WO2024213752A1 - Prévention et/ou traitement à long terme d'une maladie par des inhibiteurs de slo-1 - Google Patents

Prévention et/ou traitement à long terme d'une maladie par des inhibiteurs de slo-1 Download PDF

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WO2024213752A1
WO2024213752A1 PCT/EP2024/060054 EP2024060054W WO2024213752A1 WO 2024213752 A1 WO2024213752 A1 WO 2024213752A1 EP 2024060054 W EP2024060054 W EP 2024060054W WO 2024213752 A1 WO2024213752 A1 WO 2024213752A1
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alkyl
halogen atoms
halogenoalkyl
group
alkoxy
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PCT/EP2024/060054
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English (en)
Inventor
Nils Griebenow
Claudia Selbach
Carolin LUDWIG ERDMANN
Iring Heisler
William Hunter White
Olaf WILL
Dirk Heimbach
Chouaib Tahtaoui
Heinz Sager
Brian Mathes
Sarah George
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Elanco Animal Health Gmbh
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Publication of WO2024213752A1 publication Critical patent/WO2024213752A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • the present invention concerns inhibitors of the calcium-activated potassium channel Slo-1 of endoparasites for use in the long-term prevention and/or treatment of a disease. Further, the invention concerns a pharmaceutical formulation for use in the long-term prevention and/or treatment of a disease comprising a Slo-1 inhibitor and at least one further ingredient. The invention also concerns the use of a Slo-1 inhibitor and a pharmaceutical composition comprising such an inhibitor for long- term prevention and/or treatment of a disease as well as a method for long-term prevention and/or treatment of a disease comprising the administration of a Slo-1 inhibitor or a pharmaceutical composition comprising such an inhibitor at an effective dose to a subject in need thereof.
  • Endoparasitic infections in animals and humans are responsible for significant suffering.
  • endoparasitic infections and in particular helminthiases caused by nematodes including roundworms (such as heartworms (Dirofilarai immitis) and hookworms particularly Ancylostoma caninum) can inflict diseases through infection of, and damage to various organ systems, for example, the gastrointestinal tract, the lungs and the heart so that metabolic dysfunction, nutritional deficiencies, delayed growth, loss of productivity and death are caused.
  • Numerous classes of drugs are used to treat endoparasitic infections and more specifically, anthelminthic drugs are used to treat nematode infections in animals.
  • WO 2017/178416 A1 concerns pyrazolopyrimidine compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2018/087036 A1, WO 2019/025341 A1, and WO 2019/215182 A1 relate to quinoline compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2018/197401 A1 covers bicyclic pyrazole compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2019/002132 A1 concerns azaquinoline compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2020/083971 A2 relates to compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for the treatment, control and/or prevention of diseases, in particular of helminth iufections, as a sole agent or in combination with other active ingredients.
  • WO 2021/204930 A1 covers substituted condensed azines as anthelmintic compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2020/131629 A1, WO 2020/131631 A1, WO 2020/247747 A1, WO 2022/106469 A2 and WO 2022/117783 A1 concern compounds which are useful in the control of endoparasites, for example heartworms, in warm-blooded animals.
  • WO 2021/018839 A1 covers isoquinoline compounds, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.
  • WO 2021/122906 A1, WO 2021/122911 A1, WO 2022/122987 A1 and WO 2022/122988 A1 relate to anthelmintic compounds. These compounds can, for example, be used in the treatment of the kind of worm disease caused by helminths such as Dirofilaria, in particular Dirofilaria immitis.
  • WO 2020/014068 A1 concerns anthelminthic heterocyclic compounds and compositions comprising the same. A method of controlling helminths using these compounds is also described.
  • WO 2020/191091 A1 relates to anthelmintic aza-benzotiophene and aza-benzofuran compounds and a method for the treatment, control or prevention of a parasitic infestation or infection in an animal in need thereof by administering an effective amount of these compounds to said animal.
  • WO 2021/242581 A1 concerns anthelmintic heterocyclic compounds and a method for the treatment, control or prevention of a parasitic infestation or infection in an animal in need thereof by administering an effective amount of these compounds to said animal.
