New quinoline derivatives

Abstract

The present invention relates to novel quinoline compounds of the general formula (I) 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Q are defined herein), processes for preparing said compounds, intermediate compounds useful in preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds, as the sole agent or in combination with other active ingredients, for the manufacture of a pharmaceutical composition for the treatment, control and / or prevention of diseases, particularly helminth infections. TIFF2024535759000096.tif33150

Description

[Technical field]

[0001] The present invention relates to novel quinoline derivatives of general formula (I) as described and defined herein, to processes for the preparation of said compounds, to intermediate compounds useful for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds, as well as to the use of said compounds for the manufacture of pharmaceutical compositions for the control, treatment and / or prevention of diseases, in particular infections by helminths, more particularly infections by gastrointestinal and extraintestinal nematodes, in animals and humans, formulations and methods containing such compounds as single agents or in combination with other active ingredients, for the control, treatment and / or prevention of infections by helminths, more particularly infections by gastrointestinal and extraintestinal nematodes, in animals and humans. [Background technology]

[0002] background The development of resistance to all commercial anthelmintics appears to be an increasing problem in veterinary medicine. The widespread use of anthelmintics to manage nematode control has significantly selected for highly resistant worm populations. Thus, the spread of resistance to all anthelmintic classes threatens effective roundworm control in cattle, goats, sheep and horses. Furthermore, the current successful prevention of canine heartworm disease, which relies solely on the use of macrocyclic lactones, is at risk as loss of efficacy for multiple macrocyclic lactones has been reported for some areas of the United States, particularly those with high heartworm burden for infection. Finally, the presence of macrocyclic lactone resistance was confirmed in vivo from experimental infection studies with Dirofilaria immitis larvae from cases of suspected loss of efficacy in the Lower Mississippi Delta.

[0003] Although resistance of human helminths to anthelmintics appears to be rare at present, the prevalence of anthelmintic resistance in veterinary medicine as described above needs to be considered in the treatment of human helminthiasis as well. Continuous low-dose treatment of filariasis may result in highly resistant genotypes, and resistance has already been reported for some anthelmintics (e.g., praziquantel, benzimidazoles, niclosamide).

[0004] Therefore, resistance-breaking anthelmintics with new molecular mechanisms of action are urgently needed.

[0005] The object of the present invention is to provide compounds which can be used as anthelmintics in medicine, especially in the veterinary field, for the control, treatment and / or prevention of helminth infections in animals and humans, having sufficient or improved anthelmintic activity against a wide range of helminths, especially at relatively low doses, preferably without any adverse toxic effects on the treated organisms.

[0006] Certain quinoline carboxamides are described in JP2008-214323A as agents suitable for the treatment and / or prevention of skin diseases such as acne vulgaris, dermatitis, and the like.

[0007] WO2017 / 103851A1 discloses quinoline-3-carboxamides as H-PGDS inhibitors, useful for treating atherosclerosis, psoriasis, sinusitis, and Duchenne muscular dystrophy.

[0008] WO2018 / 087036A1 and WO2019 / 215182A1 disclose quinoline-3-carboxamides as anthelmintics in the medical, especially veterinary, field.

[0009] However, the state of the art does not describe the novel quinoline derivatives of general formula (I) of the present invention as described and defined herein.

[0010] It has now been found that the compounds according to the invention have surprising and advantageous properties, which constitute the basis of the present invention.

[0011] In particular, the compounds of the present invention have been surprisingly found to effectively interact with the Slo-1 calcium-dependent potassium channel of nematodes. This interaction is characterized by achieving paralysis / inhibition of, among others, gastrointestinal nematodes, free-living nematodes, and filariasis, and these data are shown in the biological experiments section. Thus, the compounds of the present invention can be used as anthelmintics for the control, treatment and / or prevention of gastrointestinal and extraintestinal helminth infections, especially gastrointestinal and extraintestinal infections by nematodes, including filariasis. The novel compounds of the present invention preferably have high chemical stability. In addition, it is desirable that the compounds of the present invention have suitable metabolic stability. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] JP 2008-214323 A [Patent Document 2] International Publication No. 2017 / 103851 [Patent Document 3] International Publication No. 2018 / 087036 [Patent Document 4] International Publication No. 2019 / 215182 Summary of the Invention

[0013] Description of the invention According to a first aspect, the present invention provides a compound of general formula (I): [ka] [During the ceremony: A is A1 or A2, [ka] o is 0, 1, 2, 3 or 4; R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl, -S(O)-C1-C4-halogenoalkyl and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X and Y are CR 7 R 8 , O, S, and N.R. 9 wherein at least one of X and Y is independently selected from the group consisting of 7 R 8 ), or X and Y together represent -C(O)-O- and -C(O)-NR 9 -, -S(O)-NR 9 -,-SO2-NR 9 - and -SO2-O-, R 1is hydrogen, cyano, -CHO, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl, cyano-C1-C4-alkyl, -NH-C1-C4-alkyl, - N(C1-C4-alkyl)2, NH2-C1-C4-alkyl-, C1-C4-alkyl-NH-C1-C4-alkyl-, (C1-C4-alkyl)2N-C1-C4-alkyl-, C1-C4-alkyl-C(O)-, C1-C4-halogenoalkyl-C(O)- having 1 to 5 halogen atoms, C1-C4-alkoxy-C(O)-, benzyloxy-C(O)-, C1-C4-alkoxy-C1-C4-alkyl-C(O)-, -SO2-C1-C4-alkyl and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; phenyl-C1-C4-alkyl, which may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; Heterocyclyl-C1-C4-alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is selected from halogen, -OH, -oxo, -NO2, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1 -C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms). is selected from the group consisting of R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl , 1,1-dioxido-1,2-thiazetidin-4-yl, 1-oxido-1,2-thiazetidin-3-yl, 1-oxido-1,2-thiazetidin-4-yl, 2-oxido-1,2-oxathietan-3-yl, 2-oxido-1,2-oxathietan-4-yl, 2,2-dioxido-1,2-oxathietan-3-yl, 2,2-dioxido-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3-yl yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -Iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo-3-(hydroxyimino)cyclobutyl, 2,2-diiodo-3-(hydroxyimino)cyclobutyl, 5- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl (each of which is selected from the group consisting of halogen, -OH, -oxo, -NO2, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl) )2, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms) is selected from the group consisting of R 3 is hydrogen or C1-C4-alkyl, R 4is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C1-C4-alkyl-C(O)-, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C1-C4-alkyl-C(O)-, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, R 6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C1-C4-alkyl-C(O)-, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, R 7 is selected from the group consisting of hydrogen, -OH, fluorine, C1-C4-alkyl and C1-C4-alkoxy, R 8 is selected from the group consisting of hydrogen, -OH, fluorine, C1-C4-alkyl and C1-C4-alkoxy, Or, R7 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- to 6-membered ring selected from the group consisting of C3-C6-cycloalkyl and 3- to 6-membered heterocycloalkyl, R 9 is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms and C1-C4-alkoxy, R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, R 11 is selected from the group consisting of hydrogen, C1-C4-alkyl and C1-C4-alkoxy, Or, R 10 and R 11 form together with the carbon atom to which they are attached a 3- to 6-membered ring selected from the group consisting of C3-C6-cycloalkyl and 3- to 6-membered heterocycloalkyl, Q represents a phenyl having 1 to 5 halogen atoms; where Y is O, S or NR 9 If R 7 , R 8 , R 10 and R 11 is not -OH or C1-C4-alkoxy, and X is O, S or NR 9 If R 7 and R 8 is not -OH or C1-C4-alkoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0014] definition The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced with a selection from a specified group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances. Combinations of substituents and / or variables are permitted.

[0015] The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, an optionally substituted group can be substituted with as many optional substituents as it can accommodate by replacing hydrogen atoms on any available carbon or nitrogen atom with non-hydrogen substituents. In general, if present, the number of optional substituents can be 1, 2, 3, 4 or 5, particularly 1, 2 or 3.

[0016] As used herein, the term "one or more" means, for example, "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, even more in particular 1 or 2" in the definition of substituents of a compound of general formula (I) of the present invention.

[0017] As used herein, an oxo substituent represents an oxygen atom that is attached via a double bond to a carbon or sulfur atom.

[0018] The term "ring substituent" means a substituent attached to an aromatic or non-aromatic ring that replaces an available hydrogen atom on the ring.

[0019] When a composite substituent is composed of multiple moieties, for example in (C1-C4-alkoxy)-(C1-C4-alkyl)-, the position of a given moiety can be at any suitable position of said composite substituent, i.e. the C1-C4-alkoxy moiety can be bonded to any atom of the C1-C4-alkyl moiety of said (C1-C4-alkoxy)-(C1-C4-alkyl) group. A hyphen at the beginning or end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. When a ring containing carbon atoms and optionally one or more heteroatoms such as nitrogen, oxygen or sulfur atoms is substituted with, for example, a substituent, said substituent can be bonded to any suitable position of said ring and can be bonded to any suitable carbon atom and / or suitable heteroatom.

[0020] As used herein, the position at which each subcomponent is linked to the remainder of the molecule may be indicated in the drawn structures by a hash symbol (#) or a dashed line in the substituent.

[0021] As used herein, the term "comprising" includes "consisting of."

[0022] Within this specification, when any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere within this specification.

[0023] Terms referred to in this text have the following meanings: The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

[0024] The term "C1-C6-alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C1-C4-alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3 or 4 carbon atoms, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl group, or further structural isomers thereof. In particular, said group is one having 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), such as a methyl, ethyl, n-propyl or isopropyl group.

[0025] The term "C1-C4-hydroxyalkyl" is as defined above for the term "C1-C4-alkyl" and means a linear or branched, saturated monovalent hydrocarbon radical in which one hydrogen atom is replaced by a hydroxy group, such as, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl groups.

[0026] The term "-NH(C1-C4-alkyl)" or "-N(C1-C4-alkyl)2" means a linear or branched, saturated monovalent radical, as the term "C1-C4-alkyl" is defined above, such as methylamino, ethylamino, n-propylamino, isopropylamino, N,N-dimethylamino, N-methyl-N-ethylamino or N,N-diethylamino.

[0027] The term "-S-C1-C4-alkyl", "-S(O)-C1-C4-alkyl" or "-SO2-C1-C4-alkyl" is as defined above for the term "C1-C4-alkyl" and means a linear or branched saturated group, such as, for example, a methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl or tert-butylsulfanyl group, or a methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl group, or a methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl or tert-butylsulfonyl group.

[0028] The term "C1-C4-halogenoalkyl" refers to a linear or branched, saturated monovalent hydrocarbon radical, in which the term "C1-C4-alkyl" is defined above, and in which one or more hydrogen atoms are replaced with halogen atoms, either identically or differently. In particular, said halogen atoms are fluorine atoms. More particularly, all said halogen atoms are fluorine atoms ("C1-C4-fluoroalkyl"). Said C1-C4-halogenoalkyl radicals are, 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.

[0029] The term "C1-C4-alkoxy", as the term "C1-C4-alkyl" is defined above, means a linear or branched, saturated, monovalent radical of the formula (C1-C4-alkyl)-O-, such as, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy radical, or further structural variants thereof.

[0030] The term "C1-C4-halogenoalkoxy" refers to a linear or branched, saturated monovalent C1-C4-alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by identical or different halogen atoms. In particular, said halogen atoms are fluorine atoms. Said C1-C4-halogenoalkoxy groups are, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

[0031] The term "C2-C4-alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one double bond and having 2, 3 or 4 carbon atoms. The C2-C4-alkenyl radical is, for example, ethenyl (or "vinyl"), prop-2-en-1-yl (or "allyl"), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, prop-1-en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl or 1-methylprop-1-enyl radical. In particular, the radical is allyl.

[0032] The term "C2-C4-alkynyl" refers to a straight-chain monovalent hydrocarbon radical containing one triple bond and containing 2, 3 or 4 carbon atoms. The C2-C4-alkynyl radical is, for example, an ethynyl, prop-1-ynyl, prop-2-ynyl (or "propargyl"), but-1-ynyl, but-2-ynyl, but-3-ynyl or 1-methylprop-2-ynyl radical. In particular, the alkynyl radical is prop-1-ynyl or prop-2-ynyl.

[0033] The term "C3-C6-cycloalkyl" refers to a saturated, monovalent, monocyclic hydrocarbon ring ("C3-C6-cycloalkyl") containing 3, 4, 5 or 6 carbon atoms. The C3-C6-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

[0034] The term "C3-C6-halogenocycloalkyl" refers to a saturated monovalent monocyclic hydrocarbon ring, in which the term "C3-C6-cycloalkyl" is as defined above, and in which one or more hydrogen atoms are replaced with halogen atoms, either the same or different. In particular, said halogen atoms are fluorine or chlorine atoms. The C3-C6-halogenocycloalkyl group is, for example, a monocyclic hydrocarbon ring substituted with one or two fluorine or chlorine atoms, such as 1-fluoro-cyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-chlorocyclopropyl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 2-fluoro-2-chlorocyclopropyl and 2-fluoro-3-chlorocyclopropyl groups.

[0035] The term "benzo-C5-C6-cycloalkyl" refers to a monovalent, bicyclic hydrocarbon ring in which a saturated, monovalent, monocyclic hydrocarbon ring containing 5 or 6 carbon atoms ("C5-C6-cycloalkyl") is fused to a phenyl ring. The benzo-C5-C6-cycloalkyl group is, for example, a bicyclic hydrocarbon ring, such as an indane (i.e., 2,3-dihydro-1H-indene) or tetralin (i.e., 1,2,3,4-tetrahydronaphthalene) group.

[0036] The term "spirocycloalkyl" refers to a saturated monovalent bicyclic hydrocarbon group in which two rings share one common ring carbon atom, said bicyclic hydrocarbon group containing 5, 6, 7, 8, 9, 10 or 11 carbon atoms, said spirocycloalkyl group being capable of bonding to the remainder of the molecule through any one of the carbon atoms except the spiro carbon atom. The 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.

[0037] The term "heterocycloalkyl" means a mono- or bicyclic, saturated or partially saturated heterocycle having a total of 4, 5, 6, 7, 8, 9 or 10 ring atoms ("4- to 10-membered heterocycloalkyl" groups), in particular 4, 5 or 6 ring atoms ("4- to 6-membered heterocycloalkyl" groups), which contains 1 or 2 identical or different ring heteroatoms from the N, O and S series, and wherein said heterocycloalkyl group can be attached to the remainder of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

[0038] The heterocycloalkyl group may be, but is not limited to, a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, oxolanyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-dioxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl or 1,2,4-triazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, oxanyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinyl, for example; or a 7-membered ring, such as 1,4-diazepanyl. or 1,4-oxazepanyl, for example; or a bicyclic 7-membered ring, for example 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl or 6-oxa-3-azabicyclo[3.1.1]heptane, for example; a bicyclic 8-membered ring, for example 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-dihydro-indole, 3,7-dioxa-9-azabicyclo[3.3.1]nonane or 3,9-dioxa-7-azabicyclo[3.3.1]nonane; or a bicyclic 10-membered ring, such as decahydroquinoline or 3,4-dihydroisoquinoline.

[0039] The term "heterospirocycloalkyl" means a bicyclic, saturated heterocycle having a total of 6, 7, 8, 9, 10 or 11 ring atoms, where two rings share one common ring carbon atom, and "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the set of N, O, S; said heterospirocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms, excluding the spiro carbon atom, or through the nitrogen atom, if present.

[0040] The heterospiroalkyl group may be, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, oxazaspiro[2.5]octyl, azaaspiro[4.5]decyl, oxazaspiro[5.5]undecyl. aryl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds, 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]-.

[0041] The term "6- or 10-membered aryl" means a monovalent, monocyclic or bicyclic aromatic ring having 6 or 10 carbon ring atoms, such as a phenyl or naphthyl group.

[0042] The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 9 or 10 ring atoms ("5-10 membered heteroaryl" groups), in particular 5 or 6 ring atoms ("5-6 membered heteroaryl" groups), which contains at least one ring heteroatom and may optionally contain 1, 2 or 3 further ring heteroatoms from the series: N, O and / or S, bonded via a ring carbon atom or optionally bonded via a ring nitrogen atom (where permitted by valence).

[0043] The heteroaryl group can be a 5-membered heteroaryl group, such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; or a 6-membered heteroaryl group, such as pyridinyl, dihydropyridinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, or triazinyl.

[0044] The term "heterocyclyl" refers to a heterocycle selected from the group consisting of heterocycloalkyl and heteroaryl. In particular, the term "4- to 6-membered heterocyclyl" refers to a heterocycle selected from the group consisting of 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl.

[0045] In general, unless otherwise stated, a heteroaryl or heteroarylene group includes all possible structural isomeric forms thereof, such as tautomers and positional isomers with respect to the point of attachment to the remainder of the molecule. Thus, in 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-yl and thien-3-yl.

[0046] The term "C1-C4" as used herein means an alkyl group having a finite number of carbon atoms from 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms, for example in the definition of "C1-C4-alkyl", "C1-C4-halogenoalkyl", "C1-C4-hydroxyalkyl", "C1-C4-alkoxy" or "C1-C4-halogenoalkoxy".

[0047] Furthermore, as used herein, the term "C3-C6" refers to a cycloalkyl group having a finite number of carbon atoms from 3 to 6, i.e., 3, 4, 5 or 6 carbon atoms, as used herein, for example in the definition of "C3-C6-cycloalkyl" or "C3-C6-halogenocycloalkyl".

[0048] When a range of values ​​is given, the range includes each value and sub-range within the range.

[0049] for example: "C1-C4" includes C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3, and C3-C4; "C2-C6" includes C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C3-C4" includes C3, C4, and C3-C4; "C3-C 10 ” is C3, C4, C5, C6, C7, C8, C9, C 10 , C3-C 10 , C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C 10 , C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9 and C9-C 10 Includes; "C3-C8" includes C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C3-C6" includes C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C4-C8" includes C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C4-C7" includes C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6 and C6-C7; "C4-C6" includes C4, C5, C6, C4-C6, C4-C5 and C5-C6; "C5-C 10 ” is C5, C6, C7, C8, C9, C 10 , C5-C 10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9 and C9-C 10 Includes; "C6-C 10 " is C6, C7, C8, C9, C 10 , C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9 and C9-C 10 Includes:

[0050] As used herein, the term "leaving group" refers to an atom or group of atoms that, together with the bonding electrons, is displaced in a chemical reaction as a stable species. In particular, such leaving groups are selected from the group including: halides, in particular fluorides, chlorides, bromides or iodides, (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.

[0051] As used herein, the term "saponification" refers to the hydrolysis of an ester carried out in the presence of an aqueous solution of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures thereof, which may or may not be followed by a decarboxylation reaction.

[0052] The compounds of formula (I) may exist as isotopic variations. Thus, the present invention includes one or more isotopic variations of the compounds of formula (I), particularly deuterium-containing compounds of formula (I).

[0053] The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits an unnatural proportion of one or more isotopes that constitute such compound.

[0054] The term "isotopic variant of a compound of general formula (I)" is defined as a compound of general formula (I) that exhibits unnatural proportions of one or more isotopes that constitute such compound.

[0055] The expression "unnatural proportion" should be understood to mean that the proportion of such isotope is higher than its natural abundance. The natural abundance of an isotope as applied in this context is described in "Isotopic Compositions of Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

[0056] Such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example: 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I.

[0057] For the treatment and / or prevention of the disorders specified herein, isotopic variants of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). 3 H or 14 Isotopic variations of compounds of general formula (I) incorporating one or more radioactive isotopes, such as C, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred due to their ease of incorporation and detectability. 18 F or 11 Positron-emitting isotopes, such as C, may be incorporated into the compounds of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13 C-containing compounds can be used for mass spectrometry analysis in the context of preclinical or clinical trials.

[0058] Isotopic variants of compounds of general formula (I) can generally be prepared by replacing a reagent with an isotopic variant of said reagent, preferably a deuterium-containing reagent, by methods known to those skilled in the art (e.g., those described in the schemes and / or examples herein). Depending on the desired site of deuteration, deuterium from DO can be incorporated directly into the compound, or into a reagent effective for synthesizing such a compound, in some cases. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and catalytic deuteration of acetylenic bonds are rapid routes for the incorporation of deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange hydrogen in hydrocarbon-containing functional groups for deuterium. A variety of deuterated 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, Mass., USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0059] 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 with one or more deuterium atoms, and the abundance of deuterium at each deuteration position of the compound of general formula (I) is higher than the natural abundance of deuterium (about 0.015%). In particular, in the deuterium-containing compound of general formula (I), the abundance of deuterium at each deuteration position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, and more preferably higher than 98% or 99% at that position. It is understood that the abundance of deuterium at each deuteration position is independent of the abundance of deuterium at other deuteration positions.

[0060] The selective incorporation of one or more deuterium atoms into compounds of general formula (I) can alter the physicochemical properties (e.g., acidity [CL Perrin et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or metabolic profile of the molecule and can change the ratio of metabolites to the parent compound or the amount of metabolites formed. Such changes can provide certain therapeutic advantages and therefore may be preferred in some situations. A slowing of the rate of metabolism and metabolic switching (resulting in altered ratios of metabolites) has been reported (AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of deuterium-containing compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and enhances the formation of desirable metabolites (e.g., Nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to decrease 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 could result in lower side effects and enhanced efficacy, depending on the pharmacokinetic / pharmacodynamic relationship of the particular compound. Indiplon (AJ Morales et al., Abstract 285, The 15 thNorth American Meeting of International Society of Xenobiotics, San Diego, CA, October 12-16, 2008), ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208), and odanacatib (K. Kassahun et al., WO2012 / 112363) are examples of this deuteration effect. Still other cases have been reported where a decrease in metabolic rate results in increased exposure of the drug without altering the rate of systemic clearance (e.g., 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 that exhibit this effect may have reduced dosage requirements (e.g., fewer administrations or lower doses to achieve the desired effect) and / or may result in a lower metabolic burden.

