30-4.21 (m, 2H), 2.25 -2.20(m, 1H), 2.11-2.07(m, 1H).

Intermediate 15A

8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-fluoroazetidin-1-yl)quinoline-3-carboxamide

A mixture of 8-bromo-4-chloro-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoroquinolin-3-carboxamide (Example 14A) (295 mg, 0.677 mmol), 3-fluoroazetidine hydrochloride (155 mg, 1.39 mmol) and 1,4-diazabicyclo[2.2.2]octane (310 mg, 2.764 mmol) in tetrahydrofuran (10 mL) were stirred at 60°C for 18 h. The mixture was cooled to room temperature. temperature, water was added and the aqueous layer was extracted with dichloromethane (3×10 ml). Solvents were dried and removed under reduced pressure to give 297 mg (93% of theory) of the title compound.

LC-MS (method 5): R _t = 0.67 min; m/z = 475.9 (M+H) ⁺

logP(HCOOH) (method 0) = 1.29

¹ H-NMR (400 MHz, DMSO-d6) δ 9.10-9.08 (m, 1H), 8.56 (s, 1H), 8.12-8.08 (m, 1H), 7.44-7.39 (m, 1H), 7.34-7.32 (m, 1H), 7.21-7.16 (m, 1H), 6.95-6.91 (m, 1H), 6.82-6.80 (m, 1H), 5.56-5.38 (m, 1H), 5.22-5.20 (m, 1H) , 4.73-4.53 (m, 4H), 4.28-4.26 (m, 2H), 2.19-2.16 (m, 1H), 2.09-2.00 (m, 1H).

Intermediate 16A

Ethyl 8-bromo-7-fluoro-4-[4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]quinoline-3-carboxylate

The title compound was prepared from ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate

(Example 8A) according to the procedure given for example 4A.

Yield: 82% of Theoretical Yield

LC-MS (method 4): R _t = 3.28 min; MS (ESIpos): m/z = 440 [M+H]+

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.362 (4.09), 1.374(8.34), 1.385(4.08), 2.197 (0.71), 2.207 (0.89), 2.219 (1.15), 2.224 (1.09 ), 2.229 (1.08), 2.236 (0.93), 2.247 (0.82), 2.411 (2.32), 2.433 (1.85), 3.566 (16.00), 3.795 (0.53), 3.812 (2.47), 3.824 (2.83), 3.831 (4.67 ), 3.982 (0.61), 4.439 (1.34), 4.450 (3.95), 4.462 (3.85), 4.474 (1.23), 7.787 (1.17), 7.800 (1.50), 7.816 (1.22), 8.248 (1.21), 8.258 (1.28 ), 8.265 (1.21), 8.274 (1.11), 8.956 (4.93).

Intermediate 17A

8-Bromo-7-methoxy-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxylic acid

Ethyl 8-bromo-7-fluoro-4-[4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]quinoline-3-carboxylate (Intermediate 16A) (3.00 g, 6.81 mmol), methanol (15 ml) and aqueous sodium hydroxide (8.2 ml, 5 M, 41 mmol) were stirred overnight at a bath temperature of 75°. More aqueous sodium hydroxide (2.7 ml, 5 M, 13.5 mmol) was added and the mixture was heated under reflux overnight. Water (30 ml) was added and the warm solution was acidified with concentrated hydrochloric acid to pH 2. The precipitate was filtered off, washed with water and dried in vacuo.

Yield: 2.3 g (96% pure, 88% of theoretical yield)

LC-MS (method 4): R _t = 1.63 min; MS (ESIpos): m/z = 366 [M+H]+

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.664 (2.08), 1.685 (2.17), 2.373 (0.64), 2.387 (1.49), 2.393 (1.56), 2.407 (1.48), 2.414(1.41 ), 2.429 (0.74), 3.169 (0.43), 3.521 (1.42), 3.539 (2.67), 3.558 (1.51), 3.951 (0.63), 3.972 (1.14), 4.006 (2.13), 4.012 (2.27), 4.024 (2.09 ), 4.031 (1.96), 4.068 (16.00), 7.671 (2.40), 7.687 (2.47), 8.544 (2.28), 8.559 (2.17), 8.947 (3.71), 13.709 (0.47).

Intermediate 18A

8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-methoxy-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxamide

N, N-diisopropylethylamine (0.71 ml, 4.1 mmol) and HATU (289 mg, 1.02 mmol), and solution n was stirred for 30 min at room temperature. Then (4S)-chroman-4-amine hydrochloride (380 mg, 2.05 mmol) was added and stirring continued overnight. Most of the THF was evaporated under reduced pressure, the residue was added to a mixture (2:1) of water/ethanol (50 ml) and acidified with acetic acid to pH 4.5. The mixture was stirred at 50°C for 30 min, cooled, the precipitate was filtered off, washed with water/ethanol (2:1), and dried in a vacuum.

Yield: 311 mg (76% of theoretical yield)

LC-MS (method 4): R _t = 2.72 min; MS (ESIneg): m/z = 495 [M-H]-

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.638 (1.03), 1.675(1.81), 1.711 (1.11), 2.054 (0.67), 2.081 (0.92), 2.219 (0.83), 2.232 (0.86 ), 2.240 (0.81), 2.378 (1.49), 2.409 (1.45), 3.436 (0.70), 3.464 (1.27), 3.492 (1.41), 3.519 (1.39), 3.547 (0.74), 3.692 (0.83), 3.992 (2.02 ), 4.005 (1.93), 4.019 (2.23), 4.050 (16.00), 4.216 (0.51), 4.236 (1.33), 4.257 (1.17), 4.282 (1.27), 4.297 (1.23), 5.300 (1.27), 5.320 (1.31 ), 6.787 (2.26), 6.807 (2.54), 6.925 (1.10), 6.943 (2.32), 6.962 (1.36), 7.161 (1.24), 7.180 (1.98), 7.199 (0.96), 7.403 (2.05), 7.421 (1.92 ), 7.636 (2.48), 7.660 (2.61), 8.463 (2.36), 8.487 (2.24), 8.781 (5.86), 9.114(1.89), 9.135(1.90).