  • the present invention provides compounds of general formula I.1 or I.2 in which: E1 is an aromatic bicyclic heterocycle substituted with at least one substitutent and wherein the aromatic bicyclic heterocycle is a ring system selected from the group consisting of – a ring system consisting of two 5-membered rings, – a ring system consisting of a 5-membered ring and a 6-membered ring, or – a ring system consisting of two 6-membered rings; E2 is selected from the group consisting of ⁇ an optionally substituted aromatic benzyl, ⁇ an optionally substituted 6-membered heterocycle comprising 1, 2, 3 or 4 heteroatoms in form of N, and ⁇ an optionally substituted bicyclic residue wherein the bicyclic residue is selected from the group consisting of a ring system consisting of two 5-membered rings, a ring system consisting of a 5-membered ring and a 6-membered ring, or a ring system consisting of two 6-member
  • the compounds of the claimed invention have surprising and advantageous long-lasting activity properties. It was particularly surprising and could not have been predicted by the skilled person that the pharmacokinetic properties of the compounds for use according to the invention, especially their distribution, metabolization and tolerance properties in the treated subjects, optionally further modified by formulation (e.g., by a sustained release), are so advantageous that the compounds can prevent and/or treat a disease in different body compartments for a long-term, i.e. for at least one month. Therefore, the compounds of the claimed invention can be effectively used for the long-term prevention and/or treatment of a disease, in particular a helminthic infection in an animal, preferably in a cat or a dog.
  • a disease in particular a helminthic infection in an animal, preferably in a cat or a dog.
  • the long-lasting activity properties also ensure that the compounds for use according to the invention can be applied in very convenient (i.e. less-frequent) and cost-efficient dosage regimens.
  • the compounds of the claimed invention are considered as modulators of the calcium-activated potassium channel Slo-l of nematodes.
  • Slo-1 can be regarded as the helminth' s ortholog of the human KCal .1 channel (potassium calcium-activated channel subfamily M alpha 1), which is encoded by the KCNMAl gene (KCal. l and KCNMAl are often used synonymously).
  • Slo-1 exhibits calcium- activated potassium channel activity and voltage-gated potassium channel activity. Slo-1 channels play an important role in the neuromuscular system as well as in secretory cells among others.
  • Slo-1 modulators are reported to be involved in several processes including behavioural response to ethanol, locomotion and pharyngeal pumping. More particularly, Slo-1 modulators disrupt neuromuscular transmission causing a flaccid paralysis and also affect feeding and egg-laying. Further, Slo-1 modulators also slow the development of the larvae and the adults of the corresponding helminth.
  • the claimed invention also provides a pharmaceutical composition for use in the long-term prevention and/or treatment of a disease, in particuarl a helminthic infection, comprising at least one compound of the claimed invention and at least one further ingredient.
  • the pharmaceutical composition of the claimed invention is particularly suitable for the long-term prevention and/or treatment of a disease, in particular of a helminthic infection.
  • the long-lasting activity properties of the pharmaceutical composition for use according to the invention have been surprising and could not have been predicted by the skilled person. Further the invention concerns the use of the claimed compounds for long-term prevention and/or treatment of a disease, in particular of a helminthic infection. The claimed compounds are particularly suitable for this use due to their surprising long-lasting activity properties. Lastly, the invention concerns a method for long-term prevention and/or treatment of a disease comprising the administration of a compound of the claimed invention or a pharmaceutical composition of the claimed invention at an effective dose to a subject in need thereof. The method of the claimed invention is particularly suitable for long-term prevention and/or treatment of a disease, in particular of a helminthic infection, due to the compounds of the invention which have surprising long-lasting activity properties.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a different atom or group, preferably with a selection from an 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.
  • 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.
  • the number of optional substituents, when present, is 1, 2, 3, 4 or 5, in particular 1, 2 or 3.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • 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, for example.
  • (C1-C4-alkoxy)-(C1-C4-alkyl)- it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the C1-C4-alkoxy part can be attached to any carbon atom of the C1-C4-alkyl part of said (C1-C4-alkoxy)-(C1-C4-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.
  • 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
  • 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.
  • 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”.
  • composition “comprising” X may consist exclusively of X or may include something additional, for example, X + Y.
  • Preparation of the compounds according to the invention and the detetermination of properties of compounds according to the invention requires conventional techniques known to the skilled person unless otherwise indicated. These techniques are fully explained in the literature. Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control.
  • the term “about” modifying the quantity of an ingredient, parameter, calculation, or measurement in the compositions employed in the methods of the disclosure refers to the variation in the numerical quantity that can occur, for example, through typical measuring and liquid handling procedures used for making isolated polypeptides or pharmaceutical compositions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and the like without having a substantial effect on the chemical or physical attributes of the compositions or methods of the disclosure.
  • Such variation can be within an order of magnitude, typically within 10%, more typically still within 5%, of a given value or range.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C1-C6-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C1-C4-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or a tert-butyl group, or a further constitutional isomer thereof.
  • said group has 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), for example a methyl, ethyl, n-propyl or isopropyl group.