[0061] A compound of general formula (I) may have multiple potential attack sites for metabolism. In order to optimize the above effects on physicochemical properties and metabolic profiles, a deuterium-containing compound of general formula (I) can be selected that has a specific pattern of one or more deuterium-hydrogen exchanges. In particular, the deuterium atoms of a deuterium-containing compound of general formula (I) are bonded to carbon atoms and / or to the cytochrome P of the compound of general formula (I), for example. 450 It is located in a position that is an attack site for metabolic enzymes such as

[0062] In this specification, when plural forms of words such as compounds, salts, polymorphs, hydrates, solvates, etc. are used, this is understood to also mean a single compound, salt, polymorph, stereoisomer, hydrate, solvate, etc.

[0063] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0064] The compounds of the present invention may contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. The asymmetric carbon atoms may be in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In certain cases, asymmetry may also exist due to restricted rotation around a given bond, for example, the central bond adjacent to two substituted aromatic rings in a particular compound. In certain cases, asymmetry may also exist due to restricted rotation around a double bond, or due to ring structures in which bond rotation is restricted or prevented. These geometric isomers may be designated as cis- or trans-isomers, or as (E)- and (Z)-isomers.

[0065] Preferred compounds are those which produce the more desirable biological activity. Also included within the scope of the present invention are separated, pure or partially purified structural isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0066] The preferred stereoisomer is one which results in the more desired biological activity. The purification and separation of such materials can be accomplished by standard techniques known in the art.

[0067] Optical isomers can be obtained by resolving racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts or the formation of covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers based on their physical and / or chemical differences by methods known in the art, for example, chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomeric salts. Different methods for the separation of optical isomers include the use of chiral chromatography (e.g., chiral HPLC columns) with or without conventional derivatization, optimally selected to maximize the separation of the enantiomers. Suitable chiral HPLC columns using chiral phases are manufactured by Daicel (e.g., Chiracel OD and Chiracel OJ, among many others), and are all routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of this invention can also be obtained by chiral syntheses utilizing optically active starting materials.

[0068] For the purpose of restricting different types of stereoisomers to one another, see IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0069] The present invention includes all possible stereoisomers of the compounds of the present invention, either as a single stereoisomer or as any mixture of said stereoisomers, e.g., (R)- or (S)-stereoisomers, (E)- or (Z)-isomers, cis- or trans-isomers, in any ratio. Isolation of a single stereoisomer of a compound of the present invention, e.g., a single enantiomer or a single diastereomer, can be achieved by any suitable state-of-the-art method, such as, for example, chromatography, in particular chiral chromatography.

[0070] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers, in any ratio.

[0071] Additionally, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidized, and the present invention encompasses all such possible N-oxides.

[0072] The present invention also relates to useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, particularly pharma- ceutically acceptable salts, and / or coprecipitates.

[0073] The compounds of the present invention can exist as hydrates or solvates, where the compounds of the present invention contain polar solvents, particularly water, methanol or ethanol, for example as structural elements of the crystal lattice of the compounds. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, for example, hydrates, hemi-, semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc., are possible solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

[0074] Furthermore, the compounds of the invention can exist in free form, for example as a free base or as a free acid, or as a zwitterion, or in the form of a salt, which can be any salt, organic or inorganic addition salt, in particular any pharma- ceutically acceptable organic or inorganic addition salt, which is conventionally used in pharmacology, or which is used, for example, to isolate or purify the compounds of the invention.

[0075] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0076] Suitable pharma- ceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of compounds of the invention having, for example, a sufficiently basic nitrogen atom in the chain or ring, for example acid addition salts with inorganic acids or "mineral acids", for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid, for example acid addition salts with organic acids, for example formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, and acid addition salts with nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0077] Further suitable pharma- ceutically acceptable salts of the compounds of the invention which are sufficiently acidic include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium, magnesium or strontium salts, or aluminum or zinc salts, or ammonia or organic primary, secondary or tertiary amines having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylethylamine, N-methylmorpholine ... Ammonium salts derived from phosphorus, 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 salts with quaternary ammonium ions having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

[0078] Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared via any of a number of known methods by reacting the compounds with a suitable inorganic or organic acid. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with a suitable base via a variety of known methods.

[0079] The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of said salts, in any proportion.

[0080] When compounds are referred to herein, particularly in the experimental part, for the synthesis of intermediates and examples of the present invention in the form of salts with corresponding bases or acids, the exact stoichiometry of said salt forms obtained by the respective preparation and / or purification processes is in most cases unknown.

[0081] Unless otherwise stated, the term "hydrochloride", "trifluoroacetate", "sodium salt", or "xHCl", "xCF3COOH", "xNa + " to a salt-related chemical name or structural formula, for example, to indicate a salt form, the stoichiometry of which is not specified.

[0082] This also applies if the described preparation and / or purification processes result in the synthesis intermediates or example compounds or salts thereof being obtained as solvates, such as hydrates, having unknown stoichiometry (if defined).

[0083] Furthermore, 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 two or more polymorphs, in any ratio.

[0084] Furthermore, the present invention also includes prodrugs of the compounds according to the present invention. The term "prodrug" refers to compounds which may themselves be biologically active or inactive, but which are converted (e.g., metabolically or hydrolytically) into the compounds according to the present invention during their residence time in the body.

[0085] According to a second embodiment of the first aspect, the present invention provides a compound according to the above general formula (I): A is A1 or A2, [ka] o is 0, 1, 2, 3 or 4; R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl, -S(O)-C1-C4-halogenoalkyl and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X and Y are CR 7 R 8 , O, S, and N.R. 9 wherein at least one of X and Y is independently selected from the group consisting of 7 R 8 ), or X and Y together represent -C(O)-O- and -C(O)-NR 9 -, -S(O)-NR 9 -,-SO2-NR 9 - and -SO2-O-, R 1is hydrogen, cyano, -CHO, -OH, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl, cyano-C1-C4-alkyl, -NH-C1-C4-alkyl, - N(C1-C4-alkyl)2, NH2-C1-C4-alkyl-, C1-C4-alkyl-NH-C1-C4-alkyl-, (C1-C4-alkyl)2N-C1-C4-alkyl-, C1-C4-alkyl-C(O)-, C1-C4-halogenoalkyl-C(O)- having 1 to 5 halogen atoms, C1-C4-alkoxy-C(O)-, benzyloxy-C(O)-, C1-C4-alkoxy-C1-C4-alkyl-C(O)-, -SO2-C1-C4-alkyl and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms; phenyl-C1-C4-alkyl (which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of halogen, -OH, -NO2, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms); Heterocyclyl-C1-C4-alkyl, wherein the heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl, each of which is selected from halogen, -OH, -NO2, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl ), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -S-C1-C4-halogenoalkyl having 1 to 5 halogen atoms, -S(O)-C1-C4-halogenoalkyl having 1 to 5 halogen atoms and -SO2-C1-C4-halogenoalkyl having 1 to 5 halogen atoms). is selected from the group consisting of R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl , 1,1-dioxido-1,2-thiazetidin-4-yl, 1-oxido-1,2-thiazetidin-3-yl, 1-oxido-1,2-thiazetidin-4-yl, 2-oxido-1,2-oxathietan-3-yl, 2-oxido-1,2-oxathietan-4-yl, 2,2-dioxido-1,2-oxathietan-3-yl, 2,2-dioxido-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3-yl yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -Iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-Diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo 2,2-diiodo-3-(hydroxyimino)cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydrofuran-3-yl, 4,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 2,5-dihydrofuran-2-yl, 2,3-dihydrofuran-2-yl, furan-3-yl, furan-2-yl, tetrahydrothio Thiophen-3-yl, tetrahydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,3-dihydrothiophen-3-yl, 4,5-dihydrothiophen-3-yl, 4,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-2-yl, 2,3-dihydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-2-yl Din-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-4-yl, 3,4-dihydro-2H-pyrrol-3-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2H-pyrrol-5-yl, 3H-pyrrol-2-yl, 2H-pyrrol-4-yl, 1H-pyrrol-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 4-alkyl-3-oxopiperazin-1-yl, 4-alkyl-2-oxopiperazin-1-yl (wherein said alkyl is C1-C6-alkyl), 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, R 3 is hydrogen or C1-C4-alkyl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, R 6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, R 7 is selected from the group consisting of hydrogen, -OH, fluorine, C1-C4-alkyl and C1-C4-alkoxy, R8 is selected from the group consisting of hydrogen, -OH, fluorine, C1-C4-alkyl and C1-C4-alkoxy, Or, R 7 and R 8 together form an oxo group (=O), R 9 is selected from the group consisting of hydrogen, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms and C1-C4-alkoxy, R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, R 11 is selected from the group consisting of hydrogen, C1-C4-alkyl and C1-C4-alkoxy, Q represents a phenyl having 1 to 5 halogen atoms; where Y is O, S or NR 9 If R 7 , R 8 , R 10 and R 11 is not -OH or C1-C4-alkoxy, and X is O, S or NR 9 If R 7 and R 8 is not -OH or C1-C4-alkoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0086] According to a third embodiment of the first aspect, the present invention provides a compound according to the above general formula (I): A is A1 or A2, [ka] o is 0, 1 or 2; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X and Y are CR 7 R 8 , O, S, and N.R. 9 wherein at least one of X and Y is independently selected from the group consisting of 7 R 8 ), R 1 is selected from the group consisting of hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C4-alkenyl, C3-C4-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl-C1-C3-alkyl, cyano-C1-C4-alkyl, R 2 are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-di ... cyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3is hydrogen or C1-C4-alkyl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, R 6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, Or, R 7 and R 8 together form an oxo group (=O), R 9 is hydrogen or C1-C4-alkyl, R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, R 11 is hydrogen, Q represents a phenyl having 1 to 5 substituents independently selected from fluorine, chlorine, or bromine; where Y is O, S or NR9 If R 10 is not -OH or C1-C4-alkoxy] and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0087] According to a fourth embodiment of the first aspect, the present invention provides a compound according to the above general formula (I): A is A1 or A2, [ka] o is 0, 1 or 2; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy and cyano; R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X is CR 7 R 8 , O, S, and N.R. 9 is selected from the group consisting of Y is CR 7 R 8 or O, R 1 is hydrogen or C1-C4-alkyl, R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3 is hydrogen or C1-C4-alkyl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, halogen, -OH, -NH2, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, R 6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, R7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, or R 7 and R 8 together form an oxo group (=O), R 9 is hydrogen or C1-C4-alkyl, R 10 is selected from the group consisting of hydrogen, -OH and C1-C4-alkyl, R 11 is hydrogen, Q represents a phenyl having two or three substituents independently selected from fluorine, chlorine, or bromine; where Y is O, then R 10 is not -OH. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0088] According to a fifth embodiment of the first aspect, the present invention provides a compound according to the above general formula (I): A is, [ka]

[0089] TIFF2024535759000008.tif87166, R 1 is hydrogen or methyl, R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3 is hydrogen or methyl, R 4 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl, methoxy, isopropoxy, trifluoromethyl and trifluoromethoxy, preferably hydrogen, fluorine, chlorine and C1-C4-alkoxy, more preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, -NH2, cyano, methyl, methoxy, trifluoromethoxy, and trifluoromethyl; R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy; Q is selected from the group consisting of 2,3-dichlorophenyl, 3,5-dichlorophenyl, and 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0090] According to a sixth embodiment of the first aspect, the present invention provides a compound according to the above general formula (I): A is, [ka] is selected from the group consisting of R 1 is hydrogen or methyl, R 2 are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, selected from the group consisting of 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-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, cyano, methyl, trifluoromethoxy and NH2; R 6is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy; Q is selected from the group consisting of 2,3-dichlorophenyl, 3,5-dichlorophenyl, and 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0091] According to a further embodiment of the first aspect, the present invention relates to a compound represented by the general formula (I) shown above: A is, [ka] is selected from the group consisting of R 1 is hydrogen or methyl, R 2 is selected from the group consisting of 2-oxocyclobutyl, 2-thietanyl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-hydroxycyclobutyl, 2-fluorocyclobutyl, tetrahydrofuran-2-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3 is hydrogen or methyl, R 4 is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, cyano, methyl, methoxy, trifluoromethyl, isopropoxy, and trifluoromethoxy, preferably hydrogen, fluorine, chlorine, methoxy, and isopropoxy; R 5is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, -NH2, cyano, methyl, methoxy, trifluoromethoxy, and trifluoromethyl; R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy; Q is selected from the group consisting of 2,3-dichlorophenyl, 3,5-dichlorophenyl, and 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0092] According to a further embodiment of the first aspect, the present invention relates to a compound represented by the general formula (I) shown above: A is A3 or A4, [ka] o is 0, 1 or 2; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy and cyano, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X is CR 7 R 8 , O, S, and N.R. 9 is selected from the group consisting of Y is CR 7 R 8 or O, R 1 is hydrogen or C1-C4-alkyl, R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3 is hydrogen or C1-C4-alkyl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, halogen, -OH, -NH2, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, R 6is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenalkoxy having 1 to 5 halogen atoms, R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, Or, R 7 and R 8 together form an oxo group (=O), R 9 is hydrogen or C1-C4-alkyl, R 10 is selected from the group consisting of hydrogen, -OH and C1-C4-alkyl, R 11 is hydrogen, Q represents a phenyl having two or three substituents independently selected from fluorine, chlorine or bromine; where Y is O, then R 10 is not -OH. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0093] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is A1 or A2, [ka] o is 0, 1 or 2; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X and Y are CR 7 R8 , O, S, and N.R. 9 wherein at least one of X and Y is independently selected from the group consisting of 7 R 8 ), R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, Or, R 7 and R 8 together form an oxo group (=O), R 9 is hydrogen or C1-C4-alkyl, R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, and R 11 is hydrogen, where Y is O, S or NR 9 If R 10 is not -OH or C1-C4-alkoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0094] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is A1 or A2, [ka] o is 0, 1 or 2; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is hydrogen or C1-C4-alkyl, X and Y are CR 7 R 8, O, and S, wherein at least one of X and Y is selected from the group consisting of CR 7 R 8 ), R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, Or, R 7 and R 8 together form an oxo group (=O), R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, and R 11 is hydrogen, where Y is O, S or NR 9 If R 10 is not -OH or C1-C4-alkoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0095] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is A1 or A2, [ka] o is 0 or 1; R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C1-C4-alkyl, X is CR 7 R 8 , O, S, and N.R. 9 is selected from the group consisting of Y is CR 7 R 8 and R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, Or, R 7 and R 8 together form an oxo group (=O), R 9 is hydrogen or C1-C4-alkyl, R 10 is selected from the group consisting of hydrogen, -OH, C1-C4-alkyl and C1-C4-alkoxy, and R 11 is hydrogen, where Y is O, then R 10 is not -OH or C1-C4-alkoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0096] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is A1 or A2, [ka] o is 0 or 1; R is selected from the group consisting of hydrogen and halogen; R p is hydrogen, X is CR 7 R 8 , O and S; Y is CR 7 R 8 and R 7 is selected from the group consisting of hydrogen and C1-C4-alkyl, R 8 is selected from the group consisting of hydrogen and C1-C4-alkyl, or R 7 and R 8together form an oxo group (=O), R 10 is selected from the group consisting of hydrogen, and R 11 is hydrogen. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0097] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is, [ka] TIFF2024535759000017.tif155166] and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0098] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is, [ka]

[0099] TIFF2024535759000019.tif85166] and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0100] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is, [ka]

[0101] Preferably, [ka] is selected from the group consisting of and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0102] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: A is selected from the group A1 as defined anywhere herein above; Preferably, A is [ka] is The present invention includes compounds of the formula:

[0103] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl , 1,1-dioxido-1,2-thiazetidin-4-yl, 1-oxido-1,2-thiazetidin-3-yl, 1-oxido-1,2-thiazetidin-4-yl, 2-oxido-1,2-oxathietan-3-yl, 2-oxido-1,2-oxathietan-4-yl, 2,2-dioxido-1,2-oxathietan-3-yl, 2,2-dioxido-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3-yl yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -Iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-Diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo 2,2-diiodo-3-(hydroxyimino)cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydrofuran-3-yl, 4,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 2,5-dihydrofuran-2-yl, 2,3-dihydrofuran-2-yl, furan-3-yl, furan-2-yl, tetrahydrothio Thiophen-3-yl, tetrahydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,3-dihydrothiophen-3-yl, 4,5-dihydrothiophen-3-yl, 4,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-2-yl, 2,3-dihydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-2-yl Din-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-4-yl, 3,4-dihydro-2H-pyrrol-3-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2H-pyrrol-5-yl, 3H-pyrrol-2-yl, 2H-pyrrol-4-yl, 1H-pyrrol-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 4-alkyl-3-oxopiperazin-1-yl and 4-alkyl-2-oxopiperazin-1-yl (wherein the alkyl is C1-C6-alkyl), 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl), and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0104] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R p is hydrogen or C1-C4-alkyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0105] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R p is hydrogen or methyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0106] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 3 is hydrogen or C1-C4-alkyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0107] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 3 is hydrogen or methyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0108] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy and C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0109] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 4 is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, cyano, methyl, methoxy, isopropoxy, trifluoromethyl, and trifluoromethoxy, preferably hydrogen, fluorine, chlorine, methoxy, and isopropoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0110] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 5is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0111] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 5 is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, cyano, methyl, methoxy and trifluoromethyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0112] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 6 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0113] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0114] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 are 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1-imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; Q is 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0115] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 are 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1-imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; Q is 3,5-dichlorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0116] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-oxocyclobutyl, Q is 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0117] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-oxocyclobutyl, Q is 3,5-dichlorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0118] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-thietanyl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0119] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 1-oxidothietan-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0120] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 1-imino-1-oxido-1-thietan-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0121] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 1,1-dioxidothietan-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0122] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 2-oxoazetidin-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0123] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-hydroxycyclobutyl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0124] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-fluorocyclobutyl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0125] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3,3-difluorocyclobutyl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0126] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is tetrahydrofuran-3-yl, Q is 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0127] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is tetrahydrofuran-3-yl, Q is 3,5-dichlorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0128] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 1-methylpyrrolidin-2-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0129] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 1-methylpyrrolidin-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0130] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 5-oxopyrrolidin-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0131] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 2-oxopyrrolidin-3-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0132] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 5-oxopyrrolidin-2-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0133] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is tetrahydropyran-4-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0134] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3-oxopiperazin-1-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0135] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2is 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0136] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2 is 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0137] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3 -fluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C1-C4-alkyl-C(O)-, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0138] In a further embodiment of the first aspect, the present invention provides a compound according to the present invention, comprising a compound of formula (I) above: R 2is selected from the group consisting of 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1-imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C1-C4-alkyl-C(O)-, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, preferably hydrogen, halogen and C1-C4-alkoxy, more preferably fluorine, chlorine, methoxy and isopropoxy, Q is 2,3,5-trifluorophenyl or 3,5-dichlorophenyl. or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

[0139] In a further embodiment of the first aspect, the present invention relates to a compound of formula (I) above, A is A3 or A4, [ka] Where: R p is selected from the group consisting of hydrogen, C1-C4-alkyl; preferably hydrogen. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0140] In a further aspect of the invention, in any or all of the embodiments described herein, in the definition of X and / or Y, there is provided "NR 9 " is excluded.

