Patent Description:
The occurrence of resistances against all commercial anthelmintics seems to be a growing problem in the area of veterinary medicine. The extensive utilisation of anthelmintics to manage the control of nematodes resulted in significant selection of highly resistant worm populations. Therefore, the spread of resistance against all anthelmintic drug classes threatens effective worm control in cattle, goats, sheep and horses. Furthermore, successful prevention of heartworm disease in dogs, which currently solely relies on the utilisation of macrocyclic lactones, is in danger as loss of efficacy for multiple macrocyclic lactones has been described for some regions of the United States of America - especially in those areas where the heartworm challenge for infection is high. Finally, experimental infection studies with Dirofilaria immitis larvae from suspected loss of efficacy field cases in the Lower Mississippi Delta provided in vivo confirmation of the existence of macrocyclic lactone resistance.

Although resistance of human helminths against anthelmintics seems currently to be rare, the spread of anthelmintic resistance in the veterinary field as mentioned before needs to be considered in the treatment of human helminthosis as well. Persistent underdosed treatments against filariosis may lead to highly resistant genotypes and resistances have already been described for certain anthelmintics (e.g. praziquantel, benzimidazole and niclosamide).

Therefore, resistance-breaking anthelmintics with new molecular modes of action are urgently required.

It is an object of the present invention to provide compounds which can be used as anthelmintics in the medical, especially veterinary, field with a satisfactory or improved anthelmintic activity against a broad spectrum of helminths, particularly at relatively low dosages, for the control, treatment and/or prevention of infections with helminths in animals and humans, preferably without any adverse toxic effects to the treated organism.

Certain pyrazolopyrimidine carboxamides are related to their activity increasing the efficacy of the endogenous ligand <NUM>-hydroxybutyrateas as described in <NPL>. Other pyrazolopyrimidine carboxamides are described as allosteric agonists for the high affinity nicotinic acid receptor GPR109A as in <NPL>. Furthermore, pyrazolopyrimidine carboxamides are known as protein kinase modulators (<CIT>), as active ingredients for treatment or prevention of skin dieseases (<CIT>) or as NAD(P)H oxidase inhibitors (<CIT>). A certain method for a library synthesis process of said compounds is described in <NPL>. Sulfonylphenylpyrazole compounds are also known as COX-<NUM> inhibitors (<CIT>). Further imidazopyrazole coupler for the use in image formation methods in silver halide color photographic materials are known (<CIT>).

However, the state of the art does not describe the new bicyclic pyrazole derivatives of general formula (I) of the present invention as described and defined herein.

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

In particular, the compounds of the present invention have surprisingly been found to effectively interact with Slo-<NUM> of nematodes. This interaction is characterized by achieving paralysis/inhibition in particular of gastro-intestinal nematodes, of free-living nematodes, and of filariae, for which data are given in the biological experimental section. Therefore the compounds of the present invention may be used as anthelmintics for the control, treatment and/or prevention of gastro-intestinal and extra-intestinal helminth infections, in particular gastro-intestinal and extra-intestinal infections with nematodes, including filariae.

The present invention covers compounds of formula (I) and (II) defined in the claims, which are comprised by the following broader general formulae.

In accordance with a first aspect, the present invention covers compounds of general formula (I):
<CHM>
in which :.

The term "substituted" means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.

The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be <NUM>, <NUM>, <NUM>, <NUM> or <NUM>, in particular <NUM>, <NUM> or <NUM>.

As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means "<NUM>, <NUM>, <NUM>, <NUM> or <NUM>, particularly <NUM>, <NUM>, <NUM> or <NUM>, more particularly <NUM>, <NUM> or <NUM>, even more particularly <NUM> or <NUM>".

As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.

The term "ring substituent" means a substituent attached to an aromatic or nonaromatic ring which replaces an available hydrogen atom on the ring.

Should a composite substituent be composed of more than one parts, e.g. (C<NUM>-C<NUM>-alkoxy)-(C<NUM>-C<NUM>-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the C<NUM>-C<NUM>-alkoxy part can be attached to any carbon atom of the C<NUM>-C<NUM>-alkyl part of said (C<NUM>-C<NUM>-alkoxy)-(C<NUM>-C<NUM>-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.

As used herein, the position via which a respective subsituent is connected to the rest of the molecule may in a drawn structure be depicted by a hash sign (#) or a dashed line in said substituent.

The term "comprising" when used in the specification includes "consisting of".

If within the present text any item is referred to as "as mentioned herein", it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:
The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.

The term "C<NUM>-C<NUM>-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> carbon atoms. The term "C<NUM>-C<NUM>-alkyl" means a linear or branched, saturated, monovalent hydrocarbon group having <NUM>, <NUM>, <NUM>, or <NUM> carbon atoms, e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or a tert-butyl group, or an isomer thereof. Particularly, said group has <NUM>, <NUM> or <NUM> carbon atoms ("C<NUM>-C<NUM>-alkyl"), e.g. a methyl, ethyl, n-propyl or isopropyl group.

The term "C<NUM>-C<NUM>-hydroxyalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "C<NUM>-C<NUM>-alkyl" is defined supra, and in which <NUM> or <NUM> hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, <NUM>-hydroxyethyl, <NUM>-hydroxyethyl, <NUM>,<NUM>-dihydroxyethyl, <NUM>-hydroxypropyl, <NUM>-hydroxypropyl, <NUM>-hydroxypropyl, <NUM>-hydroxypropan-<NUM>-yl, <NUM>-hydroxypropan-<NUM>-yl, <NUM>,<NUM>-dihydroxypropyl, <NUM>,<NUM>-dihydroxypropan-<NUM>-yl, <NUM>-hydroxy-<NUM>-methyl-propyl, <NUM>-hydroxy-<NUM>-methyl-propyl, <NUM>-hydroxy-<NUM>-methyl-propyl group.

The term "-NH(C<NUM>-C<NUM>-alkyl)" or "-N(C<NUM>-C<NUM>-alkyl)<NUM>" means a linear or branched, saturated, monovalent group in which the term "C<NUM>-C<NUM>-alkyl" is as defined supra, e.g. a methylamino, ethylamino, n-propylamino, isopropylamino, N,N-dimethylamino, N-methyl-N-ethylamino or N,N-diethylamino group.

The term "-S-C<NUM>-C<NUM>-alkyl", "-S(O)-C<NUM>-C<NUM>-alkyl" or "-SO<NUM>-C<NUM>-C<NUM>-alkyl" means a linear or branched, saturated group in which the term "C<NUM>-C<NUM>-alkyl" is as defined supra, e.g. a methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, isobutylsulfanyl or tert-butylsulfanyl group, 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.