Examples

Example 1

N-[(4S)-3,4-Hydro-2H-chromen-4-yl]-4-(3,6-hydro-2H-pyran-4-yl)-8-(2,3,5-trifluorophenyl )quinoline-3-carboxamide

In an argon atmosphere, 4-chloro-N-[(4S)-3,4-dihydro-2H-chromene-4-yl]-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide ( Example 3A) (500 mg, 1.07 mmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (246 mg, 1.17 mmol), potassium carbonate (295 mg, 2.13 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex dichloride (43.5 mg, 53 µmol) and degassed dioxane/water 5:1 mixture (4 ml). The vessel was closed and heated with stirring at 80°C overnight. The mixture was filtered through Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic phases were dried and evaporated. The residue (650 mg) was purified by flash chromatography on silica (50 g) with cyclohexane/ethyl acetate (8-40%).

Yield: 500 mg (91% of theoretical yield)

LC-MS (method 2): R _t = 1.14 min; MS (ESIpos): m/z = 517 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (0.50), 0.146 (0.54), 1.992 (1.11), 2.001 (1.30), 2.008 (1.31), 2.019 (1.65), 2.026 ( 1.38), 2.162 (1.42), 2.174 (1.44), 2.182 (1.34), 2.327 (0.54), 2.366 (0.64), 2.430 (2.29), 2.669 (0.53), 2.709 (0.50), 3.901 (1.68), 2.74), 4.245 (4.37), 4.253 (4.09), 4.261 (3.62), 4.270 (3.71), 4.289 (1.96), 5.225 (0.89), 5.239 (2.03) 4.46), 6.788 (4.87), 6.891 (2.01), 6.908 (4.36), 6.926 (2.57), 7.139 (2.23), 7.142 (2.32) 1.88), 7.254 (1.90), 7.264 (1.94), 7.342 (3.24), 7.360 (3.01), 7.588 (0.68), 7.596 (0.82), 7.611 (1.51), 7.624 (1.54), 7.637 (1.54), 0.96), 7.652 (0.83), 7.660 (0.76), 7.772 (2.74), 7.790 (4.75), 7.811 (4.54), 7.862 (5.09), 7.865 (5.41), 7.880 (3.55), 7.883 (3.29), 4.73), 8.096 (4.68), 8.114 (4.19), 8.117 (3.89), 8.892 (16.00), 8.938 (3.57), 8.959 (3.47).

Example 2

N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-4-(tetrahydro-2H-pyran-4-yl)-8-(2,3,5-trifluorophenyl)quinolin-3 -carboxamide

Method 1:

In an argon atmosphere, N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(3,6-dihydro-2H-pyran-4-yl)-8-(2.3, 5-trifluorophenyl)quinoline-3-carboxamide (Example 1) (500 mg, 0.97 mmol) was dissolved in ethyl acetate/ethanol (2:1, 15 ml). The catalyst, 10% palladium on activated carbon (125 mg), was added, the argon was replaced with hydrogen, and the mixture was stirred under atmospheric pressure of hydrogen for 18 hours. The reaction mixture was filtered through celite, washed with ethyl acetate and concentrated in vacuo. The residue (560 mg, crude mixture of various reduction products) was dissolved in DMSO (4.5 mL) and treated with cerium ammonium nitrate (2 M in water, 1.9 mL, 3.8 mmol) to give a brownish suspension which was stirred overnight at ambient temperature. The mixture was dissolved with more DMSO, acetonitrile and some 5 M formic acid and purified directly by preparative HPLC (C18 gradient: 0.1% aqueous formic acid/acetonitrile). Yield: 175 mg (31% of theoretical yield). The mixed fraction (75 mg) was repurified by silica flash chromatography with cyclohexane/ethyl acetate (5-50%) to give a second run of 37 mg (7% of theory).

LC-MS (method 4): R _t = 3.80 min; MS (ESIpos): m/z = 519 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.008 (2.70), 0.008 (2.80), 1.687 (1.87), 1.724 (3.01), 1.763 (2.03), 2.030 (0.72), 2.038 ( 1.16), 2.045 (1.24), 2.057 (1.32), 2.073 (1.91), 2.080 (1.57), 2.088 (1.14), 2.192 (0.71), 2.201 (1.15), 2.214 (1.69), 2.226 (1.65), 1.62), 2.248 (1.14), 2.256 (0.82), 2.269 (0.56), 2.395 (0.93), 2.425 (2.48), 2.454 (2.48), 2.523 (1.11), 3.457 (1.19), 3.486 (2.26), 2.39) 2.75), 4.239 (2.11), 4.252 (2.47), 4.262 (2.60), 4.273 (2.58), 4.280 (2.20), 4.289 (2.31) 1.08), 5.301 (2.49), 5.320 (2.53), 5.335 (1.12), 6.778 (4.25), 6.781 (4.67), 6.799 (4.92), 6.801 (5.15), 6.910 (2.31), 6.913 (2.42), 4.82) 2.00), 7.220 (1.97), 7.230 (2.00), 7.242 (1.03), 7.398 (4.14), 7.416 (3.86), 7.571 (0.69), 7.578 (0.85), 7.586 (0.98), 7.593 (1.57), 1.47), 7.606 (1.60), 7.614 (1.53), 7.620 (1.61), 7.627 (1.01), 7.634 (0.92), 7.642 (0.84) 5.89), 7.835 (6.55), 7.850 (3.13), 7.853 (2.79), 8.561 (3.72), 8.564 (3.88), 8.582 (3.67), 8.585 (3.55) 4.33).