[0141] In a further embodiment of the first aspect, the present invention relates to a compound of formula (I) above, A is, [ka] and R 1 is hydrogen, R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxidothietan ... 1-Oxido-1,2-Thiazetidin-4-yl, 1-Oxido-1,2-Thiazetidin-3-yl, 1-Oxido-1,2-Thiazetidin-4-yl, 2-Oxido-1,2-Oxathietan-3-yl, 2-Oxido-1,2-Oxathietan-4-yl, 2,2-Dioxido-1,2-Oxathietan-3-yl, 2,2-Dioxido-1,2-Oxathietan-4-yl, 4-Oxoazetidin-2-yl, 2-Oxoazetidin-3-yl, 4-Thioxoazetidin-2-yl, 2-Thioxoazetidin-3-yl, 2-Hydroxycyclobutene cyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl Chlorobutyl, 3-iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo-3-(hydroxyimino)cyclobutyl, 2,2-diiodo-3-(hydroxyimino)cyclobutyl, 5- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl (each of which is selected from the group consisting of halogen, -OH, -oxo, -NO2, cyano, C1-C4-alkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkyl, C1-C4- ...), -S-C1-C4-alkyl, -S(O)-C1-C4-alkyl, -SO2-C1-C4-alkoxy, C1-C4-alkoxy having 1 to 5 halogen atoms, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl), -S-C1-C4-alkoxy having 1 to 5 halogen atoms, -S(O)-C1-C4-alkoxy, -S(O)-C1-C and each of said 5- to 10-membered heterocycloalkyl is optionally substituted with one, two or three substituents independently selected from the group consisting of -S-C1-C4-halogenoalkyl having one to five halogen atoms, -S(O)-C1-C4-halogenoalkyl having one to five halogen atoms and -SO2-C1-C4-halogenoalkyl having one to five halogen atoms, preferably said 5- to 10-membered heterocycloalkyl is tetrahydrofuran-3-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl or 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl. is selected from the group consisting of R 3 is hydrogen, R 4 is a halogen, R 5 is hydrogen, R 6 is hydrogen, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

[0142] In a further embodiment of the first aspect, the present invention relates to a compound of formula (I) above, A is, [ka] and R 1 is hydrogen, R 2are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 1,1-dioxido-1,2-thiazetidin-3-yl , 1,1-dioxido-1,2-thiazetidin-4-yl, 1-oxido-1,2-thiazetidin-3-yl, 1-oxido-1,2-thiazetidin-4-yl, 2-oxido-1,2-oxathietan-3-yl, 2-oxido-1,2-oxathietan-4-yl, 2,2-dioxido-1,2-oxathietan-3-yl, 2,2-dioxido-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3-yl yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -Iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-Diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo 2,2-diiodo-3-(hydroxyimino)cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydrofuran-3-yl, 4,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 2,5-dihydrofuran-2-yl, 2,3-dihydrofuran-2-yl, furan-3-yl, furan-2-yl, tetrahydrothio Thiophen-3-yl, tetrahydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,3-dihydrothiophen-3-yl, 4,5-dihydrothiophen-3-yl, 4,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-2-yl, 2,3-dihydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-2-yl Din-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-4-yl, 3,4-dihydro-2H-pyrrol-3-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,selected from the group consisting of 5-dihydro-1H-pyrrol-3-yl, 2H-pyrrol-5-yl, 3H-pyrrol-2-yl, 2H-pyrrol-4-yl, 1H-pyrrol-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl, 4-ethyl-3-oxopiperazin-1-yl, 4-propyl-3-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, R 3 is hydrogen, R 4 Contains fluorine, R 5 is hydrogen, R 6 is hydrogen, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

[0143] In a further embodiment of the first aspect, the present invention relates to a compound of formula (I) above, A is, [ka] and R 1 is hydrogen, R 2are 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1,1-dioxidothietan-3-yl, 1-imino-1-oxido-1-thietan-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-3-yl, pyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidine- 3-yl, tetrahydrothiophen-3-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl, 4-ethyl-3-oxopiperazin-1-yl, 4-propyl-3-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R 3 is hydrogen, R 4 is fluorine, R 5 is hydrogen, R 6 is hydrogen, Q is 3,5-dichlorophenyl or 2,3,5-trifluorophenyl. or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

[0144] In certain further embodiments of the first aspect, the invention encompasses combinations of two or more of the above embodiments entitled "Further Embodiments of the First Aspect of the Invention".

[0145] The present invention encompasses any subcombination within any embodiment or aspect of the invention of compounds of general formula (I) above.

[0146] The present invention includes compounds of general formula (I) that are disclosed in the Examples section of the text below.

[0147] The compounds of the present invention of general formula (I) can be prepared according to the procedures shown in the experimental section (General Procedures) of the present invention. The procedures described are illustrative of the synthetic route to the compounds of general formula (I) of the present invention, and are not intended to be limiting. It is clear to those skilled in the art that the order of the transformations as illustrated can be changed in various ways. Therefore, the order of the transformations illustrated in these procedures is not intended to be limiting. Furthermore, the substituents Q, A, R 1 , R 2 , R 3 , R 4 , R 5 or R 6 Any interconversion of the exemplified transformations can be accomplished before or after the transformations illustrated. These modifications can be the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, saponification, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PG M Huts in Protective Groups in Organic Synthesis, 3rd Edition, Wiley 1999). Specific examples are described in the following paragraphs.

[0148] The saponification can be carried out in the presence of an aqueous solution of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide or mixtures thereof. The saponification may or may not be followed by a decarboxylation reaction. Preferably, the saponification is followed by a decarboxylation reaction.

[0149] According to a second aspect, the present invention encompasses a method for preparing a compound of general formula (I) as defined above, said method comprising reacting a compound of general formula 1N : [ka] [In the formula, A, R 1 , R 3 , R 4 , R 5 , R6 and Q are as defined for the compounds of general formula (I) defined above, and Hal is halogen, in particular chlorine and bromine. The intermediate compound of the general formula 1F : [ka] [In the formula, R 2# are methyl 2,2-dimethoxycyclobutane-1-carboxylate, methyl 3,3-dimethoxycyclobutane-1-carboxylate, methyl 2,2-bis(methylthio)cyclobutane-1-carboxylate, methyl 3,3-bis(methylthio)cyclobutane-1-carboxylate, ethyl thietane-3-carboxylate, ethyl thietane-2-carboxylate, ethyl oxetane-3-carboxylate, ethyl oxetane-2-carboxylate, methyl 2-fluorocyclobutane-1-carboxylate, methyl 3-fluorocyclobutane-1-carboxylate, methyl 2,2-difluorocyclobutane-1-carboxylate, methyl 3,3-difluorocyclobutane-1-carboxylate, tetrahydrofuran-1-carboxylate, methyl 2,2-difluorocyclobutane-1-carboxylate, methyl 3,3-difluorocyclobutane-1-carboxylate, methyl tetrahydrofuran ... methyl tetrahydrofuran-2-carboxylate, methyl tetrahydrofuran-3-carboxylate, methyl furan-3-carboxylate, methyl furan-2-carboxylate, methyl tetrahydrothiophene-3-carboxylate, methyl tetrahydrothiophene-2-carboxylate, methyl thiophene-3-carboxylate, methyl thiophene-2-carboxylate, methyl 1-methylpyrrolidine-2-carboxylate, methyl 1-methylpyrrolidine-3-carboxylate, methyl 5-oxopyrrolidine-3-carboxylate, methyl 2-oxopyrrolidine-3-carboxylate, methyl 5-oxopyrrolidine-2-carboxylate, and methyl tetrahydropyran-4-carboxylate. followed by a saponification reaction in the presence of an aqueous alkali metal hydroxide, and optionally an oxidation step, to give a compound of the general formula (I): [ka] [In the formula, A, R 1 , R 3 , R 4 , R 5 , R 6, and Q are as defined above, R 2 is selected from the group consisting of 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, furan-3-yl, furan-2-yl, tetrahydrothiophen-3-yl, tetrahydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, and tetrahydropyran-4-yl. obtaining a compound of formula (I), Then, optionally, the method includes converting said compound with a corresponding (i) solvent and / or (ii) base or acid into a solvate, salt and / or solvate of such salt.

[0150] According to an alternative embodiment of the second aspect, the present invention encompasses a method for preparing a compound of general formula (I) as defined above, said method comprising reacting a compound of general formula 1T : [ka] [In the formula, A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above for the compounds of general formula (I), and Hal is a halogen, in particular chlorine, bromine or iodine. The intermediate compound of the general formula 1H : [ka]

[0151] wherein Q is 2,3,5-trifluorophenyl and each R can be individually H or Me, or both R are pinacolato. whereby a compound of general formula (I): [ka] [In the formula, A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above, and Q is 2,3,5-trifluorophenyl. obtaining a compound of formula (I), Then, optionally, the method includes converting said compound with a corresponding (i) solvent and / or (ii) base or acid into a solvate, salt and / or solvate of such salt.

[0152] According to an alternative embodiment of the second aspect, the present invention encompasses a method for preparing a compound of general formula (I) as defined above, said method comprising reacting a compound of general formula 1W : [ka] [In the formula, Q, R 2 , R 3 , R 4 , R 5 and R 6 is as defined above for compounds of general formula (I). The intermediate compound of the general formula 1M : [ka] [In the formula, R 1 and A is as defined for compounds of general formula (I) as defined above. whereby a compound of general formula (I): [ka]

[0153] [In the formula, A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Q is as defined above. obtaining a compound of formula (I), Then, optionally, the method includes converting said compound with a corresponding (i) solvent and / or (ii) base or acid into a solvate, salt and / or solvate of such salt.

[0154] According to a third aspect, the present invention encompasses intermediate compounds that are useful in the preparation of compounds of general formula (I) above.

[0155] In particular, the present invention relates to a compound of general formula (II): [ka] [During the ceremony, R 2 is -OH, Cl, Br or is as defined for the compounds of general formula (I) above, R 3 , R 4 , R 5 , R 6 and Q are as defined for compounds of general formula (I) above, and R A is H or C1-C4-alkyl. and their stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures thereof.

[0156] According to a further embodiment, the present invention relates to a compound of formula (1T): [ka] [In the formula, A, R 1 , R 2 , R3 , R 4 , R 5 and R 6 is as defined for the compounds of general formula (I) defined above, and Hal is halogen, in particular chlorine, bromine or iodine, more in particular bromine. The present invention includes compounds of the formula:

[0157] According to a fourth aspect, the present invention encompasses the use of said intermediate compounds for the preparation of compounds of general formula (I) as defined above.

[0158] In particular, the present invention relates to a process for the preparation of a compound of general formula (I) as defined above, comprising a compound of general formula (II): [ka] [During the ceremony, R 2 is -OH, Cl, Br or is as defined for the compounds of general formula (I) above, R 3 , R 4 , R 5 , R 6 and Q are as defined for compounds of general formula (I) above, and R A is H or C1-C4-alkyl. This includes the use of intermediate compounds of the formula:

[0159] According to a further embodiment, the present invention encompasses the use of a compound of formula (1T) as defined above for the preparation of a compound of general formula (I) as defined above.

[0160] The present invention includes the intermediate compounds disclosed in the Examples section of the text below.

[0161] The present invention includes the intermediate compounds disclosed in the Examples section of the text below.

[0162] The compound of the present invention represented by the general formula (I) can be converted into any salt, preferably a pharma- ceutically acceptable salt, by any method known to those skilled in the art, as described herein.Similarly, any salt of the compound of the present invention represented by the general formula (I) can be converted into a free compound by any method known to those skilled in the art.

[0163] The compounds of the present invention have been found to have a high degree of chemical stability.

[0164] The compounds of general formula (I) of the present invention show a valuable pharmacological spectrum of action, which could not be expected.The compounds of the present invention have surprisingly been found to effectively interact with Slo-1, and therefore can be used to treat or prevent diseases, preferably helminth infections, particularly gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections caused by nematodes in humans and animals.

[0165] The compounds of the present invention can be utilized to control, treat and / or prevent helminth infections, particularly gastrointestinal and extraintestinal helminth infections. The method includes administering to a mammal in need thereof an amount of a compound of the present invention, or a pharma- ceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.

[0166] In another aspect, the method comprises administering to a bird, i.e., a caged bird, particularly 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, which is effective to treat the disorder.

[0167] In particular, in the field of veterinary medicine, the compounds of the invention are suitable for controlling parasites, especially helminths, occurring in animal breeding and animal husbandry in livestock, breeding, zoos, laboratories, experiments and domestic animals, due to their favorable toxicity in warm-blooded animals. They are active against all or specific development stages of parasites, especially helminths.

[0168] Agricultural livestock may, for example, include: mammals, such as sheep, goats, horses, donkeys, camels, water buffaloes, rabbits, reindeer, fallow deer, and in particular cattle and pigs; or poultry, such as turkeys, ducks, geese, and in particular chickens; or fish or crustacean animals, for example in aquaculture.

[0169] Domestic animals may include, for example: mammals, such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, and, in particular, dogs, cats; caged birds; reptiles, amphibians, or aquarium fish.

[0170] The present invention also provides methods for treating helminth infections, particularly gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections caused by nematodes.

[0171] These disorders have been well characterized in animals and can be treated by administering the pharmaceutical compositions of the present invention.

[0172] As used herein, the term "treating" or "treatment" is conventionally used for the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, or ameliorating the condition of a disease or disorder, such as, for example, a nematode infection. In particular, and especially in the field of animal health or veterinary medicine, the term "treating" or "treatment" includes prophylactic, metaphylactic, or therapeutic treatment.

[0173] Helminths that are pathogenic to humans or animals include, for example, acanthocephala, nematodes, pentastoma, and platyhelminths (e.g., monogenea, cestodes, and trematodes).

[0174] Exemplary helminths include, but are not limited to, the following: Class Monogenea: 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 Cyclophyllida, 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. 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 subclass Digenea, 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. 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. spp., Metagonimus spp., Metorchis spp., Nanophyetus spp., Notocotylus spp., Opisthorchis spp., Ornithobilharzia spp., Paragonimus spp., Paramphistomum spp., Plagiorchis spp.), Posthodiplostomum spp., Prosthogonimus spp., Schistosoma spp., Trichobilharzia spp., Troglotrema spp., Typhlocoelum spp.;. Nematodes: from the order Trichinellida, for example: Capillaria spp., Eucoleus spp., Paracapillaria spp., Trichinella spp., Trichomosoides spp., Trichuris spp.; From the order Tylenchida, for example: Micronema spp., Parastrangyloides spp., Strongyloides spp.; From the order of the Rhabditina, for example: Aelurostrongylus spp., Amidostomum spp., Ancylostoma spp., Angiostrongylus spp., Bronchonema spp., Bunostomum spp., Chabertia spp., Cooperia spp., Cooperioides spp., Crenosoma spp., Cyathostomum spp., Cyclococercus spp. 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. spp.), Heligmosomoides spp., Hyostrongylus spp., Marshallagia spp., Metastrongylus spp., Muellerius spp., Necator spp., Nematodirus spp., Neostrongylus spp.), Nippostrongylus spp., Obeliscoides spp., Oesophagodontus spp., Oesophagostomum spp., Ollulanus spp.; Ornithostrongylus spp., Oslerus spp., Ostertagia spp., Paracooperia spp., Paraclenosoma spp., Parafilaroides spp., Parelaphostrongylus spp. spp.), Pneumocaulus spp., Pneumostrongylus spp., Poteriostomum spp., Protostrongylus spp., Spicocaulus spp., Stephanurus spp., Strongylus spp., Syngamus spp., Teladorsagia spp., Trichonema spp., Trichostrongylus spp., Triodontophorus spp. spp.), Troglostrongylus spp., Uncinaria spp.;. From the order of the Spirurida, for example: Acanthocheilonema spp., Anisakis spp., Ascaridia spp.; Ascaris spp., Ascarops spp., Aspiculuris spp., Baylisascaris spp., Brugia spp., Cercopithifilaria spp., Crassicauda spp., Dipetalonema spp., Dirofilaria spp., Dracunculus spp. spp.); Draschia spp., Enterobius spp., Filaria spp., Gnathostoma spp., Gongylonema spp., Habronema spp., Heterakis spp.; Litomosoides spp., Loa spp., Onchocerca spp., Oxyuris spp., Parabronema spp., Parafilaria spp., Parascaris spp. spp., Passalurus spp., Physaloptera spp., Probstmayria spp., Pseudofilaria spp., Setaria spp., Skjrabinema spp., Spirocerca spp., Stephanofilaria spp., Strongyluris spp.), Syphacia spp., Thelazia spp., Toxascaris spp., Toxocara spp., Wuchereria spp.;. Phylum Acantocephala: 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.; Phylum Pentastoma: Order Porocephalida, for example, Linguatula spp.

[0175] The compounds of the present invention may be particularly used for the treatment and prevention, i.e. prophylaxis, of helminth infections, particularly gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections caused by nematodes.

[0176] The use of the compounds of the invention for controlling animal parasites, especially helminths, is intended to reduce or prevent disease, mortality and performance loss (in the case of meat, milk, wool, hides, eggs, honey, etc.), resulting in more economical and simpler animal rearing and better animal welfare being achieved.

[0177] The term "control" or "controlling" as used herein in relation to the animal health field means that the compounds of the invention are effective in reducing the incidence of the respective parasite in an animal infected with such parasite to a harmless level. More specifically, "control" as used herein means that the compounds of the invention are effective in killing, inhibiting the growth or inhibiting the proliferation of the respective parasite.

[0178] According to a further aspect, the present invention encompasses a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment or prevention of diseases, particularly helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections by nematodes.

[0179] The pharmaceutical activity of the compounds according to the invention can be explained by their interaction with the Slo-1 ion channel.

[0180] According to a further aspect, the present invention encompasses the use of a compound of general formula (I) as defined above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, and salt thereof, in particular a pharma-ceutically acceptable salt thereof, or a mixture thereof, for the treatment or prevention of a disease, in particular a helminth infection, in particular a gastrointestinal and extraintestinal helminth infection, more particularly a gastrointestinal and extraintestinal infection by nematodes.

[0181] According to a further aspect, the present invention encompasses the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, in particular pharma-ceutically acceptable salts thereof, or mixtures thereof, in a method for the treatment or prophylaxis of diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections by nematodes.

[0182] According to a further aspect, the present invention encompasses the use of a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, in particular pharma-ceutically acceptable salts thereof, or mixtures thereof, for preparing a pharmaceutical composition, preferably a medicament, for the prevention or treatment of diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections by nematodes.

[0183] According to a further aspect, the present invention encompasses a method for the treatment or prevention of diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections by nematodes, using an effective amount of a compound of general formula (I) as above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, in particular pharma-ceutically acceptable salts thereof, or mixtures thereof.

[0184] According to a further aspect, the present invention encompasses a compound of general formula (I) as defined above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, in particular pharma- ceutically acceptable salts thereof, or mixtures thereof, for use as an anti-endoparasitic agent.

[0185] According to a further aspect, the present invention encompasses compounds of general formula (I) as defined above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, in particular pharma-ceutically acceptable salts thereof, or mixtures thereof, for use as an anthelmintic, in particular as a nematicide, flatwormicide, scutellaricide or rheumicide.

[0186] According to a further aspect, the present invention encompasses a pharmaceutical composition, in particular a veterinary formulation, comprising a compound of general formula (I) as above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt thereof, in particular a pharma- ceutically acceptable salt, or a mixture thereof, and one or more excipients, in particular one or more pharma- ceutically acceptable excipients. Conventional procedures for preparing such pharmaceutical compositions in suitable dosage forms can be utilized.

[0187] According to a further aspect, the present invention encompasses a process for preparing a pharmaceutical composition, in particular a veterinary formulation, comprising the step of mixing a compound of general formula (I) as above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt thereof, in particular a pharma- ceutically acceptable salt, or a mixture thereof, with one or more excipients, in particular one or more pharma- ceutically acceptable excipients.

[0188] According to a further aspect, the present invention encompasses a method for the treatment or prevention of diseases, in particular helminth infections, in particular gastrointestinal and extraintestinal helminth infections, more particularly gastrointestinal and extraintestinal infections caused by nematodes, using a pharmaceutical composition, in particular a veterinary formulation, comprising an effective amount of a compound of general formula (I) as above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, in particular a pharma- ceutically acceptable salt thereof, or a mixture thereof.

[0189] The present invention further encompasses pharmaceutical compositions, in particular veterinary formulations, which contain at least one compound according to the invention, usually together with one or more pharma- ceutically suitable excipients, and their use for the abovementioned purposes.

[0190] The compounds of the present invention may have systemic and / or local activity.To this end, they can be administered in a suitable manner, for example, via oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, cutaneous, transdermal, conjunctival, auricular route, or as implant or stent.Such administration can be carried out prophylactically, metaphylactically or therapeutically.

[0191] For these administration routes, the compounds of the present invention can be administered in suitable dosage forms.

[0192] For oral administration, the compounds of the invention can be formulated into dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as tablets (uncoated or coated tablets, e.g., tablets with enteric or controlled release coatings that dissolve slowly or are insoluble), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (e.g., hard or soft gelatin capsules), dragees, granules, pellets, chewables (e.g., soft chewables), powders, emulsions, suspensions, aerosols or solutions. The compounds of the invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved form.

[0193] Parenteral administration can be carried out by avoiding the absorption step (for example, intravenously, intraarterially, intracardially, intraspinal or intralumbar) or by including absorption (for example, intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0194] Examples suitable for other administration routes are pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops, nasal solutions, nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, spot-ons, dusting powders, implants or stents.

[0195] The compounds according to the invention can be incorporated into the described dosage forms. This can be achieved by mixing with pharma- ceutically suitable excipients in a manner known per se. Pharmaceutically suitable excipients include, inter alia: Fillers and carriers (e.g. cellulose, microcrystalline cellulose (e.g. Avicel®), lactose, mannitol, starch, calcium phosphate (e.g. Di-Cafos®)), Ointment bases (e.g. petroleum jelly, paraffin, triglycerides, wax, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycols), Suppository bases (e.g. polyethylene glycol, cocoa butter, hard fats), Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycols, paraffin), surfactants, emulsifiers, dispersing agents or wetting agents (e.g. sodium dodecyl sulfate), lecithins, phospholipids, fatty alcohols (e.g. Lanette®), sorbitan fatty acid esters (e.g. Span®), polyoxyethylene sorbitan fatty acid esters (e.g. Tween®), polyoxyethylene fatty acid glycerides (e.g. Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g. Pluronic®), Buffers, acids and bases (e.g. phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), Isotonic agents (glucose, sodium chloride, etc.), Adsorbents (e.g. highly dispersed silica), thickening, gel-forming, viscosity enhancing and / or binders (e.g. polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g. Carbopol®); alginates, gelatin); Disintegrants (e.g. modified starches, sodium carboxymethylcellulose, sodium starch glycolate (e.g. Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g. AcDiSol®)), flow regulators, lubricants, glidants and release agents (e.g. magnesium stearate, stearic acid, talc, highly disperse silica (e.g. Aerosil®)); Coating materials (e.g. sugar, shellac) and film formers for rapidly or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidones (e.g. Kollidon®), polyvinyl alcohols, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates, e.g. Eudragit®), Capsule materials (e.g. gelatin, hydroxypropyl methylcellulose), synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates (e.g. Eudragit®), polyvinylpyrrolidones (e.g. Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers); Plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), Penetration enhancers, stabilizers (e.g. antioxidants, e.g. ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate); Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), Colorants (e.g. inorganic pigments, e.g. iron oxide, titanium dioxide), · Flavoring, sweetening, flavoring and / or odor masking agents.