The term "C<NUM>-C<NUM>-halogenoalkyl" means a linear or branched, saturated, monovalent hydrocarbon group in which the term "C<NUM>-C<NUM>-alkyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. More particularly, all said halogen atoms are fluorine atoms ("C<NUM>-C<NUM>-fluoroalkyl"). Said C<NUM>-C<NUM>-halogenoalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, <NUM>-fluoroethyl, <NUM>,<NUM>-difluoroethyl, <NUM>,<NUM>,<NUM>-trifluoroethyl, pentafluoroethyl, <NUM>,<NUM>,<NUM>-trifluoropropyl or <NUM>,<NUM>-difluoropropan-<NUM>-yl.

The term "C<NUM>-C<NUM>-alkoxy" means a linear or branched, saturated, monovalent group of formula (C<NUM>-C<NUM>-alkyl)-O-, in which the term "C<NUM>-C<NUM>-alkyl" is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy group, or an isomer thereof.

The term "C<NUM>-C<NUM>-halogenoalkoxy" means a linear or branched, saturated, monovalent C<NUM>-C<NUM>-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C<NUM>-C<NUM>-halogenoalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, <NUM>,<NUM>,<NUM>-trifluoroethoxy or pentafluoroethoxy.

The term "C<NUM>-C<NUM>-alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has <NUM>, <NUM> or <NUM> carbon atoms. Said C<NUM>-C<NUM>-alkenyl group is, for example, an ethenyl (or "vinyl"), a prop-<NUM>-en-<NUM>-yl (or "allyl"), prop-<NUM>-en-<NUM>-yl, but-<NUM>-enyl, but-<NUM>-enyl, but-<NUM>-enyl, prop-<NUM>-en-<NUM>-yl (or "isopropenyl"), <NUM>-methylprop-<NUM>-enyl, <NUM>-methylprop-<NUM>-enyl, <NUM>-methylprop-<NUM>-enyl or a <NUM>-methylprop-<NUM>-enyl, group. Particularly, said group is allyl.

The term "C<NUM>-C<NUM>-alkynyl" means a linear monovalent hydrocarbon group which contains one triple bond, and which contains <NUM>, <NUM> or <NUM> carbon atoms. Said C<NUM>-C<NUM>-alkynyl group is, for example, an ethynyl, a prop-<NUM>-ynyl, prop-<NUM>-ynyl (or "propargyl"), but-<NUM>-ynyl, but-<NUM>-ynyl, but-<NUM>-ynyl or <NUM>-methylprop-<NUM>-ynyl, group. Particularly, said alkynyl group is prop-<NUM>-ynyl or prop-<NUM>-ynyl.

The term "C<NUM>-C<NUM>-cycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring which contains <NUM>, <NUM>, <NUM> or <NUM> carbon atoms ("C<NUM>-C<NUM>-cycloalkyl"). Said C<NUM>-C<NUM>-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term "C<NUM>-C<NUM>-halogenocycloalkyl" means a saturated, monovalent, monocyclic hydrocarbon ring in which the term "C<NUM>-C<NUM>-cycloalkyl" is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine or chlorine atom. Said C<NUM>-C<NUM>-halogenocycloalkyl group is for example, a monocyclic hydrocarbon ring substituted with one or two fluorine or chlorine atoms, e.g. a <NUM>-fluoro-cyclopropyl, <NUM>-fluorocyclopropyl, <NUM>,<NUM>-difluorocyclopropyl, <NUM>,<NUM>-difluorocyclopropyl, <NUM>-chlorocyclopropyl, <NUM>-chlorocyclopropyl, <NUM>,<NUM>-dichlorocyclopropyl, <NUM>,<NUM>-dichlorocyclopropyl, <NUM>-fluoro-<NUM>-chlorocyclopropyl and <NUM>-fluoro-<NUM>-chlorocyclopropyl group.

The term "-NH(C<NUM>-C<NUM>-cycloalkyl)" or "-N(C<NUM>-C<NUM>-alkyl)( C<NUM>-C<NUM>-cycloalkyl)" means a linear or branched, saturated, monovalent group in which the term "C<NUM>-C<NUM>-alkyl" and the term "C<NUM>-C<NUM>-cycloalkyl" each is as defined supra, e.g. a cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, N-methyl-N-cyclopropylamino, N-ethyl-N-cyclopropylamino, N-methyl-N-cyclobutylamino, N-ethyl-N-cyclobutylamino, N-methyl-N-cyclopentylamino, N-ethyl-N-cyclopentylamino, N-methyl-N-cyclohexylamino, or N-ethyl-N-cyclohexylamino group.

The term "benzo-C<NUM>-C<NUM>-cycloalkyl" means a monovalent, bicyclic hydrocarbon ring wherein a saturated, monovalent, monocyclic hydrocarbon ring which contains <NUM> or <NUM> carbon atoms ("C<NUM>-C<NUM>-cycloalkyl") is annelated to a phenyl ring. Said benzo-C<NUM>-C<NUM>-cycloalkyl group is for example, a bicyclic hydrocarbon ring, e.g. an indane (i.e. <NUM>,<NUM>-dihydro-<NUM>H-indene) or tetraline (i.e. <NUM>,<NUM>,<NUM>,<NUM>-tetrahydronaphthalene) group.

The term "spirocycloalkyl" means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom. Said spirocycloalkyl group is, for example, spiro[<NUM>]pentyl, spiro[<NUM>]hexyl, spiro[<NUM>]heptyl, spiro[<NUM>]octyl, spiro[<NUM>]nonyl, spiro[<NUM>]heptyl, spiro[<NUM>]octyl, spiro[<NUM>]nonyl, spiro[<NUM>]decyl, spiro[<NUM>]nonyl, spiro[<NUM>]decyl, spiro[<NUM>]undecyl or spiro[<NUM>]undecyl.

The term "heterocycloalkyl" means a monocyclic or bicyclic, saturated or partially saturated heterocycle with <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms in total (a "<NUM>- to <NUM>-membered heterocycloalkyl" group), particularly <NUM>, <NUM> or <NUM> ring atoms (a "<NUM>- to <NUM>-membered heterocycloalkyl" group), which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.