Method 2:

In an argon atmosphere, 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(tetrahydro-2H-pyran-4-yl)quinoline-3-carboxamide was loaded into the flask (example 6A) (850 mg, 1.82 mmol), 2,3,5-trifluorobenzeneboronic acid (160 mg, 0.91 mmol), potassium carbonate (503 mg, 3.64 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichlorodichloromethane complex (44.6 mg, 54.6 µmol) and (2'-aminobiphenyl-2-yl)(chloro)palladium - dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (1:1 ) (42.9 mg, 54.6 µmol) and a degassed 5:1 mixture of dioxane/water (5.1 mL). The mixture was stirred in a preheated 70° C. bath for 45 minutes. Then another part of 2,3,5-trifluorobenzeneboronic acid (160 mg, 0.91 mmol) was added and stirred at the same temperature for 45 min. The last process was repeated one more time. After the starting material was consumed, water and ethyl acetate were added at room temperature, stirred and the phases were separated. The aqueous phase was extracted several times with ethyl acetate, the combined organic phases were dried and evaporated under reduced pressure. The residue (1.15 g) was purified by flash chromatography on silica (100 g) with cyclohexane/ethyl acetate (32-40%).

Yield: 833 mg (88% of theoretical yield)

LC-MS (method 2): R _t = 1.13 min; MS (ESIpos): m/z = 519 [M+H] ⁺

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.691 (1.98), 1.716(2.17), 1.736(1.98), 1.761 (2.04), 2.038 (0.81), 2.045 (1.25), 2.050 (1.33 ), 2.060 (1.42), 2.073 (1.82), 2.078 (1.55), 2.085 (1.09), 2.200 (0.78), 2.207 (1.17), 2.217 (1.73), 2.227 (1.71), 2.234 (1.72), 2.245 (1.25 ), 2.252 (0.84), 2.262 (0.56), 2.405 (1.02), 2.429 (2.67), 2.453 (2.70), 3.464 (1.17), 3.485 (2.16), 3.508 (1.29), 3.523 (1.50), 3.544 (2.52 ), 3.567 (1.39), 3.730 (1.32), 4.003 (2.20), 4.013 (3.04), 4.025 (4.09), 4.036 (2.77), 4.046 (1.82), 4.212 (0.98), 4.218 (1.16), 4.234 (3.00 ), 4.240 (2.08), 4.251 (2.37), 4.257 (1.90), 4.268 (1.90), 4.275 (2.44), 4.281 (2.12), 4.288 (2.38), 4.298 (1.00), 4.304(1.09), 4.310 (0.80 ), 5.292 (1.22), 5.304 (2.66), 5.320 (2.56), 5.331 (1.16), 5.752 (1.91), 6.783 (5.04), 6.798 (5.49), 6.915 (2.50), 6.930 (5.20), 6.945 (2.93 ), 7.154 (2.55), 7.157(2.49), 7.171 (4.18), 7.185 (2.13), 7.188 (1.98), 7.208 (2.12), 7.217 (2.09), 7.225 (2.06), 7.399 (4.31), 7.415 (4.06 ), 7.574 (0.76), 7.580 (0.94), 7.586 (1.07), 7.592 (1.68), 7.602 (1.71), 7.609 (1.64), 7.613 (1.64), 7.619 (0.99), 7.624 (0.89), 7.631 (0.78 ), 7.778 (2.81), 7.793 (5.08), 7.810 (4.86), 7.833 (6.27), 7.835 (6.27), 7.847 (3.60), 8.563 (4.14), 8.580 (3.96), 8.738 (16.00), 9.159 (4.57 ), 9.176 (4.42).

Example 3

N-[(4S)-3,4-Hydro-2H-chromen-4-yl]-7-fluoro-4-(tetrahydro-2H-pyran-4-yl)-8-(2,3,5-trifluorophenyl )quinoline-3-carboxamide

The title compound was prepared from ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (Example 8A) in a similar manner as described for Examples 4A, 5A, 6A and Example 2, Method 2.

LC-MS (method 2): R _t = 1.14 min; MS (ESIpos): m/z = 537 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.679 (4.00), 1.713(6.39), 1.737(3.34), 2.033 (2.47), 2.052 (2.85), 2.067 (3.55), 2.211 (2.97 ), 2.220 (3.09), 2.229 (2.93), 2.243 (2.14), 2.328 (0.95), 2.367 (2.64), 2.388 (4.62), 2.401 (5.48), 2.420 (5.36), 2.432 (5.24), 2.449 (2.76 ), 2.464 (2.06), 2.670 (0.95), 2.710 (0.91), 3.444 (1.32), 3.471 (3.63), 3.499 (4.04), 3.523 (3.09), 3.543 (4.29), 3.574 (2.23), 3.737 (3.01 ), 4.016 (7.26), 4.036 (6.06), 4.197 (2.06), 4.219 (4.21), 4.225 (4.91), 4.246 (4.41), 4.270 (4.74), 4.286 (4.16), 5.275 (2.27), 5.288 (5.07 ), 5.307 (5.11), 5.322 (2.19), 6.778 (9.73), 6.799 (10.85), 6.904 (4.87), 6.923 (10.35), 6.942 (6.10), 7.152 (5.03), 7.170 (8.37), 7.188 (4.00 ), 7.278 (3.96), 7.286 (4.00), 7.389 (8.87), 7.407 (8.29), 7.642 (1.57), 7.650 (1.90), 7.665 (3.42), 7.678 (3.34), 7.686 (3.34), 7.692 (3.38 ), 7.698 (2.10), 7.706 (1.86), 7.714 (1.73), 7.761 (5.44), 7.784 (10.27), 7.807 (5.61), 8.664 (5.11), 8.679 (5.65), 8.688 (5.53), 8.703 (4.95 ), 8.758 (15.75), 8.770 (16.00), 9.155 (6.72), 9.173 (6.47).