[0196] The present invention further relates to pharmaceutical compositions comprising at least one compound according to the invention, usually together with one or more pharma- ceutically suitable excipients, and to their uses according to the invention.

[0197] According to another aspect, the present invention encompasses a pharmaceutical combination, in particular a medicament, comprising at least one compound of general formula (I) according to the present invention and at least one or more further active ingredients, in particular for the treatment and / or prevention of internal and / or external parasitic infections.

[0198] The term "endoparasite" in the present invention is used as known to those skilled in the art 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 mites.

[0199] In particular, the present invention provides: one or more first active ingredients, in particular compounds of general formula (I) as defined above, and one or more further active ingredients, in particular one or more endo- and / or ecto-parasiticides The present invention also includes pharmaceutical combinations, particularly veterinary combinations, comprising

[0200] The term "combination" in the present invention is used as known to the person skilled in the art, and said combination can be a fixed combination, a non-fixed combination or a kit-of-parts.

[0201] "Fixed combination" in the present invention is used as known to those skilled in the art, and is defined as, for example, a combination in which a first active ingredient, for example, one or more compounds of general formula (I) of the present invention, and an additional active ingredient are present together in one unit dosage or one single entity.One example of "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, such as in a formulation.Another example of "fixed combination" is a pharmaceutical combination in which the first active ingredient and the additional active ingredient are present in one unit, not in a mixture.

[0202] In the present invention, the term "non-fixed combination" or "kit-of-parts" is used as known to those skilled in the art and is defined as a combination in which the first active ingredient and the further active ingredient are present in two or more units.An example of a non-fixed combination or kit-of-parts is a combination in which the first active ingredient and the further active ingredient are present separately.The components of non-fixed combination or kit-of-parts can be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered.

[0203] The compound of the present invention can be administered as the only pharmaceutical agent or in combination with one or more other pharmacoactive ingredients, where the combination does not cause unacceptable adverse effects.The present invention also encompasses such pharmaceutical combinations.For example, the compound of the present invention can be combined with known ectoparasiticides and / or endoparasiticides.

[0204] Other or further active ingredients identified herein by common name are known and can be found, for example, in the Pesticide Manual ("The Pesticide Manual" 16th Edition, British Crop Protection Council 2012) or on the Internet (e.g., http: / / www.alanwood.net / pesticides). Classification is based on the IRAC Mode of Action Classification Scheme current at the time of filing this patent application.

[0205] Examples of ecto- and / or endoparasiticides are insecticides, acaricides and nematicides, including in particular: (1) Acetylcholinesterase (AChE) inhibitors, such as carbamates, such as alanycarb, aldicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, trimethacarb, XMC, and xylylcarb; or organophosphates, such as acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, cadusafos, chlorethoxyphos, chlorfenvinphos, chlormephos, chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon, dichlorvos / DDV. P, dicrotophos, dimethoate, dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famfur, fenamiphos, fenitrothion, fenthion, fosthiazate, heptenophos, imidaphos, isofenphos, isopropyl O-(methoxyaminothiophosphoryl)salicylate, isoxathion, malathion, mecarbam, methamidophos, methidathion, mevinphos, monocrotophos, naled , omethoate, oxydemeton-methyl, parathion-methyl, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos, propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos, sulfotep, tebupirimphos, temephos, terbufos, tetrachlorvinphos, thiometon, triazophos, trichlorfon and vamidothion.

[0206] (2) GABA-regulated chloride channel blockers, such as cyclodiene-organochlorines, such as chlordane and endosulfan; or phenylpyrazoles (fiproles), such as ethiprole and fipronil.

[0207] (3) Sodium channel modulators, for example, pyrethroids, for example, acrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrin s-cyclopentenyl isomer, bioresmethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin [(1R)-trans-isomer], deltamethrin, empenthrin [(EZ)-(1R)-isomer], esfenvalerate, etofenprox, fenpropanol Fenthrin, Fenvalerate, Flucythrinate, Flumethrin, Tau-fluvalinate, Halfenprox, Imiprothrin, Kadethrin, Momfluorothrin, Permethrin, Fenothrin [(1R)-trans-isomer], Prallethrin, Pyrethrins (pyrethrum), Resmethrin, Silafluofen, Tefluthrin, Tetramethrin, Tetramethrin [(1R)-isomer], Tralomethrin and Transfluthrin or DDT or Methoxychlor.

[0208] (4) Nicotinic acetylcholine receptor (nAChR) competitive modulators, neonicotinoids, such as acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam or nicotine or sulfoxaflor or flupyradifurone.

[0209] (5) Nicotinic acetylcholine receptor (nAChR) allosteric modulators, for example, the spinosyns, e.g., spinetoram and spinosad.

[0210] (6) GluCl-gated chloride channel allosteric modulators, for example, the avermectins / milbemycins, such as abamectin, emamectin benzoate, lepimectin and milbemectin.

[0211] (7) Juvenile hormone mimetics, for example juvenile hormone analogues, for example hydroprene, kinoprene and methoprene or fenoxycarb or pyriproxyfen.

[0212] (9) Chordotonal organ modulators, such as pymetrozine or flonicamide.

[0213] (10) Mite growth inhibitors, such as clofentezine, hexythiazox and diflobidazine or etoxazole.

[0214] (12) Inhibitors of mitochondrial ATP synthase, for example ATP disruptors such as diafenthiuron or organotin compounds such as azocyclotin, cyhexatin and fenbutatin oxide or propargite or tetradifon.

[0215] (13) Uncouplers of oxidative phosphorylation via disruption of the proton gradient, such as chlorfenapyr, DNOC, and sulfluramide.

[0216] (14) Nicotinic acetylcholine receptor channel blockers, such as bensultap, cartap hydrochloride, thiocylam and thiosultap-sodium.

[0217] (15) Inhibitors of chitin biosynthesis, type 0, such as bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron.

[0218] (16) Chitin biosynthesis inhibitors, type 1, such as buprofezin.

[0219] (17) Molting disruptors (especially in Diptera, i.e., flies), e.g., Cyromazine.

[0220] (18) Ecdysone receptor agonists, such as chromafenozide, halofenozide, methoxyfenozide and tebufenozide.

[0221] (19) Octopamine receptor agonists, such as amitraz.

[0222] (20) Mitochondrial complex III electron transport inhibitors, such as hydramethylnon or acequinocyl or fluacrypyrim.

[0223] (21) Mitochondrial complex I electron transport inhibitors, for example from the group of the METI acaricides, for example fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad and tolfenpyrad or rotenone (Derris).

[0224] (22) Voltage-dependent sodium channel blockers, such as indoxacarb or metaflumizone.

[0225] (23) Inhibitors of acetyl-CoA carboxylase, such as tetronic acid derivatives and tetramic acid derivatives, such as spirodiclofen, spiromesifen and spirotetramat.

[0226] (25) Mitochondrial complex II electron transport inhibitors, for example, β-ketonitrile derivatives, such as cyenopyrafen and cyflumetofen, and carboxanilides, such as piflubumid.

[0227] (28) Ryanodine receptor modulators, for example, diamides, such as chlorantraniliprole, cyantranylprole and flubendiamide.

[0228] The following further active compounds are also usable: afidopiropen, afoxolaner, azadirachtin, benclothiaz, benzoximate, bifenazate, broflanilide, bromopropylate, quinomethionate, chlorprallethrin, cryolite, cyclaniliprole, cycloxaprid, cyhalodiamide, dichloromezothiaz, dicofol, ε-metofluthrin, ε-momfluorothrin, Momfluthrin, flometoquin, fluazaindolizine, fluensulfone, flufenerim, flufenoxystrobin, flufiprole, fluhexafon, fluopyram, fluralaner, fluxamethamide, fufenozide, guadipyr, heptafluthrin, imidaclothiz, iprodione, kappa-bifenthrin, kappa-tefluthrin, lotilaner, meperfluthrin, paichongding, pyridalyl, pyrifluquinazone, pyriminostrobin, spirobudiclofen, tetramethylfluthrin, tetraniliprole, tetrachlorantraniliprole, thioxazaphen, thiofluoximate, triflumezopyrim and iodomethane; and Bacillus firmus) (I-1582, BioNeem, Votivo), and the following 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[indole-3,4'-piperidine]-1(2H)-yl}(2-chloropyridin-4-yl)methanone (known from WO2003 / 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 WO2006 / 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 WO2010052161) (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 EP2647626) (CAS 1440516-42-6), 4-(but-2-yn-1-yloxy)-6-(3,5-dimethylpiperidin-1-yl)-5-fluoropyrimidine (known from WO2004 / 099160) (CAS 792914-58-0), PF1364 (known from JP2010 / 018586) (CAS 1204776-60-2), N-[(2E)-1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-ylindene]-2,2,2-trifluoroacetamide (known from WO2012 / 029672) (CAS 1363400-41-2), (3E)-3-[1-[(6-chloro-3-pyridyl)methyl]-2-pyridylidene]-1,1,1-trifluoro-propan-2-one (known from WO2013 / 144213) (CAS 1461743-15-6), N-[3-(benzylcarbamoyl)-4-chlorophenyl]-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (known from WO2010 / 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 CN103232431) (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-N-(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 WO2013 / 050317A1) (CAS 1332628-83-7), N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-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 WO2013 / 162715A2, WO2013 / 162716A2, US2014 / 0213448A1) (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 CN101337937A) (CAS 1105672-77-2), 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)thioxomethyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, (Liudaibenjiaxuanan, known from CN103109816A) (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 WO2012 / 034403A1) (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 WO2011 / 085575A1) (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 (CN101337940A) (CAS 1108184-52-6); (2E)- and 2(Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(difluoromethoxy)phenyl]hydrazinecarboxamide (known from CN101715774A) (CAS 1232543-85-9; cyclopropanecarboxylic acid 3-(2,2-dichloroethenyl)-2,2-dimethyl-4-(1H-benzimidazol-2-yl)phenyl ester (known from CN103524422A) (CAS 1542271-46-4); (4aS)-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 CN102391261A) (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 US2014 / 0275503A1) (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-cyclopropylmethoxy-4-trifluoromethylphenoxy)-3-(6-trifluoromethylpyridazin-3-yl)-3-azabicyclo[3.2.1]octane (known from WO2007040280A1 and WO2007040282A1) (CAS 934001-66-8), N-[3-chloro-1-(3-pyridinyl)-1H-pyrazol-4-yl]-N-ethyl-3-[(3,3,3-trifluoropropyl)thio]propanamide (known from WO2015 / 058021A1 and WO2015 / 058028A1) (CAS 1477919-27-9), N-[4-(aminothioxomethyl)-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (known from CN103265527A) (CAS 1452877-50-7), 5-(1,3-dioxan-2-yl)-4-[[4-(trifluoromethyl)phenyl]methoxy]pyrimidine (known from WO2013 / 115391A1) (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 WO2010 / 066780A1, WO2011 / 151146A1) (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 WO2014 / 187846A1) (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 WO2010 / 066780A1, WO2011151146A1) (CAS 1229023-00-0), N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylindene]-2,2,2-trifluoro-acetamide (known from DE3639877A1, WO2012029672A1) (CAS 1363400-41-2), [N(E)]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylindene]-2,2,2-trifluoro-acetamide, (known from WO2016005276A1) (CAS 1689566-03-7), [N(Z)]-N-[1-[(6-chloro-3-pyridinyl)methyl]-2(1H)-pyridinylindene]-2,2,2-trifluoro-acetamide, (CAS 1702305-40-5), 3-endo-3-[2-propoxy-4-(trifluoromethyl)phenoxy]-9-[[5-(trifluoromethyl)-2-pyridinyl]oxy]-9-azabicyclo[3.3.1]nonane (WO20, 11 / 105506A1, WO2016 / 133011A1) (CAS 1332838-17-1).

[0229] Active ingredients with unknown or unspecified mechanism of action, such as fentrifanil, fenoxacrim, cycloprene, chlorobenzilate, chlordimeform, flubenzimine, dicyclanil, amidoflumet, quinomethionate, triatene, clothiazobene, tetrasul, potassium oleate, petroleum, methoxadiazone, gossypurle, flutenzin, bromopropylate, cryolite; from another class of ingredients, for example, butacarb, dimethylan, cloethocarb, phosphocarb, pirimiphos (-ethyl), parathion (-ethyl), methacrifos, isopropyl o-salicylate, trichlorfon, sulprofos, propafos, cebufos, pyridathion, protoate, diclofenthion, demeton-S-methylsulfone, isazofos, cyanofenphos, dialifos, carbophenothion, autathiophos, allomfenvinphos (-methyl), azinphos (-ethyl), chlorpyrifos (-ethyl), phosmetilan, iodofenphos, dioxabenzophos, formothion, fonofos, flupyrazophos, fensulfothion, etrimphos; Organochlorines, such as camphechlor, lindane, heptachlor; or phenylpyrazoles, such as acetoprole, pyrafluprole, pyriprole, vaniliprole, cisapronil; or isoxazolines, such as sarolaner, afoxolaner, lotilaner, fluralaner; Pyrethroids, such as (cis-, trans-)metofluthrin, profluthrin, flufenprox, flubrocythrinate, fubufenprox, fenfluthrin, protrifenbut, pyresmethrin, RU15525, terallethrin, cis-resmethrin, heptafluthrin, bioethanomethrin, biopermethrin, fenpyrithrin, cis-cypermethrin, cis-permethrin, clocithrin, cyhalothrin (lambda-), clovaporthrin, or halogenated hydrocarbons (HCHs); Neonicotinoids, for example, nithiazine; Dichloromezotiaz, triflumezopyrim; Macrocyclic lactones, such as nemadectin, ivermectin, latidectin, moxidectin, selamectin, eprinomectin, doramectin, emamectin benzoate; milbemycin oxime; Triplen, epofenonane, diofenolan; Biological agents, hormones, or pheromones, such as natural products, e.g., thuringiensin, codlemone, or neem components; Dinitrophenols, such as dinocap, dinobuton, binapacryl; Benzoylureas, for example, Fluazuron, Penfluron; Amidine derivatives, such as chlormebuform, cymiazole, demiditraz; Bee hive varroa acaricides, for example, organic acids, e.g. formic acid, oxalic acid.

[0230] Non-limiting examples of insecticides and acaricides of particular interest for use in animal health are in particular [i.e. Mehlhorn et al. Encyclpaedic Reference of Parasitology 4th Edition (ISBN 978-3-662-43978-4)] and include: Effectors at ligand-gated chloride channels in arthropods: chlordane, heptachlor, endoculfan, dieldrin, bromocyclen, toxaphen, lindane, fipronil, pyriprole, cisapronil, afoxolaner, fluraner, sarolaner, lotilaner, fluxamethamide, broflanilide, avermectin, doramectin, eprinomectin, ivermectin, milbemycin, moxidectin, selamectin; Modulators of arthropod octopaminergic receptors: amitraz, BTS27271, cymiazole, demiditraz; Effectors at arthropod voltage-gated sodium channels: DDT, methoxychlor, metaflumizone, indoxacarb, cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, allethrin, alpha-cypermethrin, bioallethrin, beta-cyfluthrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, etofenprox, fenvalerate, flucythrinate, flumethrin, halfenprox, permethrin, fenothrin, resmethrin, tau-fluvalinate, tetramethrin; Effectors at arthropod nicotinic cholinergic synapses (acetylcholinesterase, acetylcholine receptors): bromoprypylate, bendiocarb, carbaryl, methomyl, promacyl, propoxur, azamethiphos, chlorfenvinphos, chlorpyrifos, coumaphos, cythioate, diazinon, dichlorvos, dicrotophos, dimethoate, ethion, fanfur, fenitrothion, fenthion, heptenophos, malathion, naled, phosmet, phoxim, phthalofos, propetamphos, temephos, tetrachlorvinphos, trichlorfon, imidacloprid, nitenpyram, dinotefuran, spinosad, spinetoram; Effectors during arthropod development: Cyromazine, dicyclanil, diflubenzuron, fluazuron, lufenuron, triflumuron, fenoxycarb, hydroprene, methoprene, pyriproxyfen, fenoxycarb, hydroprene, S-methoprene, pyriproxyfen.

[0231] Exemplary active ingredients from the group of endoparasiticides as further or other active ingredients in the present invention include, but are not limited to, anthelmintic and antiprotozoal active compounds.

[0232] Anthelmintic active compounds can include, but are not limited to, the following nematicidally, trematicidally and / or cestocidally active compounds: From the class of the macrocyclic lactones, for example: eprinomectin, abamectin, nemadectin, moxidectin, doramectin, selamectin, lepimectin, latidectin, milbemectin, ivermectin, emamectin, milbemycin; From the class of the benzimidazoles and probenzimidazoles, for example: oxibendazole, mebendazole, triclabendazole, thiophanate, parbendazole, oxfendazole, netobimin, fenbendazole, febantel, thiabendazole, cyclobendazole, cambendazole, albendazole sulfoxide, albendazole, flubendazole; From the class of the depsipeptides, preferably from the class of the cyclic depsipeptides, in particular from the class of the 24-membered cyclic depsipeptides, for example: emodepside, PF1022A; From the class of the tetrahydropyrimidines, for example: morantel, pyrantel, oxantel; From the class of the imidazothiazoles, for example: butamisole, levamisole, tetramisole; From the class of the aminophenylamidines, for example: amidantel, deacylated amidantel (dAMD), tribendimidine; From the class of the aminoacetonitriles, for example: monepantel; From the class of the paraherquamides, for example: paraherquamide, delquantel; From the class of the salicylanilides, for example: tribromosalan, bromoxanide, brothianide, clioxanide, closantel, niclosamide, oxyclozanide, lafoxanide; From the class of substituted phenols, for example: nitroxynil, bithionol, disophenol, hexachlorophene, niclofolane, meniclopholan; From the class of organophosphates, for example: trichlorfon, naphthalofos, dichlorvos / DDVP, crufomate, coumaphos, haloxon; From the class of the piperazinones / 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, omfalotin, oltipraz, nitrosucanate, nitroxynil, oxamniquine, mirasan, miracil, lucantone, hycantone, hetolin, emetine, diethylcarbamazine, dichlorophene, diamphenetide, clonazepam, bephenium, amoscanate, clorsulon.

[0233] Antiprotozoan active ingredients can 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 polyether 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 quinine class, for example: chloroquine; From the class of pyrimidines, for example: pyrimethamine; From the class of sulfonamides, for example: sulfaquinoxaline, trimethoprim, sulfaclozine; From the class of thiamines, for example: amprolium; From the class of lincosamides, for example: clindamycin; From the class of the carbanilides, for example: imidocarb; From the class of nitrofurans, for example: nifurtimox; From the class of quinazolinone alkaloids, for example: halofuginone; Of various other classes, for example: oxamniquine, paromomycin; From the class of vaccines or microbial antigens, 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 canis, Dictyocaulus viviparus.

[0234] All named other or further active ingredients in the present invention can optionally form salts with suitable bases or acids, if their functional groups allow this.

[0235] Based on the standard laboratory techniques known for evaluating compounds useful in the treatment of helminth infections, by standard toxicity tests, and by standard pharmacological assays for determining the treatment of the above conditions in animals, and by comparing these results with those of known active ingredients or drugs used to treat these conditions, the effective dose of the compound of the present invention can be easily determined for the treatment of each desired indication.The amount of active ingredient administered in the treatment of one of these conditions can vary widely according to such considerations as the specific compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the subject to be treated, and the nature and severity of the condition to be treated.

[0236] The total amount of active ingredient administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight / day, preferably about 0.01 mg / kg to about 20 mg / kg body weight / day. Clinically useful dosing schedules will range from one to three times daily dosing to once every four weeks. Also, a "drug holiday" during which the subject is not administered the drug for a period of time may be beneficial to the overall balance of pharmacological activity and tolerability. Additionally, subjects may receive long-acting treatments in which the subject is treated once for more than four weeks. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered more than once a day or less than once a day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, as well as the use of infusion techniques, is preferably 0.01 to 200 mg / kg total body weight. The average daily rectal dosing regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily vaginal dosage regimen is preferably 0.01-200 mg / kg total body weight. The average daily topical dosage regimen is preferably 0.1-200 mg administered between 1-4 times daily. The transdermal concentration is preferably that required to maintain a daily dose of 0.01-200 mg / kg. The average daily inhalation dosage regimen is preferably 0.01-100 mg / kg total body weight.

[0237] Of course, the particular initial and continuing dosing regimens for each subject will vary according to the nature and severity of the symptoms as determined by the attending 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 excretion of the drug, the combination of drugs, etc. The desired mode of treatment and frequency of administration of the compounds of the invention or a pharmacologic acceptable salt or ester thereof or compositions can be ascertained by one skilled in the art using conventional treatment trials.

[0238] Experimental Section Abbreviations and acronyms aq. Water-based atm standard atmosphere DAD Diode Array Detector DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide ELSD Evaporative Light Scattering Detector ESI Electrospray Ionization h time LC-MS Liquid Chromatography Combined with Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide min MCPBA Metachloroperbenzoic Acid MTBE Methyl t-butyl ether NMR nuclear magnetic resonance spectroscopy p. Page R t retention time RT room temperature THF Tetrahydrofuran TLC Thin Layer Chromatography

[0239] Various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

[0240] The test examples described herein serve to illustrate the invention, and the invention is not limited to the examples given.