Said heterocycloalkyl group, without being limited thereto, can be a <NUM>-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a <NUM>-membered ring, such as tetrahydrofuranyl, <NUM>,<NUM>-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, <NUM>,<NUM>-dioxidothiolanyl, <NUM>,<NUM>-oxazolidinyl, <NUM>,<NUM>-oxazolidinyl, <NUM>,<NUM>-thiazolidinyl or <NUM>,<NUM>,<NUM>-triazolidinyl, for example; or a <NUM>-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, <NUM>,<NUM>-dioxanyl, <NUM>,<NUM>-dioxanyl or <NUM>,<NUM>-oxazinanyl, for example; or a <NUM>-membered ring, such as azepanyl, <NUM>,<NUM>-diazepanyl or <NUM>,<NUM>-oxazepanyl, for example; or a bicyclic <NUM>-membered ring, such as <NUM>-oxa-<NUM>-azabicyclo[<NUM>. <NUM>]heptan, for example; or a bicyclic <NUM>-membered ring, such as <NUM>,<NUM>-dihydro-<NUM>-furo[<NUM>,<NUM>-c]pyrrole or <NUM>-oxa-<NUM>-azabicyclo[<NUM>. <NUM>]octan, for example; or a bicyclic <NUM>-membered ring, such as octahydro-<NUM>-pyrrolo[<NUM>,<NUM>-b]pyridine, <NUM>,<NUM>-dihydro-isoindol, <NUM>,<NUM>-dihydro-indol or <NUM>,<NUM>-dioxa-<NUM>-azabicyclo[<NUM>. <NUM>]nonan, for example; or a bicyclic <NUM>-membered ring, such as decahydroquinoline or <NUM>,<NUM>-dihydroisoquinolin, for example.

The term "heterospirocycloalkyl" means a bicyclic, saturated heterocycle with <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.

Said heterospirocycloalkyl group is, for example, azaspiro[<NUM>]hexyl, azaspiro[<NUM>]heptyl, oxaazaspiro[<NUM>]heptyl, thiaazaspiro[<NUM>]heptyl, oxaspiro[<NUM>]heptyl, oxazaspiro[<NUM>]nonyl, oxazaspiro[<NUM>]octyl, oxaazaspiro[<NUM>]octyl, azaspiro[<NUM>]decyl, oxazaspiro[<NUM>]undecyl, diazaspiro[<NUM>]heptyl, thiazaspiro[<NUM>]heptyl, thiazaspiro[<NUM>]octyl, azaspiro[<NUM>]undecyl, or one of the further homologous scaffolds such as spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]-, spiro[<NUM>]- and spiro[<NUM>]-.

The term "<NUM>- or <NUM>-membered aryl" means a monovalent, monocyclic or bicyclic aromatic ring having <NUM> or <NUM> carbon ring atoms, e.g. a phenyl or naphthyl group.

The term "heteroaryl" means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having <NUM>, <NUM>, <NUM> or <NUM> ring atoms (a "<NUM>- to <NUM>-membered heteroaryl" group), particularly <NUM> or <NUM> ring atoms (a "<NUM>- to <NUM>-membered heteroaryl" group), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).

Said heteroaryl group can be a <NUM>-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a <NUM>-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl.

The term "heterocyclyl" means a heterocycle selected from the group consisting of heterocycloalkyl and heteroaryl. Particularly, the term "<NUM>- to <NUM>-membered heterocyclyl" means a heterocycle selected from the group consisting of <NUM>- to <NUM>-membered heterocycloalkyl and <NUM>- to <NUM>-membered heteroaryl.

In general, and unless otherwise mentioned, the heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-<NUM>-yl, pyridin-<NUM>-yl and pyridin-<NUM>-yl; or the term thienyl includes thien-<NUM>-yl and thien-<NUM>-yl.

The term "C<NUM>-C<NUM>", as used in the present text, e.g. in the context of the definition of "C<NUM>-C<NUM>-alkyl", "C<NUM>-C<NUM>-halogenoalkyl", "C<NUM>-C<NUM>-hydroxyalkyl", "C<NUM>-C<NUM>-alkoxy" or "C<NUM>-C<NUM>-halogenoalkoxy" means an alkyl group having a finite number of carbon atoms of <NUM> to <NUM>, i.e. <NUM>, <NUM>, <NUM> or <NUM> carbon atoms.

Further, as used herein, the term "C<NUM>-C<NUM>", as used in the present text, e.g. in the context of the definition of "C<NUM>-C<NUM>-cycloalkyl" or C<NUM>-C<NUM>-halogenocycloalkyl, means a cycloalkyl group having a finite number of carbon atoms of <NUM> to <NUM>, i.e. <NUM>, <NUM>, <NUM> or <NUM> carbon atoms.

When a range of values is given, said range encompasses each value and sub-range within said range.

As used herein, the term "leaving group" means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(<NUM>-methylphenyl)sulfonyl]oxy, [(<NUM>-bromophenyl)sulfonyl]oxy, [(<NUM>-nitrophenyl)sulfonyl]oxy, [(<NUM>-nitrophenyl)sulfonyl]oxy, [(<NUM>-isopropylphenyl)sulfonyl]oxy, [(<NUM>,<NUM>,<NUM>-triisopropylphenyl)sulfonyl]oxy, [(<NUM>,<NUM>,<NUM>-trimethylphenyl)sulfonyl]oxy, [(<NUM>-tert-butylphenyl)sulfonyl]oxy and [(<NUM>-methoxyphenyl)sulfonyl]oxy.

An oxo substituent in the context of the invention means an oxygen atom, which is bound to a carbon atom via a double bond.

It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

The term "Isotopic variant" of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

The term "Isotopic variant of the compound of general formula (I)" is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.

The expression "unnatural proportion" means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in "<NPL>.

Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as <NUM>H (deuterium), <NUM>H (tritium), <NUM>C, <NUM>C, <NUM>C, <NUM>N, <NUM>O, <NUM>O, <NUM>P, <NUM>P, <NUM>S, <NUM>S, <NUM>S, <NUM>S, <NUM>F, <NUM>Cl, <NUM>Br, <NUM>I, <NUM>I, <NUM>I, <NUM>I and <NUM>I, respectively.

With respect to the treatment and/or prevention of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as <NUM>H or <NUM>C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as <NUM>F or <NUM>C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and <NUM>C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D<NUM>O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. 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, MA, USA; and CombiPhos Catalysts, Inc. , Princeton, NJ, USA.

The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about <NUM>%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>% or <NUM>%, preferably higher than <NUM>%, <NUM>%, <NUM>% or <NUM>%, even more preferably higher than <NUM>% or <NUM>% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [<NPL>], basicity [<NPL>], lipophilicity [<NPL>]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (<NPL>). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: <NPL>; Efavirenz: <NPL>). In other cases the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound's pharmacokinetic/ pharmacodynamic relationship. ML-<NUM> (<NPL>) and Odanacatib (<CIT>) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: <NPL>; Telaprevir: <NPL>). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P<NUM>.

Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

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.

The compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (<NPL>).

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

Further, it is possible for the compounds of the present invention to exist as tautomers. For example, any compound of the present invention which contains a substitution pattern resulting in α-CH-moiety at the bicyclic pyrazole that has an increased C-H-acidity can exist as a tautomer, or even a mixture in any amount of the two tautomers.