Example 4

N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-4-ethyl-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide

Under an argon atmosphere, 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-ethyl-7-fluoroquinoline-3-carboxamide (Example 12A) (13.0 g , 30.3 mmol), 2,3,5-trifluorobenzeneboronic acid (2.67 g, 15.2 mmol), potassium carbonate (8.37 g, 60.6 mmol) and (2'-aminobiphenyl-2-yl)(chloro)palladium - dicyclohexyl(2' ,4',6'-triisopropylbiphenyl-2-yl)phosphine (1:1) (477 mg, 606 µmol). A degassed 5:1 mixture of dioxane/water (140 ml) was added and the mixture was stirred at 70° C. for 45 minutes. Two more parts of 2,3,5-trifluorobenzeneboronic acid (2.67 g, 15.2 mmol) were added over 1.5 h and stirring was continued for 1.5 h after the last dose was added. Then more 2,3,5-trifluorobenzeneboronic acid (5.33 g, 30.3 mmol) and (2'-aminobiphenyl-2-yl)(chloro)palladium - dicyclohexyl(2',4',6'-triisopropyl-2-yl) phosphine (1:1) (238 mg, 303 μmol) was added and stirred at the same temperature for 1 h. Water and ethyl acetate were added at room temperature, stirred and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried and evaporated under reduced pressure. The residue (24 g) was purified by flash chromatography on silica with DCM and methanol (0-2%) and then a second chromatography on silica with cyclohexane-ethyl acetate (10-25%) gave 7.63 g. The remaining mixed fractions were purified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile) to give purer material (0.75 g).

Total yield: 8.38 g (58% of theoretical yield)

LC-MS (method 4): R _t = 3.99 min; MS (ESIpos): m/z = 481 [M+H] ⁺

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 0.005 (0.62), 1.305 (8.10), 1.317 (16.00), 1.318 (15.96), 1.329 (7.70), 1.397 (8.26), 2.020 (0.99 ), 2.026 (1.42), 2.031 (1.82), 2.037 (1.85), 2.042 (1.90), 2.049 (1.91), 2.054(2.16), 2.060 (1.62), 2.065 (1.16), 2.181 (0.98), 2.187 (1.48 ), 2.195 (2.06), 2.203 (1.94), 2.209 (2.04), 2.218 (1.46), 2.223 (1.05), 2.232 (0.71), 2.516 (0.89), 2.520 (0.95), 2.523 (0.96), 3.227 (0.71 ), 3.236 (1.35), 3.249 (3.27), 3.257 (3.63), 3.261 (4.26), 3.270 (4.39), 3.282 (3.24), 3.294 (1.47), 3.304 (1.17), 4.214 (0.72), 4.219 (1.14 ), 4.226 (1.21), 4.233 (2.56), 4.239 (3.13), 4.245 (2.80), 4.252 (3.53), 4.255 (3.49), 4.261 (3.70), 4.266 (2.73), 4.272 (3.23), 4.280 (1.06 ), 4.285 (1.15), 4.291 (0.88), 5.280 (1.26), 5.291 (2.88), 5.301 (2.73), 5.312 (1.11), 6.781 (6.23), 6.783 (6.34), 6.795 (6.65), 6.796 (6.62 ), 6.907 (3.27), 6.919 (6.32), 6.932 (3.61), 7.153 (2.85), 7.164 (4.85), 7.176 (2.33), 7.295 (2.49), 7.302 (2.41), 7.334 (2.71), 7.345 (4.69 ), 7.356 (2.50), 7.660 (0.92), 7.665 (1.13), 7.670 (1.32), 7.675 (2.00), 7.678 (1.91), 7.683 (2.01), 7.689 (1.92), 7.692 (1.90), 7.697 (1.20 ), 7.702 (1.05), 7.707 (0.93), 7.780 (3.82), 7.795 (7.06), 7.811 (3.81), 8.484 (4.02), 8.494(4.24), 8.500 (4.25), 8.510 (3.87), 8.812 (11.05 ), 8.818 (10.77), 9.124 (4.07), 9.137 (3.96).

Example 5

N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-fluoroazetidin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline -3-carboxamide

A mixture of 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-fluoroazetidin-1-yl)quinoline-3-carboxamide (Example 15A ) (1500 mg, 3.163 mmol) and bis(triphenylphosphine)dichloropalladium (II) (255 mg, 0.363 mmol) in 1,4-dioxane (50 mL) were stirred at room temperature for 2 h. 5-trifluorophenyl)boronic acid (2200 mg, 12.51 mmol), sodium carbonate (5000 mg, 47.175 mmol) and water (6.20 ml), stirring was continued for 18 h at 90°C. The mixture was cooled to room temperature, water was added and the aqueous layer was extracted with dichloromethane (3×100 ml). The solvents were dried and removed under reduced pressure. Purification by preparative HPLC (water/acetonitrile 80:20→5:95/ provided 675 mg (40.6% of theory) of the title compound.

LC-MS (method 5): R _t = 0.88 min; m/z = 526 (M+H) ⁺

logP(HCOOH) (method 0) = 1.93

¹ H-NMR (400 MHz, DMSO-d6) δ 1.99-2.08 (m, 1H), 2.14-2.19 (m, 1H), 4.25 (t, J=3.5 Hz, 2H), 4.57-4.74 (m, 4H ), 5.17-5.22 (m, 1H), 5.42-5.60 (m, 1H), 6.78-6.80 (m, 1H), 6.88-6.92 (m, 1H), 7.14-7.23 (m, 2H), 7.30-7.32 (m, 1H), 7.44-7.49 (m, 1H), 7.55-7.65 (m, 1H), 8.20-8.24 (m, 1H), 8.43 (s, 1H), 9.03-9.06 (m, 1H) .