[0241] General Experiment Section All reagents whose synthesis is not described in the experimental section are either commercially available, are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0242] All solvents used were commercially available and were used without further purification. Reactions were typically carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0243] The compounds and intermediates produced according to the method of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compound may be purified by chromatography, in particular flash column chromatography, for example, using a cartridge pre-packed with silica gel, such as a Biotage automated purification system (SP4® or Isolera Four®) and a Biotage SNAP cartridge KP-Sil® or KP-NH®, combined with an eluent (e.g., a gradient of hexane / ethyl acetate or dichloromethane / methanol). In some cases, the compound may be purified by preparative HPLC, for example, using a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, combined with a suitable pre-packed reverse-phase column and an eluent such as a gradient of water and acetonitrile (which may contain additives such as trifluoroacetic acid, formic acid, aqueous ammonia, etc.).

[0244] In some cases, the purification method as described above can provide the compounds of the present invention with sufficiently basic or acidic functionality in the form of a salt, for example, in the case of sufficiently basic compounds of the present invention, such as trifluoroacetate or formate salts, or in the case of sufficiently acidic compounds of the present invention, such as ammonium salts. This type of salt can be converted to its free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as a salt in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, etc.) of the compounds of the present invention isolated and described herein is not necessarily the only form in which the compounds can be applied to biological assays to determine specific biological activity.

[0245] Analytical and chromatographic methods Analytical and Preparative Liquid Chromatography Analytical (UP) LC-MS was performed using different instruments as described below. Masses (m / z) are reported from positive mode electrospray ionization (ESI-) unless negative mode is indicated.

[0246] M+1 (or M+H) refers to the molecular ion peak ±1 a.mu (atomic mass unit), respectively, as observed in mass spectrometry by electrospray ionization (ESI+ or -).

[0247] LC-MS, analysis method A1: System MS: Thermo Scientific FT-MS; System UHPLC+: Thermo Scientific UltiMate 3000; Column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; Eluent A: 1 l water + 0.01% formic acid; Eluent B: 1 l acetonitrile + 0.01% formic acid; Gradient: 0.0 min 10% B → 2.5 min 95% B → 3.5 min 95% B; Oven: 50° C.; Flow rate: 0.90 ml / min; UV detection: 210 nm / optimal integration path 210-300 nm.

[0248] LC-MS, analysis method B1: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Gemini NX-C18 3.0 μm, 50x3.0 mm; Eluent A: water + 0.05% ammonium bicarbonate by volume, Eluent B: acetonitrile; Gradient: assigned to each compound; Flow rate: 1.2 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0249] LC-MS, analysis method C1: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Luna Omega 3.0 μm, 50x3.0 mm; Eluent A: water + 0.09% by volume formic acid, Eluent B: acetonitrile + 0.1% by volume formic acid; Gradient: assigned to each compound; Flow rate: 1.5 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0250] LC-MS, analysis method A2: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: CORTECS C18 2.7 μm, 50x2.1 mm; Eluent A: water + 0.1% formic acid by volume, Eluent B: acetonitrile + 0.10% formic acid by volume; Gradient: assigned to each compound; Flow rate: 1.2 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0251] LC-MS, analysis method B2: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Infinity Lab Poroshell HPH-C18 2.7μm, 50x3.0mm; Eluent A: water + 0.04% ammonium hydroxide by volume, Eluent B: acetonitrile; Gradient: assigned to each compound; Flow rate: 1.2mL / min; Temperature: 40℃; PDA scan: 190-400nm.

[0252] LC-MS, analysis method A3: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Kinetex EVO C18 2.6 μm, 50x3.0 mm; Eluent A: water + 0.05% ammonium bicarbonate by volume, Eluent B: acetonitrile; Gradient: assigned to each compound; Flow rate: 1.5 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0253] LC-MS, analysis method B3: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Kinetex EVO C18 2.6 μm, 50x3.0 mm; Eluent A: water + 0.03 vol% ammonium hydroxide, Eluent B: acetonitrile; Gradient: assigned to each compound; Flow rate: 1.5 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0254] LC-MS, analysis method C3: Instrument: SHIMADZU LCMS-UFLC 20-AD-LCMS 2020MS detector; Column: Kinetex XB-C18 2.6 μm, 50x3.0 mm; Eluent A: water + 0.1% formic acid by volume, Eluent B: acetonitrile + 0.1% formic acid by volume; Gradient: assigned to each compound; Flow rate: 1.2 mL / min; Temperature: 40 °C; PDA scan: 190-400 nm.

[0255] Preparative HPLC Preparative reversed phase HPLC was performed using a Varian HPLC system. The column used was an XBridge Prep C18 OBD Column, 5um, 19x150mm. The instrument used reversed phase conditions (acetonitrile / water, with 0.1% ammonium bicarbonate or formic acid).

[0256] 1H-NMRデータ Proton NMR spectra were recorded using a Bruker plus 400 NMR spectrometer unless otherwise stated. All deuterated solvents such as CD3CN, CDCl3 or D6-DMSO were measured using the standard signal ( 1H and 13 When tetramethylsilane was used as the sample (d set to 0.00 for both samples and C), it typically contained 0.03% to 0.05% vol / vol tetramethylsilane.

[0257] Chemical shifts (δ) are expressed in parts per million [ppm] and the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. = broad; coupling constants are expressed in Hertz [Hz].

[0258] NMR peak list NMR peak forms are described as they appear in the spectra and possible higher order effects have not been taken into account.

[0259] Selected Examples 1 H-NMR data is 1 The results are presented in the form of a H-NMR peak list. For each signal peak, the δ value in ppm and the signal intensity in parentheses are listed. There is a semicolon or comma separator between the δ value-signal intensity pairs.

[0260] Thus, an example peak list has the following form: δ1(Intensity 1);δ2(Intensity 2);........;δ i (strength i );....;δ n (strength n )or δ1 (Intensity 1), δ2 (Intensity 2),....;δ i (strength i ),....,δ n (strength n ) The intensity of the sharp signals correlates with the signal height (cm) in the printed example of the NMR spectrum, showing the actual relationship of signal strength. From the broad signals, it is possible to show several peaks or the center of the signal and their relative intensity compared to the most intense signal in the spectrum.

[0261] 1To calibrate the chemical shifts of the H spectra, tetramethylsilane and / or, especially for spectra measured in DMSO, the chemical shifts of the solvent used were used. Thus, in the NMR peak list, a peak for tetramethylsilane may occur, but this is not necessary.

[0262] 1 The H-NMR peak list is a classical 1 It resembles a 1 H-NMR print and therefore contains all the peaks that are usually enumerated in a classical NMR interpretation.

[0263] Moreover, they are classical 1 Like the 1 H-NMR print, signals for the solvent, the stereoisomers of the target compound (which is also an object of the present invention), and / or impurity peaks may also be shown.

[0264] To show compound signals in the delta range of the solvent and / or water, the usual peaks of the solvent, e.g., the DMSO peak and the water peak in DMSO-D6, are added to our 1 H-NMR peaks are shown in the list and usually have high intensities on average.

[0265] The peaks of stereoisomers of the target compound and / or the peaks of impurities usually have, on average, a lower intensity than the peaks of the target compound (eg, having a purity of >90%).

[0266] Such stereoisomers and / or impurities may be typical for a particular preparation process, and therefore their peaks may help to recognize the reproducibility of our preparation process via "side-products-fingerprints".

[0267] The expert calculates the peaks of the target compounds using known methods (MestreC, ACD simulations, but also empirically evaluated expectations) and can, if necessary, optionally use additional intensity filters to isolate the peaks of the target compounds. This isolation is performed using the classical1 This is similar to the associated peak picking in H-NMR interpretation.

[0268] Further details on describing NMR data using peak lists can be found in Research Disclosure Database Number 564025, "Citation of NMR Peaklist Data within Patent Applications."

[0269] Synthesis procedure The general synthesis of compounds of formula (I) can be carried out according to or analogously to the schemes described in WO2018 / 087036A1 and WO2019 / 215182A1. EXAMPLES

[0270] Intermediates Intermediate 1 8-Bromo-4-[3,3-dimethoxy-1-(methoxycarbonyl)cyclobutyl]-7-fluoroquinoline-3-carboxylate ethyl [ka]

[0271] To a solution of methyl-3,3-dimethoxycyclobutane-carboxylate (8.05 g, 46.2 mmol) in dry THF (60 ml) was added dropwise bis-(trimethylsilyl)-lithium amide (LiHMDS) (50 ml, 1 M solution in THF, 50 mmol) at -78 to -68 °C and stirring was continued for 5 min at this temperature. Then a solution of ethyl 8-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (described for example as intermediate 8A in WO2019 / 215182A1, 11.0 g, 33.0 mmol) in THF (40 ml) was added during 7 min while maintaining the temperature range of -72 to -65 °C. The precipitate formed and the suspension was diluted with THF (20 ml) and allowed to stir again for 20 min. The mixture was warmed to 0° C. and then added slowly to a stirred mixture of ice water (800 ml) and acetic acid (5.7 ml, 99 mmol). The mixture was warmed to 50° C. and stirred for 40 minutes. The precipitate formed was filtered off, washed with water and dried under vacuum.

[0272] Yield: 14.0 g (90% of theoretical value) LC-MS (Analysis method A1): R t = 2.09 min; MS (ESIpos): m / z = 470 [M+H] + 1 H-NMR (600MHz, DMSO-d6): δ [ppm] = 9.10 (s, 1H), 8.10 (dd, 1H), 7.72 (t, 1H), 4.36 (q, 2H), 3.63 (s, 3H), 3.31 - 3.44 (m, 2H), 3.11 (s, 3H), 2.88 (s, 3H), 2.50 - 2.63 (m, 2H, overlapped with DMSO signals), 1.32 (t, 3H).

[0273] Intermediate 2 8-Bromo-7-fluoro-4-(3-oxocyclobutyl)quinoline-3-carboxylic acid [ka]

[0274] A suspension of ethyl 8-bromo-4-[3,3-dimethoxy-1-(methoxycarbonyl)cyclobutyl]-7-fluoroquinoline-3-carboxylate (14.0 g, 29.8 mmol) in 1,2-dimethoxyethane (100 ml) was treated with sodium hydroxide (24 ml, 5.0 M aqueous solution, 120 mmol) and stirred at 60° C. overnight. At the same temperature, hydrochloric acid (36 ml, 5.0 M, 180 mmol) was added dropwise and stirring was continued for 1.5 hours, resulting in the formation of a precipitate. Water (160 ml) was added at 60° C., resulting in more precipitate, stirring was continued for 5 minutes, and the heat was removed. The precipitate was filtered off, washed with water and dried under vacuum.

[0275] Yield: 8.59 g (100%, 85% of theoretical value) LC-MS (Analysis method A1): R t = 1.25 min; MS (ESIneg): m / z = 336 [MH] - 1 H-NMR (600MHz, DMSO-d6): δ [ppm]= 13.93 (b, 1H), 9.10 (s, 1H), 8.29 - 8.39 (m, 1H), 7.71 - 7.82 (m, 1H), 4.62 - 4.75 (m, 1H), 3.59 - 3.72 (m, 2H), 3.39 - 3.50 (m, 2H).

[0276] Intermediate 3 8-Bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-oxocyclobutyl)quinoline-3-carboxamide [ka]

[0277] 8-Bromo-7-fluoro-4-(3-oxocyclobutyl)quinoline-3-carboxylic acid (2.74 g, 8.10 mmol) in THF (32 ml) was treated with DIPEA (4.2 ml, 24 mmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate(1-) (4.62 g, 12.2 mmol) and stirred at RT for 20 min. (4S)-chroman-4-amine hydrochloride (CAS reg. no.: 1035093-81-2; 1:1; 2.11 g, 11.3 mmol) was added to the solution and stirring was continued at room temperature overnight. Hot water (150 ml) was added with stirring and most of the THF was evaporated under reduced pressure at 50°C. The mixture was sonicated for 30 minutes and the precipitate was filtered off and washed with water. The solid was taken up in boiling ethanol and water (250 ml) was added hot with stirring and the mixture was cooled to room temperature. The precipitate was filtered off, washed with water and dried under vacuum.

[0278] Yield: 2.75 g (67% of theory, purity 92%) LC-MS (Analysis method A1): R t = 1.82 min; MS (ESIpos): m / z = 469 [M+H] + 1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 9.31 (d, 1H), 8.96 (s, 1H), 8.33 (dd, 1H), 7.76 (dd, 1H), 7.36 (d, 1H), 7.18 (t, 1H), 6.93 (t, 1H), 6.80 (dd, 1H), 5.20 - 5.26 (m, 1H), 4.61 (quin, 1H), 4.19 - 4.32 (m, 2H), 3.49 - 3.68 (m, 4H), 2.17 - 2.25 (m, 1H), 2.01 - 2.09 (m, 1H).

[0279] Intermediate 4 Ethyl 4-[3-(ethoxycarbonyl)thietan-3-yl]-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate [ka]

[0280] Ethyl thietane-3-carboxylate (CAS reg. no.: 1379028-98-4; 1.07 g, 7.30 mmol) in dry THF (30 ml) was treated with LiHMDS (7.8 ml, 1.0 M, 7.8 mmol) at -78 °C and stirred at -75 to -68 °C for 4 min. A solution of ethyl 4-chloro-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (described, for example, in WO2019 / 215182 as example IR-2) in THF (10 ml) was added dropwise and stirred at this temperature range for 3 min, after which the cooling bath was removed. The reaction mixture was allowed to warm to room temperature and slowly added to a stirred mixture of acetic acid (0.9 ml, 16 mmol) and water (120 ml). The aqueous mixture was extracted several times with DCM and the combined organic layers were dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica (100 g) with cyclohexane / ethyl acetate (9-14%).

[0281] Yield: 2.22 g (86% of theoretical) LC-MS (Analytical Method A1): Rt = 2.46 min; MS (ESIpos): m / z = 494 [M+H]+ 1 H NMR (DMSO-d6) δ: 8.98 (s, 1H), 8.18 (m, 1H), 7.66-7.80 (m, 2H), 7.31-7.37 (m, 1H), 4.21-4.36 (m, 4H), 3.92-4.08 (m, 4H), 1.30 (m, 3H), 1.17 (m, 3H). Peak List 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (7.45), 1.171 (16.00), 1.189 (7.72), 1.287 (7.01), 1.304 (15.16), 1.322 (7.26), 3.930 (2.25), 3.955 (3.57), 3.969 (1.82), 3.994 (3.26), 4.030 (6.42), 4.055 (3.59), 4.218 (2.39), 4.235 (7.29), 4.253 (7.25), 4.271 (2.31), 4.298 (2.14), 4.316 (6.73), 4.333 (6.65), 4.352 (2.08), 5.753 (2.98), 7.327 (1.20), 7.339 (1.21), 7.349 (1.21), 7.662 (0.44), 7.670 (0.53), 7.678 (0.62), 7.685 (1.01), 7.698 (0.99), 7.706 (1.01), 7.712 (1.01), 7.718 (0.63), 7.726 (0.56), 7.734 (0.52), 7.752 (1.95), 7.775 (3.46), 7.798 (2.15), 8.159 (1.97), 8.174 (2.09), 8.184 (1.99), 8.199 (1.86), 8.984 (9.08).

[0282] Intermediate 5 7-Fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid [ka]

[0283] A suspension of ethyl 4-[3-(ethoxycarbonyl)thietan-3-yl]-7-fluoro-8-(2,3,5-trifluorophenyl)-quinoline-3-carboxylate (1.60 g, 3.24 mmol) in 1,2-dimethoxyethane (100 ml) was treated with sodium hydroxide (2.6 ml, 5.0 M aqueous solution, 13 mmol) and stirred at 70° C. for 8 h and at room temperature for 2 days. At 70° C. water (20 ml) was added, the heat was removed and hydrochloric acid (3.9 ml, 5.0 M, 19 mmol) was added dropwise with stirring. After cooling to RT a precipitate formed. At 60° C. more water (50 ml) was added and the organic solvent was removed under reduced pressure causing more precipitate to form. At room temperature the precipitate was filtered off, washed with water and dried under vacuum.

[0284] Yield: 1.10 g (86% of theoretical) LC-MS (Analytical Method A1): Rt = 2.04 min; MS (ESIpos): m / z = 394 [M+H]+ 1 H NMR (DMSO-d6) δ: 9.17 (m, 1H), 8.99 (s, 1H), 7.97 (t, 1H), 7.65-7.73 (m, 1H), 7.30-7.35 (m, 1H), 5.81 (m, 1H), 3.69-3.93 (m, 2H), 3.47-3.64 (m, 2H). Peak List 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.150 (0.41), 1.169 (0.60), 2.368 (0.64), 2.712 (0.69), 2.999 (0.45), 3.236 (10.41), 3.427 (8.73), 3.507 (1.48), 3.540 (7.44), 3.564 (15.58), 3.588 (8.62), 3.778 (4.29), 3.802 (8.63), 3.828 (8.63), 3.851 (3.66), 5.765 (0.88), 5.789 (3.23), 5.813 (4.68), 5.837 (3.09), 5.860 (0.79), 7.312 (2.60), 7.323 (2.72), 7.334 (2.70), 7.654 (0.95), 7.661 (1.11), 7.681 (2.24), 7.689 (2.19), 7.702 (2.31), 7.718 (1.24), 7.726 (1.13), 7.944 (3.96), 7.967 (7.59), 7.989 (4.06), 8.988 (16.00), 9.147 (3.93), 9.161 (4.18), 9.170 (4.19), 9.185 (3.91).

[0285] Working Example Example 1 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-oxocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0286] A thick-walled microwave vessel was charged with 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(3-oxocyclobutyl)quinoline-3-carboxamide (1.37 g, 2.92 mmol), 2,3,5-trifluorobenzeneboronic acid (1.03 g, 5.84 mmol), cesium fluoride (1.32 g, 8.76 mmol) and (2'-amino[biphenyl]-2-yl)(methanesulfonate-κO)palladium-dicyclohexyl(2',6'-dimethoxy[biphenyl]-2-yl)phosphine (1:1), (SPhos Pd G3), (228 mg, 292 μmol) under argon. Degassed dioxane / water (5:1) (11 ml) was added, the vessel was capped and stirred at 60° for 5 h. Further 2,3,5-trifluorobenzeneboronic acid (0.51 g, 2.92 mmol) and SPhos Pd G3 (114 mg, 146 μmol) were added and stirred for 3 h. The mixture was partitioned between water (80 ml) and ethyl acetate (80 ml) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica (100 g) with cyclohexane / ethyl acetate (23-33%).

[0287] Yield: 820 mg (54% of theoretical value) LC-MS (Analysis method A1): R t = 2.12 min; MS (ESIpos): m / z = 521 [M+H] + 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 9.29 (d, 1H), 8.83 (d, 1H), 8.46 (dd, 1H), 7.81 (t, 1H), 7.65 - 7.73 (m, 1H), 7.25 - 7.37 (m, 2H), 7.17 (t, 1H), 6.91 (t, 1H), 6.79 (d, 1H), 5.22 (br dd, 1H), 4.64 (q, 1H), 4.17 - 4.31 (m, 2H), 3.50 - 3.72 (m, 4H), 2.15 - 2.23 (m, 1H), 1.98 - 2.08 (m, 1H).