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

Further, 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 oxidised. The present invention includes all such possible N-oxides.

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

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

Further, it is possible for the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.

The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see <NPL>.

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

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

Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.

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

In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF<NUM>COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified.

This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition.

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

Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term "prodrugs" here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.

In accordance with a second embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

In accordance with a third embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

wherein when Y is O, S or N-R<NUM>, R<NUM> is not -OH,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a fourth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

wherein when Y is O, S or N-R<NUM>, R<NUM> is not -OH,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

In accordance with a fifth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

A further aspect of the present invention covers compounds of general formula (I), supra, in which G, A, R<NUM>, R<NUM>, and R<NUM> have the meaning as defined in any of the embodiments supra and.

and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In accordance with a sixth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

In accordance with a seventh embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:
G, A, R<NUM>, R<NUM>, and R<NUM> have the meaning as defined for the sixth embodiment of the first aspect supra, and wherein.

In an alternative embodiment of the sixth and seventh embodiment of the first aspect of the present invention supra, A is selected from the group consisting of:
<CHM>.

In a further alternative embodiment of the sixth and seventh embodiment of the first aspect of the present invention supra, A is selected from the group consisting of:
<CHM>.

In accordance with an eighth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which:.

In accordance with an ninth embodiment of the first aspect, the present invention covers compounds of general formula (I), supra, in which :.

In accordance with an tenth embodiment of the first aspect, the present invention covers compounds of general formula (II), supra, in which:.

In an alternative embodiment of the ninth and tenth embodiment of the first aspect of the present invention supra,.

In accordance with an eleventh embodiment of the first aspect, the present invention covers compounds of general formula (II), supra, in which :.

Further embodiments of the first aspect of the present invention:
In a further embodiment the present invention covers compounds of general formula (<NUM>) or (II), supra, in which.

In a further embodiment the present invention covers compounds of general formula (<NUM>) or (II), supra, in which.

As described above, the present invention covers compounds of general formula (I), supra, in which G is S, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

wherein R<NUM> is preferably selected from the group consisting of hydrogen and isopropyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

wherein R<NUM> is preferably selected from the group consisting of hydrogen and methyl,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which:.

wherein when Y is O, R<NUM> is not -OH,
and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

In a further embodiment of the first aspect, the present invention covers compounds of formula (I), supra, in which.

In a particular further embodiment of the first aspect, the present invention covers combinations of two or more of the above mentioned embodiments under the heading "further embodiments of the first aspect of the present invention".

The present invention covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I) or (II), supra.

The present invention covers the compounds of general formula (I) and (II) which are disclosed in the Example Section of this text, infra.

The compounds according to the invention of general formula (I) and (II) can be prepared according to the scheme <NUM> as shown in the Experimental Section to the present invention (General Procedures). The schemes and procedures described illustrate synthetic routes to the compounds of general formula (I) and (II) of the invention and are not intended to be limiting. It is clear to the person skilled in the art that the order of transformations as exemplified in scheme <NUM> can be modified in various ways. The order of transformations exemplified in these schemes is therefore not intended to be limiting. In addition, interconversion of any of the substituents, Q, A, R<NUM>, R<NUM>, or R<NUM> can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example <NPL>). Specific examples are described in the subsequent paragraphs.

In the following, several routes for the preparation of compounds of general formula (I) are described in scheme <NUM>.

In accordance with a second aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1N :
<CHM>
in which G, A, R<NUM>, R<NUM>, and Q are as defined for the compound of general formula (I) and (II) as defined supra,.

In accordance with an alternative embodiment of the second aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1T :
<CHM>
<CHM>.

In accordance with an alternative embodiment of the second aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1W :
<CHM>.

In accordance with an alternative embodiment of the second aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1X :
<CHM>.

In accordance with an alternative embodiment of the second aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1N :
<CHM>.

In accordance with a third aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1N :
<CHM>.

In accordance with an alternative embodiment of the third aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1T :
<CHM>.

In accordance with an alternative embodiment of the third aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1W :
<CHM>.

In accordance with an alternative embodiment of the third aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1X :
<CHM>.

In accordance with an alternative embodiment of the third aspect, the present invention covers methods of preparing compounds of general formula (I) and (II) as defined supra, said methods comprising the step of allowing an intermediate compound of general formula 1N :
<CHM>.

The present invention covers methods of preparing compounds of the present invention of general formula (I) and (II), said methods comprising the steps as described in the Experimental Section herein.

In accordance with a fourth aspect, the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (<NUM>) and (II), supra.

Particularly, described herein are the intermediate compounds of general formula (I-INT):
<CHM>.

Particularly, described herein are also the intermediate compounds of general formula (II-INT) supra, in which.

Particularly, described herein are also intermediate compounds of general formula (III-INT):
<CHM>.

More particularly, described herein are also intermediate compounds of general formula (III-INT) or (IV-INT) supra, in which.

Particularly preferred among the intermediates (III-INT) and (IV-INT) supra are those according to formula (IV-INT) supra.

Particularly, described herein are also the intermediate compounds of general formula (V-INT):
<CHM>.

Particularly, described herein are also the intermediate compounds of general formula (VI-INT) supra, in which.

The invention covers the following intermediate compounds:.

Also described herein is the intermediate of formula (VI-INT-<NUM>):
<CHM>
in which.

In accordance with a fifth aspect, the present invention covers the use of intermediate compounds of the general formulae (VI-INT-<NUM>), (VI-INT-<NUM>) and (IV-INT-<NUM>) supra for the preparation of a compound of general formula (I) and (II) as defined supra.

The present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.

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

Compounds of general formula (I) and (II) of the present invention demonstrate a valuable pharmacological spectrum of action, which could not have been predicted. Compounds of the present invention have surprisingly been found to effectively interact with Slo-<NUM> and it is possible therefore that said compounds be used for the treatment or prevention of diseases, preferably helminthic infections, particulary of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes in humans and animals.

Compounds of the present invention can be utilized to control, treat and/or prevent helminth infections, in particular gastro-intestinal and extra-intestinal helminth infections. This method comprises administering to a mammal in need thereof an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.

In an alternative aspect, this method comprises administering to birds, namely cage birds or in particular poultry, in need thereof an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.

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

Agricultural livestock include, for example, mammals, such as, sheep, goats, horses, donkeys, camels, buffaloes, rabbits, reindeers, fallow deers, and in particular cattle and pigs; or poultry, such as turkeys, ducks, geese, and in particular chickens; or fish or crustaceans, e.g. in aquaculture or, as the case may be, insects such as bees.

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

Also described herein are methods of treating helminth infections, particularly gastro-intestinal and extra-intestinal helminth infections, more particularly gastro-intestinal and extra-intestinal infections with nematodes.