Example 6

N-[(4S)-3,4-dipedro-2H-chromen-4-yl]-4-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-8-(2,3 ,5-trifluorophenyl)quinoline-3-carboxamide

The title compound was synthesized analogously to Example 1.

LC-MS (method 2): R _t = 1.15 min; MS (ESIpos): m/z = 535 [M+H] ⁺

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.235 (0.66), 1.981 (2.08), 1.989 (2.69), 1.998 (2.43), 2.007 (2.94), 2.016 (2.83), 2.024 (2.32 ), 2.158 (2.87), 2.170 (2.86), 2.179 (2.72), 2.192 (1.96), 2.328 (0.57), 2.366 (1.31), 2.415 (3.83), 2.710 (0.44), 3.900 (3.04), 4.186 (2.08 ), 4.214 (5.03), 4.242 (7.22), 4.250 (7.35), 4.259 (6.65), 4.267 (6.99), 4.287 (3.94), 5.230 (3.88), 5.246 (3.82), 5.865 (5.17), 6.765 (8.88 ), 6.767 (9.12), 6.786 (10.18), 6.788 (10.05), 6.885 (4.24), 6.904 (9.03), 6.923 (5.30), 7.138 (4.63), 7.142 (4.76), 7.159 (7.78), 7.177 (3.82 ), 7.180 (3.67), 7.332 (8.89), 7.352 (6.35), 7.659 (1.33), 7.667 (1.60), 7.674 (1.88), 7.682 (3.03), 7.686 (2.92), 7.695 (3.04), 7.703 (3.02 ), 7.708 (3.04), 7.715 (1.97), 7.723 (1.71), 7.731 (1.56), 7.767 (6.31), 7.790 (12.55), 7.813 (6.93), 8.177 (6.63), 8.192 (7.10), 8.201 (6.80 ), 8.216 (6.23), 8.914 (15.39), 8.924 (16.00), 8.940 (6.05), 8.961 (5.60).

Example 7

N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-methoxy-4-(tetrahydro-2H-pyran-4-yl)-8-(2,3,5-trifluorophenyl )quinoline-3-carboxamide

In an argon atmosphere, 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-methoxy-4-(tetrahydro-2H-pyran-4-yl)quinoline was loaded into the vessel -3-carboxamide (Intermediate 18A), (200 mg, 0.4 mmol), 2,3,5-trifluorobenzeneboronic acid (141 mg, 0.80 mmol), cesium fluoride (182 mg, 1.21 mmol), (2-dicyclohexylphosphino-2 ',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium (II) methanesulfonate (31.4 mg, 40.2 µmol) and degassed dioxane/water 5:1 mixture (2 ml), covered and stirred at 60° C. overnight. The mixture was treated with aqueous formic acid (0.48 ml, 2.4 mmol) and DMSO and purified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile). The product was suspended in ethanol/water (3:1, 4 ml), stirred overnight, filtered, washed with ethanol/water (3:1) and dried in vacuo.

Yield: 138 mg (63% of theoretical yield)

LC-MS (method 2): R _t = 1.08 min; MS (ESIpos): m/z = 549 [M+H]+

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.669 (0.85), 1.701 (1.34), 1.730 (0.71), 2.036 (0.61), 2.049 (0.74), 2.194 (0.69), 2.205 (0.66 ), 2.217 (0.67), 2.230 (0.47), 2.365 (0.50), 2.384 (0.44), 2.414 (1.11), 2.433 (1.06), 2.445 (1.10), 2.461 (0.67), 3.462 (0.75), 3.488 (0.82 ), 3.506 (0.71), 3.534 (1.04), 3.564 (0.54), 3.698 (0.67), 3.931 (16.00), 4.011 (1.49), 4.020 (1.56), 4.037 (1.35), 4.226 (1.03), 4.249 (1.41 ), 4.258 (1.28), 4.275 (0.99), 5.264 (0.50), 5.279 (1.10), 5.299 (1.12), 5.313 (0.51), 5.753 (0.81), 6.770 (1.91), 6.790 (2.17), 6.898 (1.05 ), 6.916 (2.21), 6.935 (1.29), 7.049 (0.79), 7.143 (1.04), 7.162 (1.77), 7.180 (0.85), 7.375 (1.84), 7.393 (1.72), 7.521 (0.68), 7.533 (0.71 ), 7.541 (0.70), 7.716 (2.41), 7.740 (2.55), 8.575 (2.30), 8.599 (2.15), 8.623 (3.23), 8.631 (3.13), 9.082 (1.39), 9.099 (1.37).

Table 1: Examples

Table 2a-2e: Intermediates

Experimental part - biological analyzes

Examples were tested in separate biological assays one or more times. When tested more than once, data are reported as mean values and as median values, where

• the mean, also called the arithmetic mean, is the sum of the values obtained divided by the number of iterations of the test, and

• The median is the average of a group of values when ranked in ascending or descending order. If the number of values in the dataset is odd, the median is the mean. If the number of values in the dataset is even, the median is the average of the two averages.