[0288] Example 2 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0289] 7-Fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (950 mg, 2.42 mmol) in THF (4 ml) was treated with DIPEA (1.1 ml, 6.0 mmol) and 1-[bis(dimethylamino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (1-) (1.19 g, 3.14 mmol) and stirred at room temperature for 15 min. (4S)-chroman-4-amine hydrochloride (1:1) (538 mg, 2.90 mmol) was added to the cloudy solution and stirring was continued at room temperature overnight. The reaction mixture was poured into hot water at 50° C., stirred at 50° C. for 30 min and cooled to room temperature. The precipitate was filtered off, washed with water and dried under vacuum. Yield: 1.19 g (94% of theoretical)

[0290] The product was 100% pure by LC-MS and was used in the next step. LC-MS (Analysis method A1): R t = 2.33 min; MS (ESIpos): m / z = 525 [M+H] +

[0291] For NMR, the sample was repurified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile). 1 H NMR (DMSO-d6) δ: 9.22 (d, 1H), 9.00 (m, 1H), 8.81 (d, 1H), 7.91 (m, 1H), 7.65-7.73 (m, 1H), 7.39 (br d, 1H), 7.30 (br m, 1H), 7.17 (m, 1H), 6.93 (m, 1H), 6.79 (d, 1H), 5.48 (m, 1H), 5.26-5.32 (m, 1H), 4.20-4.32 (m, 2H), 3.87 (m, 2H), 3.36-3.57 (m, 2H), 2.53-2.55 (m, 3H), 2.25 (m, 1H), 2.05-2.13 (m, 1H). Peak List 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 2.063 (1.06), 2.069 (1.37), 2.075 (2.07), 2.081 (2.25), 2.091 (2.46), 2.103 (3.08), 2.109 (2.67), 2.115 (1.78), 2.121 (1.30), 2.213 (0.74), 2.224 (1.60), 2.231 (2.53), 2.241 (3.06), 2.248 (2.63), 2.251 (2.40), 2.258 (2.65), 2.269 (1.83), 2.276 (1.20), 2.286 (0.56), 3.482 (2.06), 3.496 (2.91), 3.500 (4.87), 3.515 (5.69), 3.519 (6.74), 3.539 (9.53), 3.558 (4.62), 3.844 (3.91), 3.847 (4.08), 3.858 (6.06), 3.863 (8.01), 3.865 (7.93), 3.876 (9.96), 3.881 (4.78), 3.883 (4.29), 3.895 (4.70), 4.209 (1.69), 4.215 (2.00), 4.227 (2.35), 4.232 (5.09), 4.237 (3.41), 4.249 (3.88), 4.254 (3.02), 4.278 (3.12), 4.283 (3.43), 4.290 (3.26), 4.295 (3.03), 4.306 (1.73), 4.312 (1.58), 5.267 (1.22), 5.278 (2.79), 5.284 (3.70), 5.288 (3.05), 5.294 (3.62), 5.299 (2.76), 5.311 (1.15), 5.438 (0.73), 5.446 (0.78), 5.457 (2.68), 5.465 (2.64), 5.476 (3.94), 5.484 (3.73), 5.495 (2.63), 5.503 (2.37), 5.514 (0.70), 5.522 (0.60), 5.756 (0.50), 6.787 (8.30), 6.804 (8.97), 6.910 (2.60), 6.913 (3.40), 6.916 (2.51), 6.925 (5.18), 6.928 (7.08), 6.931 (4.65), 6.940 (3.15), 6.943 (3.96), 6.946 (2.68), 7.157 (4.25), 7.172 (6.38), 7.173 (6.38), 7.188 (3.42), 7.279 (1.66), 7.297 (2.67), 7.302 (2.78), 7.306 (2.19), 7.316 (1.54), 7.320 (1.70), 7.329 (0.83), 7.386 (3.95), 7.391 (3.93), 7.393 (3.92), 7.399 (3.93), 7.407 (3.57), 7.662 (1.21), 7.668 (1.47), 7.675 (1.73), 7.680 (2.69), 7.684 (2.57), 7.690 (2.68), 7.697 (2.64), 7.701 (2.62), 7.707 (1.67), 7.713 (1.47), 7.719 (1.35), 7.891 (5.14), 7.909 (9.32), 7.927 (5.15), 8.808 (15.44), 8.817 (16.00), 8.987 (3.04), 8.994 (3.37), 8.999 (3.61), 9.006 (5.77), 9.013 (3.40), 9.018 (3.29), 9.025 (2.77), 9.217 (5.41), 9.220 (5.54), 9.233 (5.30), 9.236 (5.22).

[0292] Example 3 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(1,1-dioxidothietan-3-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0293] N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)-quinoline-3-carboxamide (400 mg, 0.76 mmol) was suspended in DCM (9 ml). MCPBA (359 mg, 77% purity, 1.60 mmol) was added and the formed solution was stirred at room temperature overnight. The precipitated reaction mixture was diluted with DCM (15 ml) and aqueous potassium carbonate (15 ml, 0.5 M) and stirred vigorously. The remaining precipitate was filtered off. More DCM was added to the filtrate and the phases were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were dried and evaporated. The residue was combined with the first precipitate and purified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile).

[0294] Yield: 380 mg (90% of theoretical value) LC-MS analysis method A1): R t = 2.08 min; MS (ESIpos): m / z = 557 [M+H] + 1 H NMR (DMSO-d6) δ: 9.38 (m, 1H), 8.86 (d, 1H), 8.65 (m, 1H), 7.85 (m, 1H), 7.65-7.71 (m, 1H), 7.43 (d, 1H), 7.27 (m, 1H), 7.18 (m, 1H), 6.92 (m, 1H), 6.80 (d, 1H), 5.23-5.30 (m, 1H), 4.74-4.87 (m, 3H), 4.64-4.72 (m, 2H), 4.20-4.31 (m, 2H), 2.22-2.29 (m, 1H), 2.10-2.16 (m, 1H).

[0295] Example 4, Example 5, Example 6 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(1-oxidothietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide Mixture of diastereomers (Example 4) [ka]

[0296] N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (400 mg, 0.76 mmol) was added in DCM (8 ml). MCPBA (137 mg, 77% purity, 0.61 mmol) was added and the formed solution was stirred at room temperature for 20 min. Water was added, the phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried and evaporated. The residue (410 mg) was purified by preparative HPLC (RP 18, gradient with 0.1% aqueous formic acid and acetonitrile) to give 217 mg of mixed fractions. This material was repurified by preparative LC (Method 1) to give two separated isomers.

[0297] Isomer 1 (Example 5) Yield: 26 mg (6% of theoretical value) LC-MS (Analysis method A1): R t = 1.89 min; MS (ESIpos): m / z = 541 [M+H] + 1 H NMR (DMSO-d6) δ: 9.33 (br d, 1H), 8.82 (d, 1H), 8.45 (m, 1H), 7.65-7.81 (m, 2H), 7.39 (d, 1H), 7.24-7.32 (m, 1H), 7.18 (m, 1H), 6.92 (m, 1H), 6.80 (d, 1H), 5.91 (m, 1H), 5.26 (br m, 1H), 4.20-4.32 (m, 2H), 3.88-3.99 (m, 2H), 3.47-3.58 (m, 2H), 2.23 (m, 1H), 2.04-2.13 (m, 1H) Peak List 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.149 (1.62), 0.146 (1.64), 1.056 (0.53), 2.072 (3.49), 2.103 (3.61), 2.218 (3.04), 2.229 (3.36), 2.241 (3.59), 2.250 (2.55), 2.263 (2.13), 2.367 (2.09), 2.407 (0.51), 2.712 (2.08), 3.242 (1.87), 3.509 (5.61), 3.516 (4.16), 3.539 (9.78), 3.563 (6.74), 3.568 (5.92), 3.908 (5.06), 3.925 (6.95), 3.942 (5.90), 3.958 (4.82), 4.208 (1.85), 4.235 (4.98), 4.264 (5.56), 4.274 (5.40), 4.289 (4.78), 4.308 (2.10), 5.249 (3.77), 5.267 (4.73), 5.280 (3.97), 5.293 (1.39), 5.752 (13.70), 5.863 (1.33), 5.886 (4.96), 5.909 (7.31), 5.933 (4.73), 5.956 (1.21), 6.788 (9.95), 6.809 (11.07), 6.898 (4.22), 6.917 (8.80), 6.935 (5.07), 7.160 (5.33), 7.177 (8.64), 7.195 (4.13), 7.284 (3.76), 7.383 (8.99), 7.402 (8.33), 7.658 (1.77), 7.673 (3.38), 7.686 (3.36), 7.699 (3.45), 7.714 (1.82), 7.722 (1.58), 7.760 (5.73), 7.783 (10.89), 7.805 (6.10), 8.427 (6.26), 8.442 (6.66), 8.451 (6.62), 8.466 (6.15), 8.816 (15.13), 8.823 (16.00), 9.317 (7.21), 9.336 (6.84).

[0298] Isomer 2 (Example 6) : Yield: 109mg (theoretical value: 26%) LC-MS (Analytical Method A1): R t = 1.90 min; MS (ESIpos): m / z = 541 [M+H] + 1 H NMR (DMSO-d6) δ: 9.37 (d, 1H), 8.81 (d, 1H), 8.52 (m, 1H), 7.80 (m, 1H), 7.65-7.72 (m, 1H), 7.42 (d, 1H), 7.25-7.33 (m, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.80 (d, 1H), 5.27 (br m, 1H), 4.38-4.48 (m, 1H), 4.17-4.31 (m, 4H), 3.50-3.59 (m, 2H), 2.21-2.30 (m, 1H), 2.13 (m, 1H). ピークリスト 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.054 (0.66), 1.231 (0.71), 2.105 (2.73), 2.125 (3.29), 2.140 (4.26), 2.233 (3.52), 2.243 (3.80), 2.255 (3.82), 2.277 (2.24), 2.366 (1.32), 2.430 (0.47), 2.709 (1.24), 3.190 (0.52), 3.272 (2.57), 3.441 (3.26), 3.481 (1.76), 3.506 (5.14), 3.529 (9.30), 3.560 (10.10), 3.584 (5.48), 4.185 (5.09), 4.202 (12.56), 4.220 (13.98), 4.228 (11.12), 4.236 (10.66), 4.255 (9.63), 4.279 (5.41), 4.299 (2.33), 4.379 (2.04), 4.397 (3.40), 4.411 (4.26), 4.429 (6.16), 4.447 (3.37), 4.461 (2.96), 4.480 (1.29), 5.239 (1.34), 5.253 (4.15), 5.269 (6.16), 5.286 (4.28), 5.301 (1.55), 6.784 (10.78), 6.804 (12.11), 6.894 (3.47), 6.913 (7.15), 6.925 (4.04), 6.931 (4.12), 7.155 (5.80), 7.174 (9.65), 7.192 (4.67), 7.286 (3.27), 7.408 (10.27), 7.426 (9.67), 7.673 (3.77), 7.681 (3.76), 7.690 (3.90), 7.710 (2.03), 7.717 (1.77), 7.771 (6.30), 7.794 (12.17), 7.817 (6.79), 8.492 (6.47), 8.507 (7.11), 8.516 (7.14), 8.531 (6.52), 8.801 (14.53), 8.812 (16.00), 9.361 (10.25), 9.381 (10.18).

[0299] Example 7 N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolanyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0300] Synthesis by intermediates 4 and 5 starting from methyl tetrahydrofuran-3-carboxylate and ethyl 4-chloro-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate and the procedure described for Example 2.

[0301] LC-MS (Analysis method A1): R t = 2.16 min; MS (ESIpos): m / z = 523 [M+H] + 1 H NMR (chloroform-d) δ: 8.79 (m, 1H), 8.57-8.62 (m, 1H), 7.51 (t, 1H), 7.25-7.29 (m, 2H), 7.20 (m, 1H), 6.99-7.07 (m, 1H), 6.89-6.94 (m, 2H), 6.85 (d, 1H), 6.15-6.24 (m, 1H), 5.40 (br m, 1H), 4.50 (m, 1H), 4.28-4.41 (m, 3H), 4.10-4.23 (m, 2H), 3.81-3.89 (m, 1H), 2.46-2.57 (m, 1H), 2.31-2.46 (m, 2H), 2.21 (m, 1H). Peak List NMR: 1H-NMR (600 MHz, DMSO-d6) δ [ppm]: 2.060 (0.68), 2.224 (1.03), 2.424 (0.41), 3.289 (16.00), 3.783 (0.71), 4.054 (0.45), 4.063 (0.50), 4.128 (0.56), 4.224 (1.58), 4.236 (1.44), 4.263 (1.17), 4.339 (1.00), 4.352 (0.99), 5.279 (0.94), 6.778 (1.23), 6.792 (1.38), 6.905 (0.65), 6.918 (1.28), 6.930 (0.79), 7.150 (0.68), 7.162 (1.17), 7.175 (0.68), 7.268 (0.80), 7.353 (1.16), 7.364 (1.02), 7.669 (0.70), 7.785 (0.64), 7.800 (1.24), 7.815 (0.72), 8.579 (0.94), 8.767 (1.45), 8.774 (1.45), 9.139 (0.83), 9.151 (1.09).

[0302] Examples 8 and 9 N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3S)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (Example 8) and N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3R)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (Example 9) [ka]

[0303] Step 1: Ethyl 4-(2,5-dihydrofuran-3-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate [ka]

[0304] To a solution of ethyl 4-chloro-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (800 mg, 2.1 mmol) in dioxane (10 mL) and H2O (2 mL) was added 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 mg, 2.3 mmol), Pd(dppf)Cl2 (153 mg, 0.2 mmol) and K2CO3 (576 mg, 4.2 mmol). The reaction mixture was stirred overnight at 80° C. under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-20%) to give ethyl 4-(2,5-dihydrofuran-3-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (619 mg, 1.48 mmol) as a yellow oil.

[0305] LC-MS (Analytical method B2): R t = 1.283 min; MS (ESIpos): m / z = 418 (M+H) + .

[0306] Step 2: 7-Fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate ethyl [ka]

[0307] To a solution of ethyl 4-(2,5-dihydrofuran-3-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (619 mg, 1.5 mmol) in EtOH (10 mL) was added Pd / C (80 mg, 0.8 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature under hydrogen atmosphere (1.5 atm). After completion of the reaction, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-20%) to give ethyl 7-fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (592 mg, 1.4 mmol) as a yellow oil. LC-MS (Analytical method B2): R t = 1.336 min; MS (ESIpos): m / z = 420 (M+H) + .

[0308] Step 3: 7-Fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid [ka]

[0309] To a solution of ethyl 7-fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (592 mg, 1.4 mmol) in the mixed solvent THF / MeOH / H2O (V:V:V=1:1:1, 6 mL) was added LiOH (169 mg, 7.1 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and then water was added. The solution was adjusted to pH=4 with HCl (2N) and then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (590 mg, 1.4 mmol) as a yellow oil. LC-MS (Analytical method B2): R t= 0.715 min; MS (ESIpos): m / z = 392 (M+H) + .

[0310] Step 4: N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3S)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (Example 8) and N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3R)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (Example 9) [ka]

[0311] To a solution of 7-fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (590 mg, 1.41 mmol) in DMF (10 mL) was added HATU (806.28 mg, 2.12 mmol), DIEA (365.41 mg, 2.83 mmol) and (4S)-3,4-dihydro-2H-1-benzopyran-4-amine (608.51 mg, 1.56 mmol). The resulting mixture was stirred at room temperature overnight. Water was then added and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=0-20%) to give N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (582 mg, 1.1 mmol) as a yellow oil.

[0312] The two isomers were separated by Chiral Prep-HPLC (Column: Lux 5μm Cellulose-2, 2.12*25cm, 5μm; Mobile phase A: Hexane (0.5% 2M NH3-MeOH), Mobile phase B: EtOH; Flow rate: 20mL / min; Gradient: 10%B to 10%B in 31 min; Wavelength: 220 / 254nm; RT1(min): 16.40; RT2(min): 26.04; Sample solvent: EtOH) to give N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3S)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide ( Example 8 ) (69.7 mg, 133.40 mmol, 13.44% yield, 98.7% purity) was obtained as a white solid.

[0313] 1H NMR (400 MHz, DMSO-d6): 9.19 (d, 1H), 8.78 (s, 1H), 8.59 (t, 1H), 7.82 (t, 1H), 7.80-7.79 (m, 1H), 7.36 (t, 1H), 7.33-7.26 (m, 1H), 7.16 (t, 1H), 6.92 (t, 1H), 6.79 (d, 1H), 5.29-5.28 (m, 1H), 4.36 (t, 1H), 4.32-4.20 (m, 3H), 4.24-4.07 (m, 1H), 4.04-3.92 (m, 1H), 3.84-3.75 (m, 1H), 2.50-2.49 (m, 1H), 2.26-2.23 (m, 2H), 2.21-2.01 (m, 1H). LC-MS (Analysis method A2): R t = 1.408 min; MS (ESIpos): m / z = 523 (M+H) + . and N-[(4S)-3,4-dihydro-2H-1-benzopyran-4-yl]-7-fluoro-4-(oxolan-(3R)-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide ( Example 9) (97.2 mg, 186.03 μmol, yield 13.44%, purity 99.3%), and its absolute structure was confirmed by single crystal spectroscopy.

[0314] 1H NMR (400 MHz, DMSO-d6): 9.19 (d, 1H), 8.78 (s, 1H), 8.59 (t, 1H), 7.82 (t, 1H), 7.80-7.79 (m, 1H), 7.36 (t, 1H), 7.33-7.26 (m, 1H), 7.16 (t, 1H), 6.92 (t, 1H), 6.79 (d, 1H), 5.29-5.28 (m, 1H), 4.36 (t, 1H), 4.32-4.20 (m, 3H), 4.24-4.07 (m, 1H), 4.04-3.92 (m, 1H), 3.84-3.75 (m, 1H), 2.50-2.49 (m, 1H), 2.26-2.23 (m, 2H), 2.21-2.01 (m, 1H). LC-MS (Analysis method A2): R t = 1.269 min; MS (ESIpos): m / z = 523 (M+H) + .

[0315] The absolute configurations of the carbon atoms (4S; 3S, and 3R) of Examples 8 and 9 were confirmed by single crystal X-ray analysis.

[0316] Example 10 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(1-imino-1-oxide-1λ) 4 -thietan-3-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (mixture of diastereomers) [ka]

[0317] A suspension of N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)-quinoline-3-carboxamide (75 mg, 0.14 mmol) in methanol (2 ml) and DCM (0.4 ml) was added to diacetoxy(phenyl)-λ 3 The mixture was treated with -iodine (115 mg, 0.36) and ammonium carbamate (22.3 mg, 0.29 mmol). The mixture was dissolved and stirred at room temperature for 30 min. Saturated aqueous sodium bicarbonate was then added and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash chromatography on silica (25 g) with cyclohexane / ethyl acetate (12-55%).

[0318] Yield: 39 mg (49% of theoretical value) LC-MS (Analysis method A1): R t = 1.90 min; MS (ESIpos): m / z = 556 [M+H] + 1H NMR (DMSO-d6) δ: 9.33-9.43 (m, 1H), 8.82-8.89 (m, 1H), 8.72-8.80 (m, 1H), 7.79-7.88 (m, 1H), 7.64-7.75 (m, 1H), 7.24-7.34 (m, 1H), 7.13-7.23 (m, 1H), 6.86-6.96 (m, 1H), 6.75-6.84 (m, 1H), 5.22-5.34 (m, 1H), 4.97-5.07 (m, 1H), 4.69-4.85 (m, 1H), 4.42-4.66 (m, 4H), 4.14-4.36 (m, 2H), 2.18-2.31 (m, 1H), 2.05-2.18 (m, 1H).

[0319] Example 11 4-((1R,5R)-3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0320] A 20 mL round-bottom flask was charged with 4-chloro-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (200 mg, 0.41 mmol), (1s,5s)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (80 mg, 0.62 mmol), DMSO (5.00 mL) and DIEA (159 mg, 1.23 mmol). The resulting solution was stirred at 75° C. for 4 h. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=2:1) ​​to give the crude product. The crude product (90 mg) was further purified by preparative HPLC [mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 50% B to 60% B in 7 min] to give 4-((1R,5R)-3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (19.3 mg, 8.1% yield) as an off-white solid.

[0321] 1H-NMR (300 MHz, DMSO-d6): δ [ppm] = 9.47 (d, 1H), 8.44 (d, 1H), 8.20-8.10 (m, 1H), 7.72-7.58 (m, 2H), 7.35-7.15 (m, 3H), 6.95-6.90 (m, 1H), 6.79 (d, 1H), 5.20-5.10 (m, 1H), 4.26-4.12 (m, 6H), 4.01-3.92 (m, 6H), 2.20-2.00 (m, 2H). LC-MS (analysis method B1, 0-95% B in 0.01-2.00 min, 100% B in 2.00-2.70 min): R t = 1.75 min; MS (ESIpos): m / z = 580 (M+H) + .

[0322] Example 12 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0323] Step 1: Synthesis of ethyl 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate [ka]

[0324] A 100 mL round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with ethyl 4-bromo-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (100 mg, 0.234 mmoL), 2-oxa-5-azabicyclo[4.1.0]heptane hydrogen chloride (38 mg, 0.281 mmoL), potassium carbonate (130 mg, 0.936 mmoL) and acetonitrile (10 mL). The resulting solution was stirred at 70° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to give ethyl 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (100 mg, 96% yield) as a pale yellow solid.

[0325] Step 2: 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid [ka]

[0326] An 8 mL round-bottom flask was charged with ethyl 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate (80 mg, 0.179 mmol), THF (1 mL), MeOH (1 mL), HO (1 mL) and lithium hydroxide monohydrate (34 mg, 0.810 mmol). The resulting solution was stirred at room temperature for 4 h. Upon completion of the reaction, THF was removed under vacuum and the pH value of the mixture was adjusted to 5 with 1 M HCl. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (65 mg, 86.7% yield) as a yellow oil.

[0327] Step 3: 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0328] A 20 mL round bottom flask was charged with 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid (65 mg, 0.156 mmol), N,N-dimethylformamide (3 mL), (S)-chroman-4-amine (24 mg, 0.161 mmol), HATU (60 mg, 0.157 mmol) and N,N-diisopropylethylamine (67 mg, 0.519 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC [mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 70% B to 75% B in 14 min] to give 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (5.4 mg, 6.3% yield) as an off-white solid.

[0329] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.15-9.13 (m, 1H), 8.66-8.61 (m, 2H), 7.70-7.66 (m, 2H), 7.36-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.91-6.90 (m, 1H), 6.78 (d, 1H), 5.23-5.22 (m, 1H), 4.27-4.22 (m, 2H), 3.87-3.86 (m, 2H), 3.78-3.76 (m, 1H), 3.01-2.90 (m, 1H), 2.25-2.15 (m, 1H), 2.04-1.99 (m, 1H), 1.24-1.13 (m, 3H), 0.85-0.70 (m, 1H). LC-MS (analysis method B1, 5-95% B in 0.01-2.00 min, 95% B in 2.00-2.70 min): R t1 = 1.87 minutes; MS(ESIpos): m / z = 550 (M+H) + .

[0330] Example 13 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((S)-chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide [ka]

[0331] A 20 mL round-bottom flask was charged with (S)-4-chloro-N-(chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide (70 mg, 0.14 mmol), 2-oxa-5-azabicyclo[4.1.0]heptane hydrogen chloride (28 mg, 0.21 mmol), DMSO (2.0 mL) and DIEA (54 mg, 0.42 mmol). The resulting solution was stirred at 70° C. for 4 h. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=2:1) ​​to give the crude product. The crude product was further purified by preparative HPLC [mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 80% B to 90% B in 14 min] to give 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-((S)-chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide (17.8 mg, 22.6% yield) as an off-white solid.