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

The term "treating" or "treatment" as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as a nematode infection. In particular, and particularly in the animal health or veterinary field, the term "treating" or "treatment" includes prophylactic, metaphylactic or therapeutical treatment.

Helminths pathogenic for humans or animals include, for example, acanthocephala, nematodes, pentastoma and platyhelmintha (e.g. monogenea, cestodes and trematodes).

Exemplary helminths include, without any limitation:.

The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of helminth infections, particularly gastro-intestinal and extra-intestinal helminth infections, more particularly gastro-intestinal and extra-intestinal infections with nematodes.

By using the compounds of the present invention to control animal parasites, in particular helminths, it is intended to reduce or prevent illness, cases of deaths and performance reductions (in the case of meat, milk, wool, hides, eggs, honey and the like), so that more economical and simpler animal keeping is made possible and better animal well-being is achievable.

The term "control" or "controlling", as used herein with regard to the animal health field, means that the compounds of the present invention are effective in reducing the incidence of the respective parasite in an animal infected with such parasites to innocuous levels. More specifically, "controlling", as used herein, means that the compounds of the present invention are effective in killing the respective parasite, inhibiting its growth, or inhibiting its proliferation.

In accordance with a further aspect, the present invention covers compounds of general formula (I), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prevention of diseases, in particular of helminth infections, particulary of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes.

The pharmaceutical activity of the compounds according to the invention can be explained by their interaction with the Slo-<NUM> ion channel.

In accordance with a further aspect, the present invention covers compounds of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in the treatment or prevention of diseases, in particular of helminth infections, particulary of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes.

In accordance with a further aspect, the present invention covers compounds of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use in a method of treatment or prevention of diseases, in particular of helminth infections, particulary of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes.

Described herein is the use of a compound of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for the preparation of a pharmaceutical composition, preferably a medicament, for the prevention or treatment of diseases, in particular of helminth infections, particulary of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes.

Further described herein is a method of treatment or prevention of diseases, in particular of helminth infections, particularly of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes, using an effective amount of a compound of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

Also described herein are compounds of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use as an antiendoparasitical agent.

Further described herein are compounds of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same, for use as a anthelmintic agent, in particular for use as a nematicidal agent, a platyhelminthicidal agent, an acanthocephalicidal agent, or a pentastomicidal agent.

In accordance with a further aspect, the present invention covers pharmaceutical compositions, in particular a veterinary formulation, comprising a compound of general formula (I) and (II), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s). Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.

Also described herein is a method for preparing a pharmaceutical composition, in particular a veterinary formulation, comprising the step of mixing a compound of general formula (I) and (II), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, with one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).

Also described herein is a method of treatment or prevention of diseases, in particular of helminth infections, particularly of gastro-intestinal and extra-intestinal helminth infections, more particulary of gastro-intestinal and extra-intestinal infections with nematodes, using a pharmaceutical composition, in particular a veterinary formulation, comprising an effective amount of a compound of general formula (I) and (II), as described supra, or stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures of same.

The present invention furthermore covers pharmaceutical compositions, in particular veterinary formulations, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.

It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. Such administration can be carried out prophylactically, methaphylactically or therapeutically.

For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, chewables (for example soft chewables), powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia 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, ocular 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 (such as, for example, patches), milk, pastes, foams, spot-ons, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,.

The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prevention of an endo- and/or ectoparasiticidal infection.

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

Also described herein is a pharmaceutical combination, in particular a veterinary combination, which comprises:.

The term "combination" in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a "fixed combination" is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects. The present invention also covers such pharmaceutical combinations. For example, the compounds of the present invention can be combined with known ectoparasiticides and/or endoparasiticides.

The other or further active ingredients specified herein by their common names are known and described, for example, in the <NPL>) or can be searched in the internet (e.g. http://www. net/pesticides). The classification is based on the current IRAC Mode of Action Classification Scheme at the time of filing of this patent application.

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

Exemplary active ingredients from the group of endoparasiticides, as a further or other active ingredient in the present invention, include, without limitation, anthelmintically active compounds and antiprotozoal active compounds.

Anthelmintically active compounds, including, without limitation, the following nematicidally, trematicidally and/or cestocidally active compounds:.

Antiprotozoal active ingredients in the present invention, including, without limitation, the following active ingredients:.

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

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of helminth infections, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in animals, and by comparison of these results with the results of known active ingredients or medicaments that are used to treat these conditions, the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the subject treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered will generally range from about <NUM>/kg to about <NUM>/kg body weight per day, and preferably from about <NUM>/kg to about <NUM>/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for "drug holidays", in which a subject is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. Furthermore, it is possible to have long-acting treatments, wherein the subject gets treated once for more than four weeks. It is possible for a unit dosage to contain from about <NUM> to about <NUM> of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from <NUM> to <NUM>/kg of total body weight. The average daily rectal dosage regimen will preferably be from <NUM> to <NUM>/kg of total body weight. The average daily vaginal dosage regimen will preferably be from <NUM> to <NUM>/kg of total body weight. The average daily topical dosage regimen will preferably be from <NUM> to <NUM> administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from <NUM> to <NUM>/kg. The average daily inhalation dosage regimen will preferably be from <NUM> to <NUM>/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each subject will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the subject, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

The 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.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

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

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4® or Isolera Four®) and eluents such as gradients of hexane/ethyl acetate or dichloromethane/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

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

Analytical (UP)LC-MS was performed by means of different equipments as described below. The masses (m/z) are reported from the positive mode electrospray ionisation unless the negative mode is indicated (ESI-).

Instrument type: Waters UPLC system; column: Zorbax Eclipse Plus C18, <NUM> x <NUM>,<NUM>, <NUM>,<NUM>; eluent A: acetonitrile + <NUM> formic acid / L, eluent B: millipore water + <NUM>,<NUM> formic acid / L; gradient: <NUM> <NUM>% A → <NUM> <NUM>% A → <NUM> <NUM>% A → <NUM> <NUM>% A→ <NUM> <NUM>% A; oven: <NUM>; flow: <NUM>/min; UV-detection: <NUM>. Waters SQD2 MS detector: <NUM>-<NUM> Amu, ES-ionization, positive.