The examples were synthesized one or more times. When synthesizing more than once, biological assay data are reported as mean values or median values calculated using datasets obtained from testing one or more synthetic batches.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays:

In vitro assay 1: C. elegans Slo-1a - action against recombinant C. elegans cell line

Obtaining a stable cell line C. elegans CHO

The CHO cell line was obtained from ATCC, ATCC code CRL-9096. For transfection of plasmid DNA to express C. elegans Slo-1a (accession number AAL28102), CHO cells were passaged to 40% confluence before adding the transfection solution to the cell culture. The transfection solution included 300 µl of OptiMEM (Life Technologies, Nr.: 31985), 2 µl (= 6 µg) of plasmid DNA containing the C. elegans Slo 1 gene and 9 µl of FugeneHD (Promega, Nr.: E2311) and this was added to cells before incubation for 48 hours at 37°C, 5% CO ₂ . The transfection medium was changed to selection medium which contained additional G418 (2 mg/ml, Invitrogen, Nr.: 10131) and the cells were plated in a 384-well plate (300 cells/well). A few weeks later, the remaining surviving cells were tested with voltage sensitive dye (Membrane Potential Analysis Kit, Molecular Devices Nr.: R8034) for K+ channel expression. Clones of positive cells were purified by limited dilution. To do this, the clone with the highest and most reliable signal in the voltage sensitive dye assay was further subcloned (incubated) in a 384-well plate (0.7 cells/well) to obtain clonal purity. This creates a final stable CHO cell line expressing C. elegans Slo-1a.

Cell Culture Conditions

Cells were cultured at 37°C and 5% CO ₂ in MEMalpha with Gutamax I (Invitrogen, Nr.: 32571), supplemented with 10% (v/v) heat-inactivated fetal bovine serum (Invitrogen, Nr.: 10500), G418 (1 mg/ml, Invitrogen, Nr.: 10131). Cells were separated using Accutase (Sigma, Nr.: A6964).

Membrane potential measurements

Laboratory testing of compounds was performed on 384-well microtiter plates (MTPs, Greiner, Nr.: 781092). 8000 cells/well were seeded on 384-well MTP and cultured for 20-24 hours at 37°C and 5% CO ₂ . After removing the cell culture medium, the cells were washed once with thyrode (150 mM NaCl, 0.3 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.8 mM NaH ₂ PO ₄ , 5 mM glucose, 28 mM Hepes, pH 7.4), and then the voltage sensitive Membrane Potential Assay dye diluted in tyrode for 1 hour at room temperature was loaded.

After starting fluorescence measurement using FLIPR Tetra (Molecular Devices, Exc. 510-545 nm, Emm. 565-625 nm), test compounds were added followed by KCl tyrode (final assay concentration: 70 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.8 mM NaH ₂ PO ₄ , 5 mM glucose, 28 mM Hepes, pH 7.4, including voltage sensitive dye). The measurement was completed after 7 minutes.

Statistical evaluation

Data were evaluated using ActivityBase XLfit software (IDBS) to fit the curve and calculate the half maximum effective concentration (EC ₅₀ ) and are reported as negative logarithm (pE50).

For the following examples, pE ₅₀ > 6.5-7.5 was found: 14.

For the following examples, pE ₅₀ > 7.5-8.5 was found: 5, 13.

For the following examples pE ₅₀ > 8.5 was found: 1, 2, 4, 7, 10, 11, 12, 15, 16, 19, 21.

In vitro assay 2: D. immitis Slo-1a - activity against recombinant D. immitis cell line

Obtaining a stable cell line D. immitis Slo-1 CHO

The CHO cell line was obtained from ATCC, ATCC code CRL-9096. For transfection of plasmid DNA to express D. immitis Slo-1 (based on protein sequence JQ730003, hamster optimized codon), CHO cells were passaged to 40% confluence before adding the transfection solution to the cell culture. The transfection solution included 300 µl of OptiMEM (Life Technologies, Nr.: 31985), 2 µl (= 6 µg) of plasmid DNA containing the D. immitis Slo-1 gene and 9 µl of FugeneHD (Promega, Nr.: E2311), and this was added to cells before incubation for 48 hours at 37°C, 5% CO ₂ . The transfection medium was changed to selection medium which contained additional G418 (2 mg/ml, Invitrogen, Nr.: 10131) and the cells were plated in a 384-well plate (300 cells/well). A few weeks later, the remaining surviving cells were tested with voltage sensitive dye (Membrane Potential Analysis Kit, Molecular Devices Nr.: R8034) for K+ channel expression. Clones of positive cells were purified by limited dilution. For this, the clone with the highest and most reliable signal in the voltage sensitive dye assay was further subcloned (incubated) in a 384-well plate (0.7 cells/well) to obtain clonal purity. This creates the final stable CHO cell line expressing D. immitis_Slo-1.

Cell Culture Conditions

Cells were cultured at 37°C and 5% CO ₂ in MEMalpha with Gutamax I (Invitrogen, Nr.: 32571), supplemented with 10% (v/v) heat-inactivated fetal bovine serum (Invitrogen, Nr.: 10500), G418 (1 mg/ml, Invitrogen, Nr.: 10131). Cells were separated using Accutase (Sigma, Nr.: A6964).

Membrane potential measurements

Laboratory testing of compounds was performed on 384-well microtiter plates (MTPs, Greiner, Nr.: 781092). 8000 cells/well were seeded on 384-well MTP and cultured for 20-24 hours at 37°C and 5% CO ₂ . After removing the cell culture medium, the cells were washed once with thyrode (150 mM NaCl, 0.3 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.8 mM NaH ₂ PO ₄ , 5 mM glucose, 28 mM Hepes, pH 7.4), and then the voltage sensitive Membrane Potential Assay dye diluted in tyrode for 1 hour at room temperature was loaded.

After starting fluorescence measurement using FLIPR Tetra (Molecular Devices, Exc. 510-545 nm, Emm. 565-625 nm), test compounds were added followed by KCl tyrode (final assay concentration: 70 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.8 mM NaH ₂ PO ₄ , 5 mM glucose, 28 mM Hepes, pH 7.4, including voltage sensitive dye). The measurement was completed after 7 minutes.

Statistical evaluation of data

Data were evaluated using ActivityBase XLfit software (IDBS) to fit the curve and calculate the half maximum effective concentration (EC ₅₀ ) and are reported as negative logarithm (pE50).

For the following examples, pE ₅₀ > 5.3-6.5 were found: 8, 9, 13, 14, 17, 18, 19.