[0332] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.13-9.12 (m, 1H), 8.64-8.55 (m, 2H), 7.70-7.64 (m, 2H), 7.51-7.50 (m, 2H), 7.35-7.30 (m, 1H), 7.18-7.15 (m, 1H), 6.92-6.90 (m, 1H), 6.80-6.78 (m, 1H), 5.24-5.23 (m, 1H), 4.26-4.25 (m, 2H), 3.87-3.86 (m, 2H), 3.80-3.75 (m, 1H), 3.31-3.30 (m, 2H), 3.00-2.90 (m, 1H), 2.19-2.16 (m, 1H), 2.05-2.03 (m, 1H), 1.18-1.13 (m, 1H), 0.80-0.70 (m, 1H). LC-MS (analysis method C1, 5-100% B in 0.01-2.00 min, 100% B in 2.00-2.70 min): R t = 1.54 min; MS (ESIpos): m / z = 564 (M+H) + .

[0333] Example 14 4-((1R,5R)-3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((S)-chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide [ka]

[0334] Step 1: 8-(3,5-dichlorophenyl)-7-fluoro-4-hydroxyquinoline-3-carboxylic acid [ka]

[0335] A 250 mL three-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with 8-bromo-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5.00 g, 17.54 mmol), (3,5-dichlorophenyl)boronic acid (6.67 g, 35.09 mmol), K2CO3 (4.84 g, 35.09 mmol), XPhos Pd G2 (1.38 g, 1.75 mmol), 1,4-dioxane (50 mL) and H2O (10 mL). The resulting solution was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was diluted with 10% NaOH, filtered, the filtrate was washed with MTBE and the pH value of the mixture was adjusted to 5 with 1 M HCl. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 8-(3,5-dichlorophenyl)-7-fluoro-4-hydroxyquinoline-3-carboxylic acid (7.2 g, 80% purity, 93.5%) as a white solid.

[0336] Step 2: 4-Chloro-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carbonyl chloride [ka]

[0337] A 250-mL flask was charged with 8-(3,5-dichlorophenyl)-7-fluoro-4-hydroxyquinoline-3-carboxylic acid (7.2 g, 80% purity, 16.6 mmol), DCM (100 mL), oxalyl dichloride (20 mL), and DMF (0.02 mL). The resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting solution was concentrated in vacuo to give 4-chloro-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carbonyl chloride (crude), which was used directly in the next step.

[0338] Step 3: (S)-4-Chloro-N-(chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide [ka]

[0339] A 250 mL three-neck round bottom flask, purged and maintained under an inert atmosphere of nitrogen, was charged with 4-chloro-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carbonyl chloride (crude), DCM (100 mL), (S)-chroman-4-amine (2.47 g, 16.6 mmol) and TEA (3.35 g, 22.2 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=3:1) to give (S)-4-chloro-N-(chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide (6.1 g, 74% yield) as an off-white solid.

[0340] Step 4: 4-((1R,5R)-3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((S)-chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide [ka]

[0341] A 20 mL round-bottom flask was charged with (S)-4-chloro-N-(chroman-4-yl)-8-(3,5-dichlorophenyl)7-fluoroquinoline-3-carboxamide (200 mg, 0.400 mmol), (1s,5s)-3,7-dioxa-9-azabicyclo[3.3.1]nonane (77 mg, 0.60 mmol), DMSO (5.00 mL) and DIEA (155 mg, 1.20 mmol). The resulting solution was stirred at 75° C. for 4 h. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=2:1) ​​to give the crude product. The crude product was further purified by preparative HPLC [mobile phase A: water (0.05% FA), mobile phase B: ACN; gradient: 50% B to 90% B in 8 min] to give 4-((1R,5R)-3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-((S)-chroman-4-yl)-8-(3,5-dichlorophenyl)-7-fluoroquinoline-3-carboxamide (17.1 mg, 7.2% yield) as an off-white solid.

[0342] 1 H-NMR (300 MHz, DMSO-d6): δ [ppm] = 9.36 (d, 1H), 8.45 (s, 1H), 8.14-8.07 (m, 1H), 7.73-7.71 (m, 1H), 7.67-7.49 (m, 3H), 7.35-7.32 (m, 1H), 7.26-7.16 (m, 1H), 6.96-6.91 (m, 1H), 6.81-6.80 (m, 1H), 5.19-5.15 (m, 1H), 4.28-4.23 (m, 2H), 4.16-4.11 (m, 4H), 4.01-3.94 (m, 6H), 2.18-2.01 (m, 2H). LC-MS (analysis method B1, 0-95% B in 0.01-2.00 min, 95% B in 2.00-2.70 min): R t = 1.92 min; MS (ESIpos): m / z = 594 (M+H)+ .

[0343] Example 15 N-((S)-chroman-4-yl)-7-fluoro-4-((1R,3S)-3-fluorocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0344] Step 1: 7-Fluoro-4-hydroxy-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate ethyl [ka]

[0345] To a solution of ethyl 8-bromanyl-7-fluoranyl-4-oxidanyl-quinoline-3-carboxylate (10.00 g, 31.84 mmol) in toluene (100 mL) and water (25 mL), [2,3,5-tris(fluoranyl)phenyl]boronic acid (6.72 g, 38.20 mmol), XPhos Pd G3 (2.70 g, 3.18 mmol), and CsF (6.31 g, 95.51 mmol) were added. The reaction mixture was stirred at 100° C. for 16 h under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with petroleum ether. The precipitated solid was collected by filtration and washed with petroleum ether to give ethyl 7-fluoranyl-4-oxidanyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (4.00 g, 10.95 mmol, 34.40% yield) as a black solid.

[0346] LC-MS (analysis method A3, 95% B in 1.20-1.90 min): R t= 1.012 min; MS (ESIpos): m / z = 366 (M+H) + .

[0347] Step 2: Ethyl 4-bromo-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate [ka]

[0348] To a solution of ethyl 7-fluoranyl-4-oxidanyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (3.93 g, 10.76 mmol) in DCM (40 mL) and DMF (8 mL) was added POBr3 (4.63 g, 16.14 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-50%) to give ethyl 4-bromanyl-7-fluoranyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (3.37 g, 7.87 mmol, yield 73.15%).

[0349] LC-MS (analysis method A3, 95% B in 1.20-1.90 min): R t = 1.262 min; MS (ESIpos): m / z = 428 (M+H) + .

[0350] Step 3: Ethyl 4-(3,3-dimethoxy-1-(methoxycarbonyl)cyclobutyl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate [ka]

[0351] To a solution of methyl 3,3-di(methoxy)cyclobutanecarboxylate (2.00 g, 11.46 mmol) in THF (20 mL) was added LiHMDS (15.3 mL, 15.27 mmol, 1M in THF) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 30 min. To the above mixture was added ethyl 4-bromanyl-7-fluoranyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (3.27 g, 7.64 mmol) in THF (20 mL) dropwise at −78° C. The resulting mixture was stirred at −78° C. for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-30%) to obtain ethyl 4-[3,3-di(methoxy)-1-methoxycarbonyl-cyclobutyl]-7-fluoranyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (2.9 g, 5.56 mmol, yield 72.82%).

[0352] LC-MS (analytical method A3, 95% B in 1.20-1.90 min): R t = 1.295 min; MS (ESIpos): m / z = 522 (M+H) + .

[0353] Step 4: 7-Fluoro-4-(3-oxocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid [ka]

[0354] To a solution of ethyl 4-[3,3-di(methoxy)-1-methoxycarbonyl-cyclobutyl]-7-fluoranyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (2.85 g, 5.47 mmol) in DME (30 mL) was added NaOH (874 mg, 21.86 mmol) in water (2.4 mL). The reaction mixture was stirred at 60° C. for 16 hours. Then, aqueous HCl solution (9N, 3.6 mL) was added to the above mixture at 60° C. The resulting mixture was stirred at 60° C. for another 2 hours. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-fluoranyl-4-(3-oxidanylidenecyclobutyl)-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylic acid (2.60 g, 6.68 mmol).

[0355] LC-MS (analytical method B3, 95% B in 1.40-1.90 min): R t = 0.929 min; MS (ESIpos): m / z = 390 (M+H) + .

[0356] Step 5: 7-Fluoro-4-((1r,3r)-3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid [ka]

[0357] To a solution of 7-fluoranyl-4-(3-oxidanylidenecyclobutyl)-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylic acid (2.50 g, 6.42 mmol) in MeOH (20 mL) was added sodium borohydride (364 mg, 9.63 mmol) portionwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was treated with water and acidified to pH=5 with HCl (2N). The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-fluoranyl-8-(3-fluoranyl-2,5-difluoro-phenyl)-4-(3-hydroxycyclobutyl)quinoline-3-carboxylic acid (1.20 g, 3.07 mmol, 47.75% yield).

[0358] LC-MS (analysis method C3, 2-100% B in 0.01-1.20 min, 100% B in 1.20-1.75 min): R t = 1.035 min; MS (ESIpos): m / z = 392 (M+H) + .

[0359] Step 6: N-((S)-chroman-4-yl)-7-fluoro-4-((1R,3S)-3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0360] To a solution of 7-fluoranyl-8-(3-fluoranyl-2,5-difluoro-phenyl)-4-(3-hydroxycyclobutyl)quinoline-3-carboxylic acid (640 mg, 1.64 mmol) in DMF (6 mL) was added (4S)-chroman-4-amine (488 mg, 3.27 mmol), HATU (932.81 mg, 2.45 mmol) and DIEA (634 mg, 4.91 mmol). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-50%) to obtain N-[(4S)-chroman-4-yl]-7-fluoro-4-(3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (280 mg, 535.90 μmol, yield 32.77%) as a white solid.

[0361] LC-MS (analytical method A3, 95% B in 1.20-1.90 min): R t = 1.135 min; MS (ESIpos): m / z = 523 (M+H) + .

[0362] Step 7: N-((S)-chroman-4-yl)-7-fluoro-4-((1R,3S)-3-fluorocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0363] To a stirred solution of N-[(4S)-chroman-4-yl]-7-fluoro-4-(3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (272 mg, 520.58 μmol) in DCM (3 mL) was added BAST (346 mg, 1.56 mmol) dropwise under nitrogen atmosphere at 0° C. The resulting mixture was stirred under nitrogen atmosphere at 0° C. for 0.5 h, and the resulting mixture was treated with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate:petroleum ether=1:2) and further purified by preparative HPLC (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; gradient: 47% B to 72% B in 9 min) to give N-[(4S)-chroman-4-yl]-7-fluoranyl-4-(3-fluorocyclobutyl)-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxamide (32.3 mg, 60.66 μmol, 11.65% yield, 98.5% purity) as a white solid.

[0364] 1 H-NMR (400 MHz, DMSO-D6): δ [ppm] = 9.17 (d, 1H), 8.77 (d, 1H), 8.28-8.25 (m, 1H), 7.76-7.68 (m, 2H), 7.34-7.29 (m, 2H), 7.18-7.15 (m, 1H), 6.92-6.91 (m, 1H), 6.79 (d, 1H), 5.28-5.14 (m, 2H), 4.76-4.72 (m, 1H), 4.28-4.20 (m, 2H), 2.92-2.62 (m, 4H), 2.25-2.15 (m, 1H), 2.05-2.00 (m, 1H). LC-MS (analysis method B3, 30-70% B in 0.01-1.90 min, 70-95% B in 1.90-2.00 min, 95% B in 2.00-2.70 min): R t1 = 1.846 min; MS (ESIpos): m / z = 525 (M+H) + .

[0365] Example 16 N-((S)-chroman-4-yl)-7-fluoro-4-(3-oxopiperazin-1-yl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide [ka]

[0366] Step 1: To a solution of 4-chloro-N-((S)-chroman-4-yl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxamide (100 mg, 0.205 mmol) in ACN (3 mL) was added potassium carbonate (85 mg, 0.616 mmol) and piperazin-2-one (31 mg, 0.308 mmol). The reaction mixture was stirred at 70° C. for 36 h. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol 10:1) and further purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% to 55% in 8 min; 254 nm; RT1: 6.6.) to give 35.0 mg (30.71%) of the product as a white solid.

[0367] LC-MS (Analytical method A3, 5-95% B in 0-3.00 min): Rt = 1.598 min; MS (ESIpos): m / z = 551 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.28-9.26 (m, 1H), 8.72 (d, 1H), 8.37-8.33 (m, 1H), 8.12 (s, 1H), 7.74-7.66 (m, 2H), 7.39-7.37 (m, 1H), 7.31-7.25 (m, 1H), 7.19-7.15 (m, 1H), 6.80-6.78 (m, 1H), 5.23-5.22 (m, 1H), 4.27-4.22 (m, 2H), 3.84 (s, 2H), 3.53-3.44 (m, 4H), 2.27-2.20 (m, 1H), 2.15-2.02 (m, 1H).

[0368] Experimental Section - Biological Assays The Examples were tested one or more times in the selected biological assay. When tested more than once, the data are reported as either the mean or median, where: The average value, also called the arithmetic mean, represents the sum of the values ​​obtained divided by the number of tests · The median represents the middle value of a group of values ​​when ranked in ascending or descending order. If the number of values ​​in a data set is odd, the median is the middle value. If the number of values ​​in a data set is even, the median is the arithmetic mean of the two middle values.

[0369] The examples were synthesized one or more times. When synthesized more than once, the data from the biological assays represent the mean or median values ​​calculated using data sets derived from testing one or more synthetic batches.

[0370] The in vitro activity of the compounds of the present invention has been demonstrated in the following assays: In vitro assay 1: Dirofilaria immitis Slo-1-recombinant D. immitis cell line activity Generation of stable D. immitis Slo-1 CHO cell lines The CHO cell line was obtained from ATCC, code ATCC CRL-9096. For transfection with plasmid DNA to express D. immitis Slo-1 (based on protein sequence JQ730003, codon optimized for hamster), CHO cells were passaged to 40% confluence before the transfection solution was added to the cell culture. The transfection solution contained 300 μL OptiMEM (Life Technologies, Nr.: 31985), 2 μL (= 6 μg) plasmid DNA containing the D. immitis Slo 1 gene and 9 μL FugeneHD (Promega, Nr.: E2311) and was added to the cells before incubating for 48 h at 37 °C and 5% CO2. The transfection medium was replaced with selection medium containing additional G418 (2mg / ml, Invitrogen, Nr.:10131) and the cells were seeded in 384-well plates (300 cells / well). After a few weeks, the remaining viable cells were tested for K+ channel expression using a voltage-sensitive dye (Membrane Potential Assay Kit, Molecular Devices Nr.:R8034). Positive cell clones were purified by limiting dilution. For this, the clones with the highest and most robust signal in the voltage-sensitive dye assay were further subcloned (incubated) in 384-well plates (0.7 cells / well) to obtain clonal purity. This generated the final stable CHO cell line expressing Dirofilaria immitis Slo-1.

[0371] Cell culture conditions Cells were cultured at 37°C and 5% CO2 in MEMalpha containing 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 detached using Accutase (Sigma, Nr.:A6964).

[0372] Membrane potential measurement Compound testing in the laboratory was performed in 384-well microtiter plates (MTPs, Greiner, Nr.:781092). 8000 cells / well were plated onto 384-well MTPs and cultured for 20-24 h at 37 °C and 5% CO2. After removing the cell culture medium, cells were washed once with Tyrode's (150 mM NaCl, 0.3 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.8 mM NaH2PO4, 5 mM glucose, 28 mM Hepes, pH 7.4) and then loaded with the voltage-sensitive dye of the membrane potential assay kit diluted in Tyrode's for 1 h at room temperature.

[0373] Fluorescence measurements were started using a FLIPR Tetra (Molecular Devices, Exc. 510-545 nm, Emm. 565-625 nm) before the addition of test compound, followed by KCl Tyrode (final assay concentrations: 70 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 0.8 mM NaH2PO4, 5 mM glucose, 28 mM Hepes, pH 7.4, containing voltage-sensitive dye). Measurements were completed after 7 min.

[0374] statistics Data were curve-fitted using ActivityBase XLfit software (IDBS) to obtain median effective concentrations (EC 50 ) and is evaluated by calculating the negative common logarithm (pE 50 ) was reported.

[0375] Or, E.C. 50 was calculated using four parameters plotted by Scilligence ELN / Regmol Software Tool, Bioassay.

[0376] EC >1 nM to 10 nM for the following Examples: 1, 7, 8, 9, 10, 12, 13, 15 50 However, it was found.

[0377] For the following Example: 3, EC 50 However, it was found.

[0378] For the following Example: 6, pE >100 nM to 1 μM 50 However, it was found.

[0379] In vitro assay 2: Nippostrongylus brasiliensis (NIPOBR) Adult hookworms were washed with saline 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 nematodes were incubated in medium at final concentrations of 10 μg / ml (10 ppm) and 1 μg / ml (1 ppm), respectively. An aliquot of the medium was used to determine acetylcholinesterase activity in comparison with a negative control. The principle of measuring acetylcholinesterase as a readout for anthelmintic activity has been described by Rapson et al. (1986) and Rapson et al. (1987).

[0380] For the following Examples: 7, 8, 9, 10, 15, 16, EC 50 was ≦0.1 ppm.

[0381] In vitro assay 3: Dirofilaria immitis microfilariae (DIROIM L1) ≧250 Dirofilariae, freshly purified from blood, were added to wells of a microtiter plate containing nutrient medium and test compound in DMSO. Compounds were tested in duplicate in a concentration-response assay. Larvae exposed to DMSO and no test compound were used as negative controls. Larvae were assessed after 72 hours of incubation with compounds. Efficacy was determined as a reduction in motility compared to the negative control. A wide range of concentrations was measured and concentration-response curves and EC 50 values ​​were calculated.

[0382] For the following Examples: 1, 3, 6, 7, 8, 9, 10, 13, 15, EC 50 was <0.1 ppm.

[0383] In vitro assay 4: Dirofilaria immitis (DIROIM L4) Ten third stage larvae of Dirofilaria immitis, freshly isolated from their vector (intermediate host), were added to wells of a microtiter plate containing test compounds in nutrient medium and DMSO. Compounds were tested in duplicate in a concentration-response assay. Larvae exposed to DMSO and no test compound were used as negative controls. Larvae were evaluated after 72 hours of incubation with the compounds. Within these 72 hours of incubation, the majority of the negative control larvae molt into fourth stage larvae. Efficacy was determined as a reduction in motility compared to the negative control. Based on the evaluation of a wide concentration range, concentration-response curves as well as EC 50 values ​​were calculated.

[0384] For the following Examples: 1, 7, 8, 9, 10, 15, EC 50 was <0.1 ppm.

[0385] In vitro assay 5: Haemonchus contortus (HAEMCO) Solvent: Dimethyl sulfoxide To prepare a suitable preparation of the active compound, 10 mg of active compound are dissolved in 0.5 ml of solvent and the concentrate is diluted to the desired concentration with "Ringer's solution".

[0386] Approximately 40 red stomach worm (Haemonchus contortus) larvae are transferred to the test tube containing the compound solution.

[0387] After 5 days the mortality of the larvae is recorded: 100% efficacy means that all the larvae are killed, 0% efficacy means that no larvae are killed.

[0388] Formulation Examples Exemplary formulations consisted of active agent in 10% Transcutol, 10% Cremophor EL and 80% isotonic saline. First, the active agent was dissolved in Transcutol. After dissolution in Transcutol, Cremophor and isotonic saline were added. These formulations were used as service formulations in the following in vivo assays.

[0389] An example of a formulation according to the invention is the following Formulation Example F1, in which the active substance was dissolved in Transcutol to form a 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 formulation (Formulation Example F1) had a volume of 1 mL.

[0390] Stock solution A: 4.0 mg compound of Example 2, 0.100mL Transcutol.

[0391] Formulation Example F1: 0.100mL Stock solution A, 0.100mL Cremophor EL, and 0.800mL isotonic saline.

[0392] In vivo assays In vivo assay 1: filarial nematodes of the genus A. viteae (Acanthocheilonema viteae) Jirds (Meriones unguiculatus) experimentally infected with infective A. viteae larvae by subcutaneous injection were then treated once with formulated test compounds by oral gavage or intraperitoneal administration. Efficacy was expressed as the % reduction in worm numbers compared to placebo-treated groups at necropsy 12 weeks after infection, using Abbot's formula.

[0393] In vivo assay 2: Filarial nematodes of L. sigmodontis (Litomosoides sigmodontis) Mice were experimentally infected with infective L. sigmodontisno larvae by subcutaneous injection and then treated once with formulated test compounds by oral gavage or intraperitoneal administration. Efficacy was calculated by counting emerged larvae versus untreated animals at necropsy 5 weeks after infection using Abbot's formula.

[0394] In vivo assay 3: Gastrointestinal nematodes of Haemonchus contortus and Trichostrongylus colubriformis Jirds (Meriones unguiculatus), immunosuppressed by administration of rodent chow containing hydrocortisone 21-acetate, were experimentally infected by oral gavage with third instar larvae of T. colubriformis and H. contortus, respectively, and treated once orally or intraperitoneally with formulated test compounds on day 6 post-infection. Three days after treatment, the gerbils were euthanized and dissected to recover H. contortus from the stomach and T. colubriformis from the small intestine. Efficacy is expressed as a % reduction in nematode counts compared to the placebo-treated group using the Abbott formula.