<NUM>H-NMR data were determined with a Bruker Avance <NUM> (equipped with a flow cell (<NUM>µl volume), or with a Bruker AVIII <NUM> equipped with <NUM> cryo CPTCI probe head, or with a Bruker AVIII <NUM> (<NUM>) equipped with a <NUM> probe head, or with a Bruker AVII <NUM> (<NUM>) equipped with a <NUM> cryo TCI probe head, or with a Bruker AVIII <NUM> (<NUM>) equipped with a <NUM> cryo CPMNP probe head, or with a Bruker AVIII <NUM> (<NUM>) equipped with a <NUM> broadband head or a <NUM> Prodigy™ probe head, with tetramethylsilane as reference (<NUM>) and the solvents CD<NUM>CN, CDCl<NUM> or D<NUM>-DMSO. Alternative <NUM>H- and <NUM>C-NMR instrument types: Bruker DMX300 CH NMR: <NUM>; <NUM>C NMR: <NUM>), Bruker Avance III <NUM> (<NUM>H NMR: <NUM>; <NUM>C NMR: <NUM>) or Bruker <NUM> Ultrashield (<NUM>H NMR: <NUM>; <NUM>C NMR: <NUM>).

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

The synthesis of the compounds of the formula (I) and (II) can be performed according to or in analogy to the following scheme <NUM>. <CHM>
wherein the substituents have the meaning as defined for the intermediate compounds supra, such as in particular for intermediate compound (VI-INT) and (IV-INT) supra, very particularlyfor intermediate compounds (VI-INT-<NUM>), (VI-INT-<NUM>), (VI-INT-<NUM>), and (IV-INT-<NUM>) supra.

Certain substituted pyrazolothiones can be readily converted with <NUM>-chloro ketoesters (wherein RA is preferably selected from methyl, ethyl or t-butyl ), dissolved in alcohols like ethanol, preferably under boiling conditions, into pyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylates VI-INT-<NUM> as described with analogous systems in <CIT>, followed by bromination with N-bromosuccinimide in inert solvents like dichloromethane or tetrachlorometane, preferably at ambient temperature, to obtain esters VI-INT-<NUM>. Such intermediate esters react under hydrolytic conditions to yield pyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylic acids VI-INT-<NUM> as described with similar syntheses in <NPL>. Pyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylic acids VI-INT-<NUM> can be converted into the corresponding amides IV-INT-<NUM> by amide coupling conditions, e.g. via carboxylic acid chlorides formed from VI-INT-<NUM>, which are combined with amines R'-NH-A under basic conditions, e.g. pyridine, triethylamine or N,N-diisopropyl ethylamine or via amide formation from the carboxylic acids VI-INT-<NUM> which are combined with amines R'-NH-A and dehydration reagents, e.g. N-(<NUM>-dimethylaminoisopropyl)-N'-ethylcarbodiimide-hydrochloride (EDC). Similar syntheses are described in <CIT> for example.

Pyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylic amides IV-INT-<NUM> can be converted via a Suzuki cross coupling reaction with boronic acids or boronic esters Q-B(OR)<NUM> (R=H; R = methyl or R,R = pinacolate) as described with similar reactions in <CIT>, into aryl- or hetaryl-substituted final compounds II.

<NUM>-Methyl-<NUM>-pyrazol-<NUM>-ol (<NUM>, <NUM> mmol) was dissolved in toluene (<NUM>), then, Lawesson's reagent (<NUM>, <NUM> mmol) was added. The resulting mixture was refluxed <NUM> hours and was left overnight at room temperature. The mixture was concentrated and used without further purification in the next step.

A mixture of ethyl <NUM>-chloro-<NUM>-methyl-<NUM>-oxopentanoate (<NUM>, <NUM> mmol), known from <NPL>, and <NUM>-methyl-<NUM>,<NUM>-dihydro-<NUM>-pyrazole-<NUM>-thione (<NUM>, <NUM> mmol (theoretically expected)) in ethanol (<NUM>) was refluxed for <NUM> and then concentrated in vacuo. The residue was treated with water, and the resulting mixture was extracted with ethyl acetate. The combined organic solvents were dried over sodium sulfate and concentrated in vacuo. The remaining oil was purified via a silica gel column (<NUM>:<NUM> hexane / ethyl acetate) to obtain the title compound as colourless solid. Yield: <NUM> (<NUM> mmol; <NUM> % of th.

To a solution of ethyl <NUM>-isopropyl-<NUM>-methylpyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylate (<NUM>, <NUM> mmol) in dry carbon tetrachloride (<NUM>) was added N-bromosuccinimide (<NUM>, <NUM> mmol). The resulting mixture was stirred at room temperature for <NUM> hours. Then, it was diluted with dichloromethane and washed with water, followed by brine. The separated organic layer was dried over sodium sulfate. The product was used in the next step without further purification. Yield: <NUM> (<NUM> mmol; <NUM> % of th.

To the solution of ethyl <NUM>-bromo-<NUM>-isopropyl-<NUM>-methylpyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylate (<NUM>, <NUM> mmol) in EtOH (<NUM>), water (<NUM>) and THF (<NUM>) was added LiOH (<NUM>, <NUM> mmol). The resulting solution was stirred overnight at room temperature. The mixture was concentrated until the aqueous solution remained, washed three times with dichloromethane and acidified with conc. The precipitated product was filtered, washed with water and dried. Yield: <NUM> (purity <NUM> %; <NUM> mmol; <NUM> % of th.

LC-MS (Method L0): Rt = <NUM>; MS (ESIpos): m/z = <NUM>; <NUM> [M+H]+.

<NUM>H-NMR (<NUM>,<NUM>) MHz, DMSO-d6) δ [ppm]: <NUM> (bs, <NUM>, COOH), <NUM> (hept, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>).

A flask was charged with <NUM>-bromo-<NUM>-isopropyl-<NUM>-methylpyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxylic acid (<NUM>, <NUM> % purity, <NUM> mmol), (<NUM>)-chroman-<NUM>-amine hydrochloride (<NUM>, <NUM> mmol), N,N-diisopropyl ethylamine (<NUM>, <NUM> mmol), <NUM>-(N,N-dimethylamino) pyridine (<NUM>, <NUM> mmol), <NUM>-hydroxy-<NUM>H-benzotriazole (<NUM>, <NUM> mmol) and <NUM>-ethyl-<NUM>-(<NUM>-dimethylaminopropyl)carbodiimide hydrochloride (<NUM>, <NUM> mmol) in <NUM> dichloromethane. The reaction mixture was stirred at ambient temperature overnight, then mixed with water, the dichloromethane phase was separated, dried via a sodium sulfate / silica gel cartridge and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent cyclohexane / ethyl acetate gradient) to obtain the title compound. Yield: <NUM> (<NUM> mmol, <NUM> % of th.

<NUM>H-NMR (<NUM>,<NUM>) MHz, DMSO-d6) δ [ppm]: <NUM> (d, <NUM>, NH), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (dd, <NUM>), <NUM> (d, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (hept, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, <NUM>).