For the following examples, pE ₅₀ > 6.5-7.5 were found: 1, 10, 12, 15, 20.

For the following examples, pE ₅₀ > 7.5-8.5 were found: 2, 3, 4, 5, 6, 7, 16, 22.

In Vitro Assay 3: Nippostrongylus brasiliensis (NIPOBR)

Nippostrongylus brasiliensis adults were washed with physiological buffer containing 100 U/mL penicillin, 0.1 mg/mL streptomycin, and 2.5 µg/mL amphotericin B. Test compounds were dissolved in DMSO and the worms were incubated in medium to a final concentration of 10 µg/mL ( 10 ppm), respectively, 1 µg/ml (1 ppm). An aliquot of the medium was used to determine the activity of acetylcholinesterase compared to the negative control. The principle of measuring acetylcholinesterase as an indicator of anthelmintic activity is described in

Rapson et al (1986) and Rapson et al (1987).

For the following examples, activity (AChE inhibition compared to negative control) was over 80% at 10 µg/mL: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22.

For the following examples, activity (AChE inhibition compared to negative control) was over 80% at 1 µg/mL: 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 15, 16, 17 , 18, 19, 20, 21, 22.

In vitro assay 4: Dirofilaria immitis microfilariae (DIROIM L1)

≥ 250 Dirofilaria immitis microfilariae that had been freshly purged of blood was added to the wells of a microtiter plate containing growth medium and test compound in DMSO. Compounds were tested in a concentration-dependency analysis in duplicate. Larvae exposed to DMSO but not to test compounds were used as negative controls. Larvae were evaluated after 72 hours of incubation with the compound. Efficacy was defined as the reduction in motility compared to the negative control. Based on evaluation of a wide range of concentrations, concentration-response curves as well as EC ₅₀ values were calculated.

For the following examples, the EC50 was < 0.1 ppm: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22.

In vitro assay 5: Dirofilaria immitis (DIROIM L4)

10 third-stage larvae of Dirofilaria immitis that had just been isolated from their vector (intermediate host) were added to the wells of a microtiter plate containing growth medium and test compound in DMSO. Compounds were tested in a concentration-dependency analysis in duplicate. Larvae exposed to DMSO but not to test compounds were used as negative controls. Larvae were evaluated after 72 hours of incubation with the compound. During these 72 hours of incubation, most of the negative control larvae progressed to fourth instar larvae.

Efficacy was defined as the reduction in motility compared to the negative control. Based on the assessment of a wide range of concentrations, concentration-response curves as well as EC50 values were calculated.

For the following examples, the EC50 was < 0.1 ppm: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22.

In Vitro Assay 6: Cooperia curticei (COOPCU)

Solvent: dimethyl sulfoxide

To obtain a suitable preparation of the active compound, 10 mg of the active compound was dissolved in 0.5 ml of solvent, and the concentrate was dissolved with Ringer's solution to the desired concentration.

About 40 nematode larvae (Cooperia curticei) were transferred to a test tube containing a compound solution.

After 5 days, the percentage of larval mortality was measured. 100% efficiency means that all larvae are killed; 0% means no larvae are killed.

In this test, for example, the following compounds from the preparation examples showed a good activity of 90% at an application rate of 20 ppm: 1.

In this test, for example, the following compounds from the preparation examples showed a good activity of 100% at an application rate of 4 ppm: 2.

In this test, for example, the following compounds from the preparation examples showed a good activity of 90% at an application rate of 4 ppm: 1.

In this test, for example, the following compounds from the preparation examples showed a good activity of 100% at an application rate of 0.8 ppm: 2.

In this test, for example, the following compounds from the preparation examples showed a good activity of 90% at an application rate of 0.8 ppm: 1.

In Vitro Assay 7: Haemonchus contortus (HAEMCO)

Solvent: dimethyl sulfoxide

To obtain a suitable preparation of the active compound, 10 mg of the active compound was dissolved in 0.5 ml of solvent, and the concentrate was dissolved with Ringer's solution to the desired concentration.

About 40 red stomach worm (Haemonchus contortus) larvae were transferred to a test tube containing a compound solution.

After 5 days, the percentage of larval mortality was measured. 100% efficiency means all larvae are killed, 0% means no larvae are killed.

In this test, for example, the following compounds from the preparation examples showed a good activity of 90% at an application rate of 20 ppm: 2.

In this test, for example, the following compounds from the preparation examples showed a good activity of 80% at an application rate of 20 ppm: 1.

In this test, for example, the following compounds from the preparation examples showed a good activity of 90% at an application rate of 4 ppm: 2.

Composition examples

Exemplary compositions consisted of the active substance in 10% Transcutol, 10% Cremophor EL and 80% isotonic saline. First, the active substance was dissolved in Transcutol. After dissolution in Transcutol, Cremophor and isotonic saline were added. These compositions were used as working compositions in the following in vivo assay.

An example of a composition according to the present invention is the following exemplary composition F1. The active substance was then dissolved in Transcutol to form stock solution A. Then 0.100 ml of this stock solution A was taken and 0.100 ml of Cremophor EL and 0.800 ml of isotonic saline were added. The resulting liquid composition (Composition Example F1) had a volume of 1 ml.

Stock Solution A:

4.0 mg compound from example 2,

F1 composition example:

0.100 ml stock solution A,

0.100 ml Cremophor EL, and

0.800 ml isotonic saline solution.

In vivo analysis

Haemonchus contortus / Trichostrongylus colubriformis / Gerbil

Gerbils experimentally infected with Haemonchus and/or Trichostrongylus were treated once during late prepotency. Test compounds were prepared as solutions or suspensions and administered orally or intraperitoneally. The same application form was used for both applications. The volume of application was usually a maximum of 20 ml/kg. As an example, a 40 g body weight gerbil was treated with 0.200 ml of the composition of Example F1. This corresponded to a treatment of 20 mg/kg body weight.