[0395] The following examples were tested in in vivo tests 1, 2, and / or 3 and had the following activities: 100%:1 against A. viteae at ≤25.0 mg / kg per oral dose; Against L. sigmodontis, 80% or more at ≤3.0 mg / kg per oral or intraperitoneal dose: 4, 15; For H. contortus and / or T. colubriformis, 100% at ≤1.0 mg / kg, i.p.: 1, 5, 8, 9, 10, 15 and 16.

Claims

1. General formula (I) 【Chemical 1】 [During the ceremony, A is A1 or A2, 【Chemistry 2】 o is 0, 1, 2, 3 or 4; R is hydrogen, halogen, cyano, nitro, —OH, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C ３ -C ６ -cycloalkyl, -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, -S-C １ -C ４ -halogenoalkyl, -S(O)-C １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl, R ｐ is hydrogen, C １ -C ４ - alkyl, X and Y are CR ７ R ８ , O, S, and N-R ９ wherein at least one of X and Y is independently selected from the group consisting of ７ R ８ is), or X and Y together represent —C(O)—O— or —C(O)—NR ９ -, -S(O)-NR ９ -, -SO ２ -NR ９ - and -SO ２ forming a ring member selected from the group consisting of —O—; R １ is hydrogen, cyano, —CHO, —OH, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms ３ -C ６ -halogenocycloalkyl, 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 , N.H. 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(O) having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl-C(O)-, 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 having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl; Phenyl-C １ -C ４ -Alkyl (which is a halogen, -OH, -NO ２ , cyano, C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -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 having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, -S(O)-C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl); Heterocyclyl-C １ -C ４ -alkyl, wherein said heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is selected from halogen, —OH, —NO ２ , cyano, C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -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 having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, -S(O)-C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl) is selected from the group consisting of R ２ are 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thioxocyclobutyl, 3-thioxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidethietan-3-yl, 1-oxidethietan-2-yl, 1-imino-1-oxide-1-thietan-3-yl, 1-imino-1-oxide-1-thietan-2-yl, 1,1-dioxidethietan-3-yl, 1,1-dioxidethietan-2-yl, 1,1-dioxide-1,2-thiazetidin-3-yl , 1,1-dioxide-1,2-thiazetidin-4-yl, 1-oxide-1,2-thiazetidin-3-yl, 1-oxide-1,2-thiazetidin-4-yl, 2-oxide-1,2-oxathietan-3-yl, 2-oxide-1,2-oxathietan-4-yl, 2,2-dioxide-1,2-oxathietan-3-yl, 2,2-dioxide-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3- yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo-3-(hydroxyimino)cyclobutyl, 2,2-diiodo-3-(hydroxyimino)cyclobutyl, 5- to 10-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heteroaryl (each of which is halogen, —OH, —oxo, —NO, ２ , Cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -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 having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, -S(O)-C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl) is selected from the group consisting of R ３ is hydrogen or C １ -C ４ - alkyl, R ４ is hydrogen, halogen, -OH, cyano, C １ -C ４ -Alkyl, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy-C １ -C ４ -Alkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C １ -C ４ -Alkyl-C(O)-, -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 selected from the group consisting of fluorine, chlorine, methoxy and isopropoxy, R ５ is hydrogen, halogen, -OH, cyano, C １ -C ４ -Alkyl, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy-C １ -C ４ -Alkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, 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 hydrogen, halogen, -OH, cyano, C １ -C ４ -Alkyl, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy-C １ -C ４ -Alkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, 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 hydrogen, -OH, fluorine, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, R ８ is 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 together with the carbon atoms to which they are attached, form C ３ -C ６ - forms a 3- to 6-membered ring selected from the group consisting of cycloalkyl and 3- to 6-membered heterocycloalkyl, R ９ is hydrogen, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and C １ -C ４ -alkoxy, R １０ is hydrogen, -OH, C １ -C ４ -Alkyl and C １ -C ４ -From alkoxy is selected from the group R １１ is hydrogen, C １ -C ４ -Alkyl and C １ -C ４ - from the group consisting of alkoxy Selected, Or, R １０ and R １１ together with the carbon atoms to which they are attached, form C ３ -C ６ - forms a 3- to 6-membered ring selected from the group consisting of cycloalkyl and 3- to 6-membered heterocycloalkyl, Q represents a phenyl having 1 to 5 halogen atoms; where Y is O, S or N—R ９ If R ７ , R ８ , R １０ and R １１ of Both -OH and C １ -C ４ -alkoxy, and where X is O, S or N-R ９ If R ７ and R ８ Neither -OH nor C １ -C ４ -Also not alkoxy) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

2. A is A1 or A2, 【Chemistry 3】 o is 0, 1, 2, 3 or 4; R is hydrogen, halogen, cyano, nitro, —OH, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C ３ -C ６ -cycloalkyl, -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, -S-C １ -C ４ -halogenoalkyl, -S(O)-C １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl, R ｐ But hydrogen, C １ -C ４ - alkyl, X and Y are CR ７ R ８ , O, S, and N-R ９ wherein at least one of X and Y is independently selected from the group consisting of ７ R ８ is), or X and Y together form —C(O)—O— or —C(O)—NR ９ -, -S(O)-NR ９ -, -SO ２ -NR ９ - and -SO ２ forming a ring member selected from the group consisting of —O—; R １ is hydrogen, cyano, -CHO, -OH, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms ３ -C ６ -halogenocycloalkyl, 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 , N.H. 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(O) having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl-C(O)-, 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 having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl; Phenyl-C １ -C ４ -Alkyl (which is a halogen, -OH, -NO ２ , cyano, C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -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 having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, -S(O)-C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl); Heterocyclyl-C １ -C ４ -alkyl, wherein said heterocyclyl substituent is selected from the group consisting of 4- to 10-membered heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl, each of which is selected from halogen, —OH, —NO ２ , cyano, C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -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 having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, -S(O)-C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and -SO having 1 to 5 halogen atoms ２ -C １ -C ４ -halogenoalkyl) is selected from the group consisting of R ２ 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thioxocyclobutyl, 3-thioxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 1-oxidethietan-3-yl, 1-oxidethietan-2-yl, 1-imino-1-oxide-1-thietan-3-yl, 1-imino-1-oxide-1-thietan-2-yl, 1,1-dioxidethietan-3-yl, 1,1-dioxidethietan-2-yl, 1,1-dioxide-1,2-thiazetidin-3-yl , 1,1-dioxide-1,2-thiazetidin-4-yl, 1-oxide-1,2-thiazetidin-3-yl, 1-oxide-1,2-thiazetidin-4-yl, 2-oxide-1,2-oxathietan-3-yl, 2-oxide-1,2-oxathietan-4-yl, 2,2-dioxide-1,2-oxathietan-3-yl, 2,2-dioxide-1,2-oxathietan-4-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 4-thioxoazetidin-2-yl, 2-thioxoazetidin-3- yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-mercaptocyclobutyl, 3-mercaptocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 2-chlorocyclobutyl, 3-chlorocyclobutyl, 2,2-dichlorocyclobutyl, 3,3-dichlorocyclobutyl, 2-bromocyclobutyl, 3-bromocyclobutyl, 2,2-dibromocyclobutyl, 3,3-dibromocyclobutyl, 2-iodocyclobutyl, 3 -iodocyclobutyl, 2,2-diiodocyclobutyl, 3,3-diiodocyclobutyl, 3-methoxyiminocyclobutyl, 2-fluoro-3-(methoxyimino)cyclobutyl, 2,2-difluoro-3-(methoxyimino)cyclobutyl, 2-chloro-3-(methoxyimino)cyclobutyl, 2,2-dichloro-3-(methoxyimino)cyclobutyl, 2-bromo-3-(methoxyimino)cyclobutyl, 2,2-dibromo-3-(methoxyimino)cyclobutyl, 2-iodo-3-(methoxyimino)cyclobutyl, 2,2-diiodo-3-(methoxyimino)cyclobutyl, 3-(hydroxyimino)cyclobutyl, 2-fluoro-3-(hydroxyimino)cyclobutyl, 2,2-difluoro-3-(hydroxyimino)cyclobutyl, 2-chloro-3-(hydroxyimino)cyclobutyl, 2,2-dichloro-3-(hydroxyimino)cyclobutyl, 2-bromo-3-(hydroxyimino)cyclobutyl, 2,2-dibromo-3-(hydroxyimino)cyclobutyl, 2-iodo 2,2-diiodo-3-(hydroxyimino)cyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2,5-dihydrofuran-3-yl, 2,3-dihydrofuran-3-yl, 4,5-dihydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 2,5-dihydrofuran-2-yl, 2,3-dihydrofuran-2-yl, furan-3-yl, furan-2-yl, tetrahydrothio thiophen-3-yl, tetrahydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,3-dihydrothiophen-3-yl, 4,5-dihydrothiophen-3-yl, 4,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-2-yl, 2,3-dihydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-2-yl dihydro-1H-pyrrol-3-yl, 4,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, 4,5-dihydro-1H-pyrrol-3-yl, 3,4-dihydro-2H-pyrrol-4-yl, 3,4-dihydro-2H-pyrrol-3-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydro-1H-pyrrol-3-yl, 2H-pyrrol-5-yl, 3H-pyrrol-2-yl, 2H-pyrrol-4-yl, 1H-pyrrol-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 4-alkyl-3-oxopiperazin-1-yl or 4-alkyl-2-oxopiperazin-1-yl, wherein the alkyl is C, １ -C ６ -alkyl), 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R ３ is hydrogen or C １ -C ４ - alkyl, R ４ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, preferably hydrogen, halogen and C １ -C ４ -alkoxy, more preferably selected from the group consisting of fluorine, chlorine, methoxy and isopropoxy, R ５ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -NH ２ , —NH(C １ -C ４ -alkyl), -N(C １ -C ４ -alkyl) ２ is selected from the group consisting of R ６ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -NH ２ , —NH(C １ -C ４ -alkyl), -N(C １ -C ４ -alkyl) ２ is selected from the group consisting of R ７ is hydrogen, -OH, fluorine, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, R ８ is 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 But hydrogen, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl and C １ -C ４ -alkoxy, R １０ is hydrogen, -OH, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, R １１ But hydrogen, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, Q represents phenyl having 1 to 5 halogen atoms; where Y is O, S or N—R ９ If R ７ , R ８ , R １０ and R １１ Neither -OH nor C １ -C ４ -alkoxy, and where X is O, S or N-R ９ If R ７ and R ８ Neither -OH nor C １ -C ４ -Also not alkoxy, 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

3. A is A1 or A2, 【Chemistry 4】 o is 0, 1 or 2; R is hydrogen, halogen, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, cyano, C having 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, R ｐ But hydrogen, C １ -C ４ - alkyl, X and Y are CR ７ R ８ , O, S, and N-R ９ wherein at least one of X and Y is independently selected from the group consisting of ７ R ８ (which is R １ But 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 Examples of the thietanyl compounds include 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido-1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, and 2,2-difluorocyclobutyl. cyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R ３ is hydrogen or C １ -C ４ - alkyl, R ４ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, preferably hydrogen, halogen and C １ -C ４ -alkoxy, more preferably selected from the group consisting of fluorine, chlorine, methoxy and isopropoxy, R ５ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -NH ２ , —NH(C １ -C ４ -alkyl), -N(C １ -C ４ -alkyl) ２ is selected from the group consisting of R ６ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, -NH ２ , —NH(C １ -C ４ -alkyl), -N(C １ -C ４ -alkyl) ２ is selected from the group consisting of R ７ is hydrogen and C １ -C ４ - alkyl, R ８ is hydrogen and C １ -C ４ - alkyl, Or, R ７ and R ８ together form an oxo group (=O), R ９ is hydrogen or C １ -C ４ - alkyl, R １０ is hydrogen, -OH, C １ -C ４ -Alkyl and C １ -C ４ -alkoxy, R １１ is hydrogen, Q represents phenyl having 1 to 5 substituents independently selected from fluorine, chlorine, or bromine; where Y is O, S or N—R ９ If R １０ is -OH or C １ -C ４ -Also not alkoxy, 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

4. A is A1 or A2, 【Chemistry 5】 o is 0, 1 or 2; R is hydrogen, halogen, C １ -C ４ -Alkyl, C １ -C ４ - selected from the group consisting of alkoxy, and cyano; R ｐ But hydrogen, C １ -C ４ - alkyl, X is CR ７ R ８ , O, S, and N-R ９ is selected from the group consisting of Y is CR ７ R ８ or O, R １ is hydrogen or C １ -C ４ - alkyl, R ２ 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidethietan-3-yl, 1-oxidethietan-2-yl, 1-imino-1-oxide-1-thietan-3-yl, 1-imino-1-oxide-1-thietan-2-yl, 1,1-dioxidethietan-3-yl, 1,1-dioxidethietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R ３ is hydrogen or C １ -C ４ - alkyl, R ４ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, preferably hydrogen, halogen and C １ -C ４ -alkoxy, more preferably selected from the group consisting of fluorine, chlorine, methoxy and isopropoxy, R ５ is hydrogen, halogen, -OH, -NH ２ , Cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ - selected from the group consisting of halogenoalkoxy, R ６ is hydrogen, halogen, -OH, cyano, C １ -C ４ - alkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy, R ７ is hydrogen and C １ -C ４ - alkyl, R ８ is hydrogen and C １ -C ４ - alkyl, Or, R ７ and R ８ together form an oxo group (=O), R ９ is hydrogen or C １ -C ４ - alkyl, R １０ is hydrogen, —OH and C １ -C ４ - alkyl, R １１ is hydrogen, Q represents phenyl having two or three substituents independently selected from fluorine, chlorine, or bromine; where Y is O, then R １０ is not -OH, 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

5. A is, 【Chemistry 6】 【change】 Preferably, 【Chemistry 7】 is selected from the group consisting of R １ is hydrogen or methyl, R ２ 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidethietan-3-yl, 1-oxidethietan-2-yl, 1-imino-1-oxide-1-thietan-3-yl, 1-imino-1-oxide-1-thietan-2-yl, 1,1-dioxidethietan-3-yl, 1,1-dioxidethietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R ３ is hydrogen or methyl, R ４ is selected from the group consisting of hydrogen, fluorine, chlorine, —OH, cyano, methyl, methoxy, trifluoromethyl, isopropoxy, and trifluoromethoxy, preferably hydrogen, fluorine, chlorine, methoxy, and isopropoxy; R ５ is hydrogen, fluorine, chlorine, —OH, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy and NH ２ is selected from the group consisting of R ６ is selected from the group consisting of hydrogen, fluorine, chlorine, —OH, cyano, methyl, and methoxy; Q is selected from the group consisting of 2,3-dichlorophenyl, 3,5-dichlorophenyl, and 2,3,5-trifluorophenyl; 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

6. A is, 【Chemistry 8】 Preferably, 【Chemistry 9】 is selected from the group consisting of R １ is hydrogen or methyl, R ２ 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2-thietanyl, 1-oxidethietan-3-yl, 1-oxidethietan-2-yl, 1-imino-1-oxide-1-thietan-3-yl, 1-imino-1-oxide-1-thietan-2-yl, 1,1-dioxidethietan-3-yl, 1,1-dioxidethietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, selected from the group consisting of 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-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, chlorine, fluorine, methoxy and isopropoxy; R ５ is hydrogen, chlorine, fluorine, —OH, cyano, methyl, trifluoromethoxy and NH ２ is selected from the group consisting of R ６ is selected from the group consisting of hydrogen, fluorine, chlorine, —OH, cyano, methyl, and methoxy; Q is selected from the group consisting of 2,3-dichlorophenyl, 3,5-dichlorophenyl, and 2,3,5-trifluorophenyl; 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

7. R ２ 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1-imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl , 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; Q is 2,3,5-trifluorophenyl or 3,5-dichlorophenyl; 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

8. R ２ is selected from the group consisting of 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1-imino-1-oxide-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3-fluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, tetrahydropyran-4-yl, 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl; R ４ is hydrogen, halogen, -OH, cyano, C １ -C ４ -Alkyl, C ３ -C ６ -cycloalkyl, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkyl, C １ -C ４ -alkoxy-C １ -C ４ -Alkyl, C １ -C ４ -alkoxy, C with 1 to 5 halogen atoms １ -C ４ -halogenoalkoxy, C １ -C ４ -Alkyl-C(O)-, -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 selected from the group consisting of fluorine, chlorine, methoxy and isopropoxy, Q is 2,3,5-trifluorophenyl or 3,5-dichlorophenyl; 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

9. R ２ is 3-hydroxycyclobutyl, 3-fluorocyclobutyl, tetrahydrofuran-3-yl or 3-oxocyclobutyl; Q is 2,3,5-trifluorophenyl or 3,5-dichlorophenyl; 10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

10. The compound is 【Chemistry 10】 Selected from:

10. The compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

11. A method for preparing a compound of general formula (I) according to any one of claims 1 to 10, which comprises reacting a compound of general formula 1N: 【Chemistry 11】 [In the formula, A, R １ , R ３ , R ４ , R ５ , R ６ and Q is as defined for the compounds of general formula (I) according to any one of claims 1 to 10. by reacting an intermediate compound of general formula 1F: 【Chemistry 12】 [In the formula, R ２＃ are methyl 2,2-dimethoxycyclobutane-1-carboxylate, methyl 3,3-dimethoxycyclobutane-1-carboxylate, methyl 2,2-bis(methylthio)cyclobutane-1-carboxylate, methyl 3,3-bis(methylthio)cyclobutane-1-carboxylate, ethyl thietane-3-carboxylate, ethyl thietane-2-carboxylate, ethyl oxetane-3-carboxylate, ethyl oxetane-2-carboxylate, methyl 2-fluorocyclobutane-1-carboxylate, methyl 3-fluorocyclobutane-1-carboxylate, methyl 2,2-difluorocyclobutane-1-carboxylate, methyl 3,3-difluorocyclobutane-1-carboxylate, tetrahydrofuran methyl tetrahydrofuran-2-carboxylate, methyl tetrahydrofuran-3-carboxylate, methyl furan-3-carboxylate, methyl furan-2-carboxylate, methyl tetrahydrothiophene-3-carboxylate, methyl tetrahydrothiophene-2-carboxylate, methyl thiophene-3-carboxylate, methyl thiophene-2-carboxylate, methyl 1-methylpyrrolidine-2-carboxylate, methyl 1-methylpyrrolidine-3-carboxylate, methyl 5-oxopyrrolidine-3-carboxylate, methyl 2-oxopyrrolidine-3-carboxylate, methyl 5-oxopyrrolidine-2-carboxylate, and methyl tetrahydropyran-4-carboxylate. followed by a saponification reaction in the presence of an aqueous alkali metal hydroxide, and optionally an oxidation step, whereby a compound of general formula (I): 【Chemistry 13】 [In the formula, A, R １ , R ３ , R ４ , R ５ , R ６ and Q are as defined for compounds of general formula (I) according to any one of claims 1 to 10, and R ２ is selected from the group consisting of 2-oxocyclobutyl, 3-oxocyclobutyl, 2-thiooxocyclobutyl, 3-thiooxocyclobutyl, 3-thietanyl, 2-thietanyl, oxetan-3-yl, oxetan-2-yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, furan-3-yl, furan-2-yl, tetrahydrothiophen-3-yl, tetrahydrothiophen-2-yl, thiophen-3-yl, thiophen-2-yl, 1-methylpyrrolidin-2-yl, 1-methylpyrrolidin-3-yl, 5-oxopyrrolidin-3-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, and tetrahydropyran-4-yl. obtaining a compound of formula (I), Or, general formula 1T: 【Chemistry 14】 [In the formula, A, R １ , R ２ , R ３ , R ４ , R ５ and R ６ Any one of claims 1 to 10 as defined for compounds of general formula (I) in paragraph (1), and Hal is halogen, in particular chlorine, bromine or iodine. by reacting an intermediate compound of general formula 1H: 【Chemistry 15】 wherein Q is 2,3,5-trifluorophenyl and each R can individually be H or Me, or both R are pinacolato. whereby a compound of general formula (I): 【Chemistry 16】 [In the formula, A, R １ , R ２ , R ３ , R ４ , R ５ , R ６ and Q is as defined for the compounds of general formula (I) according to any one of claims 1 to 10. obtaining a compound of formula (I), Or, general formula 1W: 【Chemistry 17】 [In the formula, Q, R ２ , R ３ , R ４ , R ５ and R ６ is as defined for the compounds of general formula (I) according to any one of claims 1 to 10. by reacting an intermediate compound of general formula 1M: 【Chemistry 18】 [In the formula, R １ and A is as defined for the compounds of general formula (I) according to any one of claims 1 to 10. thereby reacting a compound of general formula (I): 【Chemistry 19】 [In the formula, A, R １ , R ２ , R ３ , R ４ , R ５ , R ６ and Q is as defined for the compounds of general formula (I) according to any one of claims 1 to 10. A step of obtaining a compound of A method comprising:

12. General formula (II): 【Chemistry 20】 [During the ceremony, R ２ is OH, Cl, Br or as defined for compounds of general formula (I) according to claim 1, R ３ , R ４ , R ５ , R ６ and Q are as defined for the compounds of general formula (I) according to claim 1, and R Ａ is H or C １ -C ４ -alkyl] or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

13. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 and one or more pharmaceutically acceptable excipients.

14. A compound of general formula (I) as defined in claim 1 or a pharmaceutical composition as defined in claim 13 for use in the control, treatment and / or prevention of diseases.

15. 15. The compound or pharmaceutical composition of claim 14, wherein the disease is a helminth infection.

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