A microwave tube was charged with <NUM> dioxane, <NUM>-bromo-N-[(<NUM>)-<NUM>,<NUM>-dihydro-<NUM>-chromen-<NUM>-yl]-<NUM>-isopropyl-<NUM>-methylpyrazolo[<NUM>,<NUM>-b][<NUM>,<NUM>]thiazole-<NUM>-carboxamide (<NUM>, <NUM> mmol), <NUM>,<NUM>-dichlorophenyl boronic acid (<NUM>, <NUM> mmol), aqueous <NUM> sodium carbonate solution (<NUM>) and (<NUM>,<NUM>'-bis(diphenylphosphino)-ferrocene-palladium-dichloromethane complex (<NUM>, <NUM> mmol). The reaction mixture was degassed with argon for <NUM> and was treated in a microwave device (Biotage) for <NUM> at <NUM>. The crude mixture was filtered and washed through a silica gel / sodium sulfate cartridge. The solvents of the filtrate were evaporated under reduced pressure; the remaining raw material was purified by flash column chromatography using a cyclohexane / ethyl acetate gradient to obtain the title compound as an off-white solid. Yield: <NUM> (<NUM> mmol, <NUM> % of th. regarding the boronic acid).

The following examples <NUM>-<NUM> were prepared analogously:.

<NUM>H-NMR see NMR peak list table <NUM>.

LC-MS (Method L0): Rt = <NUM>; MS (ESIpos): m/z = <NUM> [M+H]+.

LC-MS (Method L0): Rt = <NUM>; MS (ESIpos): m/z =<NUM> [M+H]+.

LC-MS (Method L0): Rt = <NUM>; MS (ESIpos): m/z =<NUM>; <NUM> [M+H]+.

<NUM>H-NMR data of selected examples are written in form of <NUM>H-NMR-peak lists. To each signal peak are listed the δ-value in ppm and the signal intensity in round brackets. Between the δ-value - signal intensity pairs are semicolons as delimiters.

The peak list of an example has therefore the form:
δ<NUM> (intensity<NUM>); δ<NUM> (intensity<NUM>);. ; δ<NUM> (intensityi);. ; δn (intensityn).

Intensity of sharp signals correlates with the height of the signals in a printed example of a NMR spectrum in cm and shows the real relations of signal intensities. From broad signals several peaks or the middle of the signal and their relative intensity in comparison to the most intensive signal in the spectrum can be shown.

For calibrating chemical shift for <NUM>H spectra, we use tetramethylsilane and/or the chemical shift of the solvent used, especially in the case of spectra measured in DMSO. Therefore in NMR peak lists, tetramethylsilane peak can occur but not necessarily.

The <NUM>H-NMR peak lists are similar to classical <NUM>H-NMR prints and contains therefore usually all peaks, which are listed at classical NMR-interpretation.

Additionally they can show like classical <NUM>H-NMR prints signals of solvents, stereoisomers of the target compounds, which are also object of the invention, and/or peaks of impurities.

To show compound signals in the delta-range of solvents and/or water the usual peaks of solvents, for example peaks of DMSO in DMSO-D<NUM> and the peak of water are shown in our <NUM>H-NMR peak lists and have usually on average a high intensity.

The peaks of stereoisomers of the target compounds and/or peaks of impurities have usually on average a lower intensity than the peaks of target compounds (for example with a purity ><NUM>%).

Such stereoisomers and/or impurities can be typical for the specific preparation process. Therefore their peaks can help to recognize the reproduction of our preparation process via "side-products-fingerprints".

An expert, who calculates the peaks of the target compounds with known methods (MestreC, ACD-simulation, but also with empirically evaluated expectation values) can isolate the peaks of the target compounds as needed optionally using additional intensity filters. This isolation would be similar to relevant peak picking at classical <NUM>H-NMR interpretation.

Further details of NMR-data description with peak lists you find in the publication "Citation of NMR Peaklist Data within Patent Applications" of the Research Disclosure Database Number <NUM>.

Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

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

A CHO cell line was obtained from ATCC, code ATCC CRL-<NUM>. For transfection with plasmid DNA to express C. elegans Slo-1a (accession number AAL28102) CHO cells were passaged to <NUM>% confluence before adding the transfection solution to the cell culture. The transfection solution included <NUM>µL OptiMEM (Life Technologies, Nr. : <NUM>), <NUM>µL (= <NUM>µg) of plasmid DNA containing the C. elegans Slo 1a gene and 9µL FugeneHD (Promega, Nr. : E2311), and was added to the cells prior to incubation for <NUM> hours at <NUM>, <NUM>% CO<NUM>. The transfection medium was exchanged for the selection medium which contains additional G418 (<NUM>/ml, Invitrogen, Nr. : <NUM>) and the cells were seeded into <NUM> well plates (<NUM> cells/well). After a few weeks, the remaining surviving cells were tested with a voltage sensitive dye (Membrane Potential Assay Kit, Molecular Devices Nr. : R8034) for K+ channel expression. Positive cell clones were purified by the limited dilution technique. For this the clone with the highest and most robust signal in the voltage sensitive dye assay was further subcloned (incubated) in <NUM> well plates (<NUM> cells/well) in order to obtain clonal purity. This generated a final stable CHO cell line expressing the C. elegans Slo-1a.

Cells were cultured at <NUM> and <NUM>% CO<NUM> in MEMalpha with Gutamax I (Invitrogen, Nr. : <NUM>), supplemented with <NUM>% (v/v) heat inactivated fetal bovine serum (Invitrogen, Nr. : <NUM>), G418 (<NUM>/ml, Invitrogen, Nr. Cells were detached using Accutase (Sigma, Nr.

Laboratory compound testing was performed on <NUM>-well microtiter plates (MTPs, Greiner, Nr. <NUM> cells/well were plated onto <NUM>-well MTPs and cultured for <NUM> to <NUM> hours at <NUM> and <NUM>% CO<NUM>. After removal of the cell culture medium, the cells were washed once with tyrode (<NUM> NaCl, <NUM> KCl, <NUM> CaCl<NUM>, <NUM> MgCl<NUM>, <NUM> NaH<NUM>PO<NUM>, <NUM> Glucose, <NUM> Hepes, pH <NUM>) and then loaded with the voltage sensitive dye of the Membrane Potential Assay Kit diluted in tyrode for <NUM> at room temperature.

After starting the measurement of fluorescence using a FLIPR Tetra (Molecular Devices, Exc. <NUM>-<NUM>, Emm. <NUM>-<NUM>), test compounds were added followed by the addition of KCl tyrode (final assay concentration: <NUM> KCl, <NUM> CaCl<NUM>, <NUM> MgCl<NUM>, <NUM> NaH<NUM>PO<NUM>, <NUM> Glucose, <NUM> Hepes, pH <NUM>, including the voltage sensitive dye). The measurement was completed after <NUM> minutes.