Efficacy was defined for each group as the reduction in the number of worms in the stomach and small intestine, respectively, after opening, compared with the number of worms in the control group infected and treated with placebo.

The following examples have been tested and have activity ≥70% or higher with this treatment:

The following examples have been tested and have activity ≥80% or higher with this treatment:

Claims (129)

1. Compound of general formula (I):

wherein: A is A1 or A2,

o is 0, 1 or 2, R is selected from the group consisting of halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and cyano, R _p is selected from the group consisting of hydrogen, X is selected from the group consisting of CR ⁷ R ⁸ , O and S, Y is CR ⁷ R ⁸ or O, R ¹ is hydrogen or C ₁ -C ₄ -alkyl, R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R ³ is hydrogen, R ⁴ is selected from the group consisting of hydrogen, halogen, -OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R ⁵ is selected from the group consisting of hydrogen, R ⁶ is selected from the group consisting of hydrogen, R ⁷ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, R ⁸ is selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl, R ¹⁰ is selected from the group consisting of hydrogen, R ¹¹ is hydrogen, Q is 2,3,5-trifluorophenyl, where is the compound formula

excluded; or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 2. Connection according to claim 1, where: A is selected from the group consisting of

preferably

R ¹ is hydrogen or methyl, R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R ³ is hydrogen, R ⁴ is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl, methoxy, trifluoromethyl and trifluoromethoxy, preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy, R ⁵ is selected from the group consisting of hydrogen, R ⁶ is selected from the group consisting of hydrogen, Q is 2,3,5-trifluorophenyl, where is the compound formula

excluded; or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 3. Connection according to claim 1, where: A is selected from the group consisting of

preferably

R ¹ is hydrogen or methyl, R ² is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R ³ is hydrogen, R ⁴ is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy, isopropoxy and trifluoromethyl, preferably chlorine, fluorine, methoxy and isopropoxy, R ⁵ is selected from the group consisting of hydrogen, R ⁶ is selected from the group consisting of hydrogen, Q is 2,3,5-trifluorophenyl, where is the compound formula

excluded; or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 4. The connection according to any one of paragraphs. 1-3 where: R ² is tetrahydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl, and their stereoisomer, tautomer, or pharmaceutically or veterinarily acceptable salt, or a mixture thereof. 5. Connection according to any one of paragraphs. 1-3 where: R ² is 3,6-dihydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl, or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 6. The connection according to any one of paragraphs. 1-3 where: R ² is ethyl, R ⁴ is selected from the group consisting of hydrogen, halogen, OH, cyano, C ₁ -C ₄ -alkyl, C ₁ -C ₄ haloalkyl having 1 to 5 halogen atoms, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy having from 1 to 5 halogen atoms, preferably hydrogen, halogen and C ₁ -C ₄ -alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, Q is 2,3,5-trifluorophenyl, provided that R ⁴ is not hydrogen when A is

or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 7. Connection according to any one of paragraphs. 1-3 where: R ² is 3-fluoroazetidin-1-yl, Q is 2,3,5-trifluorophenyl, or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 8. The method of obtaining compounds of General formula (I) according to any one of paragraphs. 1-7, said method comprising the step of introducing an intermediate compound of general formula 1N:

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, in reaction with a compound of general formula 1F:

in which R ² is 3-fluoroazetidine, thus obtaining a compound of general formula (I):

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7 and R ² is 3-fluoroazetidine, or the step of introducing an intermediate compound of general formula 1T:

in which A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, and in which Hal is a halogen, in particular chlorine, bromine or iodine, with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

in reaction with a compound of general formula 1H:

in which Q is 2,3,5-trifluorophenyl and each R individually can be H or Me or both R are pinacolate, thus obtaining a compound of general formula (I):

in which A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, or the step of introducing an intermediate compound of general formula 1W:

in which Q, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

in reaction with a compound of general formula 1M:

in which R ¹ and A have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, thus obtaining a compound of general formula (I):

in which A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, or the step of introducing an intermediate compound of general formula 1N:

in which Q, A, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, in reaction with a compound of general formula 2A:

in which R ² represents ethyl or 3,6-dihydro-2H-pyran-4-yl, with the proviso that R ⁴ is not hydrogen, when R ² is ethyl, and when A is

Met is magnesium or zinc and X is chlorine, bromine or iodine, thus obtaining a compound of general formula (I):

in which A, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7 and R ² is ethyl or 3,6-dihydro-2H-pyran-4-yl, with the proviso that R ⁴ is not hydrogen when R ² is ethyl and when A is

9. Compound of general formula (II):

wherein: R ² is OH or is as defined for the compound of general formula (I) according to any one of paragraphs. 1-7, R ³ , R ⁴ , R ⁵ , R ⁶ and Q have the meanings as defined for the compounds of General formula (I) according to any one of paragraphs. 1-7, and R ^A is H or C ₁ -C ₄ -alkyl, or a stereoisomer, tautomer or pharmaceutically or veterinarily acceptable salt thereof, or a mixture thereof. 10. Pharmaceutical composition for the control, treatment and/or prevention of helminth infection, containing a compound of General formula (I) according to any one of paragraphs. 1-7 in an effective amount and one or more pharmaceutically acceptable excipients. 11. The use of compounds of General formula (I) according to any one of paragraphs. 1-7 for the control, treatment and/or prevention of a disease, wherein the disease is a helminth infection. 12. The use of compounds of General formula (I) according to any one of paragraphs. 1-7 for the preparation of a medicament for the control, treatment and/or prevention of a disease, wherein the disease is a helminth infection. 13. A method for controlling helminthic infections in humans and/or animals by introducing an anthelmintic effective amount of at least one compound of general formula (I) according to any one of paragraphs. 1-7 to a person or animal in need of it.