The data were evaluated by using the ActivityBase XLfit software (IDBS) for curve fitting and calculation of the half-maximal effective concentration (EC<NUM>) and are reported as negative decadic logarithm (pEso).

For the following examples, pEso ><NUM>,<NUM> - <NUM>,<NUM> has been found for: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

For the following examples, pEso ><NUM>,<NUM> has been found for: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

Adult Nippostrongylus brasiliensis were washed with saline buffer containing <NUM> U/ml penicillin, <NUM>/ml streptomycin and <NUM>µg/ml amphotericin B. Test compounds were dissolved in DMSO and worms were incubated in medium in a final concentration of <NUM>µg/ml (<NUM> ppm) respectively 1µg/ml (<NUM> ppm). An aliquot of the medium was used to determine the acetylcholine esterase activity in comparison to a negative control. The principle of measuring acetylcholine esterase as readout for anthelmintic activity was described in Rapson et al (<NUM>) and Rapson et al (<NUM>).

For the following examples, activity (reduction of AChE compared to negative control) was higher than <NUM>% at <NUM>µg/ml: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

For the following examples, activity (reduction of AChE compared to negative control) was higher than <NUM>% at <NUM>µg/ml: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

≥ <NUM> Dirofilaria immitis microfilariae, which were freshly purified from blood, were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. Compounds were tested in concentration-response assay in duplicate. Larvae exposed to DMSO and no test compounds were used as negative controls. Larvae were evaluated after <NUM> of incubation with the compound. Efficacy was determined as the reduction of motility in comparison to the negative control. Based on the evaluation of a wide concentration range, concentration-response curves as well as EC<NUM>-values were calculated.

For the following examples, the EC<NUM> was <<NUM> ppm: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

<NUM> Dirofilaria immitis third-stage larvae, which were freshly isolated from their vector (intermediate host), were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. Compounds were tested in concentration-response assay in duplicate. Larvae exposed to DMSO and no test compounds were used as negative controls. Larvae were evaluated after <NUM> of incubation with the compound. Within these <NUM> of incubation the majority of larvae in negative control moult to fourth-stage larvae. Efficacy was determined as the reduction of motility in comparison to the negative control. Based on the evaluation of a wide concentration range, concentration-response curves as well as EC<NUM>-values were calculated.

For the following examples, the EC<NUM> was <<NUM> ppm: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

<NUM> Litomosoides sigmodontis third-stage larvae, which were freshly isolated from the pleural cavity of an infected rodent, were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. Compounds were tested in concentration-response assay in duplicate. Larvae exposed to DMSO and no test compounds were used as negative controls. Larvae were evaluated after <NUM> of incubation with the compound. Efficacy was determined as the reduction of motility in comparison to the negative control. Based on the evaluation of a wide concentration range, concentration-response curves as well as ECso-values were calculated.

For the following examples, the EC<NUM> was <<NUM> ppm: <NUM>, <NUM>, <NUM>, <NUM>.

To produce a suitable preparation of active compound, <NUM> of active compound are dissolved in <NUM> solvent, and the concentrate is diluted with "Ringer's solution" to the desired concentration.

Approximately <NUM> nematode larvae (Cooperia curticei) are transferred into a test tube containing the compound solution.

After <NUM> days percentage of larval mortality is recorded. <NUM> % efficacy means all larvae are killed; <NUM>% efficacy means no larvae are killed.

In this test for example, the following compounds from the preparation examples showed good activity of <NUM>% at an application rate of <NUM> ppm: <NUM>, <NUM>.

In this test for example, the following compounds from the preparation examples showed good activity of <NUM>% at an application rate of <NUM> ppm: <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>.

In this test for example, the following compounds from the preparation examples showed good activity of <NUM>% at an application rate of <NUM> ppm: <NUM>.

Approximately <NUM> larvae of the red stomach worm (Haemonchus contortus) are transferred into a test tube containing compound solution.

After <NUM> days the percentage of larval mortality is recorded. <NUM> % efficacy means all larvae are killed, <NUM>% efficacy means no larvae are killed.

In this test for example, the following compounds from the preparation examples showed good activity of <NUM>% at an application rate of <NUM> ppm: <NUM>, <NUM>, <NUM>.

Exemplary formulations consisted of the active substance in <NUM>% Transcutol, <NUM>% Cremophor EL and <NUM>% isotonic saline solution. First the active substance was dissolved in Transcutol. After solution in Transcutol, Cremophor and isotonic saline solution were added. These formulations were used as service formulations in the following in vivo assay.

An example for a formulation according to the present invention is the following formulation Example F1. Therein, the active substance was dissolved in Transcutol to form a stock solution A. Then <NUM> of this stock solution A were taken and <NUM> Cremophor EL and <NUM> isotonic saline solution were added. The resulting liquid formulation (formulation example F1) had a volume of <NUM>.

Gerbils, experimentally infected with Haemonchus and / or Trichostrongylus, were treated once during late prepatency. Test compounds were formulated as solutions or suspensions and applied orally or intraperitoneally. For both applications the same service formulation was used. The volume of the application amounted to normally <NUM>/kg at a maximum. By way of example, a gerbil with <NUM> body weight was treated with <NUM> of the formulation of formulation example F <NUM>. This corresponded to a treatment with <NUM>/kg body weight.

Efficacy was determined per group as reduction of worm count in stomach and small intestine, respectively, after necropsy compared to worm count in an infected and placebo-treated control group.

The following examples were tested and had an activity of ≥<NUM>% or higher at the given treatment:.

Claim 1:
A compound of general formula (I):
<CHM>
in which :
A is selected from the group consisting of
<CHM>
G is S,
R<NUM> is hydrogen or methyl,
R<NUM> is selected from the group consisting of
hydrogen, chlorine, fluorine,
-NH<NUM>, -NH(CH<NUM>), -N(CH<NUM>)<NUM>,
methoxy, ethoxy,
methyl, ethyl, propyl, isopropyl, cyclopropyl,
trifluoromethyl and trifluoromethoxy,
R<NUM> is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy and trifluoromethyl,
Q is a substituted phenyl ring of the formula (QI)
<CHM>
in which:
Z<NUM> is selected from the group consisting of hydrogen, fluorine, chlorine, methyl and methoxy,
Z<NUM> is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, methyl, ethyl, methoxy, ethoxy, -NH(CH<NUM>), -N(CH<NUM>)<NUM>, trifluoromethyl, trifluoromethoxy,
Z<NUM> is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, methoxy,-NH(CH<NUM>) and -N(CH<NUM>)<NUM>,
Z<NUM> is selected from the group consisting of hydrogen, fluorine, chlorine, methyl and methoxy,
Z<NUM> is selected from the group consisting of hydrogen, fluorine, chlorine methyl and methoxy,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.