  • C1-C4-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C4-alkyl” is defined supra, and in which 1 hydrogen atoms are replaced with a hydroxy group, for example a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2- methyl-propyl, 1-hydroxy-2-methyl-propyl group.
  • -NH(C 1 -C 4 -alkyl) or “-N(C 1 -C 4 -alkyl) 2 ” means a linear or branched, saturated, monovalent group in which the term “C 1 -C 4 -alkyl” is as defined supra, for example a methylamino, ethylamino, n-propylamino, isopropylamino, N,N-dimethylamino, N-methyl-N-ethylamino or N,N- diethylamino group.
  • -S-C 1 -C 4 -alkyl means a linear or branched, saturated group in which the term “C 1 -C 4 -alkyl” is as defined supra, for example 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
  • C1-C4-halogenoalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C4-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom. More particularly, all said halogen atoms are fluorine atoms (“C1-C4-fluoroalkyl”).
  • Said C1-C4-halogenoalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • C1-C4-alkoxy means a linear or branched, saturated, monovalent group of formula (C1-C4-alkyl)-O-, in which the term “C1-C4-alkyl” is as defined supra, for example a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy group, or a further constitutional isomer thereof.
  • C1-C4-halogenoalkoxy means a linear or branched, saturated, monovalent C1-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said C1-C4-halogenoalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C 2 -C 4 -alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3 or 4 carbon atoms.
  • Said C 2 -C 4 -alkenyl group is, for example, an ethenyl (or “vinyl”), a prop-2-en-1-yl (or “allyl”), prop-1-en-1-yl, but-3-enyl, but-2-enyl, but-1-enyl, prop-1-en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl or a 1-methylprop-1-enyl, group.
  • C 2 -C 4 -alkynyl means a linear monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3 or 4 carbon atoms.
  • Said C 2 -C 4 -alkynyl group is, for example, an ethynyl, a prop-1-ynyl, prop-2-ynyl (or “propargyl”), but-1-ynyl, but-2-ynyl, but-3-ynyl or 1-methylprop-2-ynyl, group.
  • said alkynyl group is prop-1-ynyl or prop-2-ynyl.
  • C 3 -C 6 -cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms (“C 3 -C 6 -cycloalkyl”).
  • Said C 3 -C 6 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • C3-C6-halogenocycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring in which the term “C3-C6-cycloalkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine or chlorine atom.
  • Said C3-C6-halogenocycloalkyl group is for example, a monocyclic hydrocarbon ring substituted with one or two fluorine or chlorine atoms, for example a 1-fluoro- cyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1- chlorocyclopropyl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 2-fluoro- 2-chlorocyclopropyl and 2-fluoro-3-chlorocyclopropyl group.
  • benzo-C5-C6-cycloalkyl means a monovalent, bicyclic hydrocarbon ring wherein a saturated, monovalent, monocyclic hydrocarbon ring which contains 5 or 6 carbon atoms (“C5-C6-cycloalkyl”) is annelated to a phenyl ring.
  • Said benzo-C5-C6-cycloalkyl group is for example, a bicyclic hydrocarbon ring, for example an indane (i.e.2,3-dihydro-1H-indene) or tetraline (i.e. 1,2,3,4-tetrahydronaphthalene) group.
  • 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 5, 6, 7, 8, 9, 10 or 11 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[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
  • heterocycloalkyl means a monocyclic or bicyclic, saturated or partially saturated heterocycle with 4, 5, 6, 7, 8, 9 or 10 ring atoms in total (a “4- to 10-membered heterocycloalkyl” group), particularly 4, 5 or 6 ring atoms (a “4- to 6-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 can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, oxolanyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl or 1,2,4-triazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, ox
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common 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[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, oxaazaspiro[2.5]octyl, azaspiro[4.5]decyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, s
  • 6- or 10-membered aryl means a monovalent, monocyclic or bicyclic aromatic ring having 6 or 10 carbon ring atoms, for example a phenyl or naphthyl group.
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 9 or 10 ring atoms (a “5- to 10-membered heteroaryl” group), particularly 5 or 6 ring atoms (a “5- to 6-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 5- membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6- membered heteroaryl group, such as, for example, pyridinyl, dihydropyridinyl, pyridazinyl, pyrimidinyl, tetrahydropyrimidinyl, pyrazinyl or triazinyl.
  • a 5- membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazoly
  • heterocyclyl means a heterocycle selected from the group consisting of heterocycloalkyl and heteroaryl.
  • heteroaryl means a heterocycle selected from the group consisting of 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl.
  • the heteroaryl or heteroarylene groups include all possible constitutional isomeric forms thereof, for example: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • C1-C4 as used in the present text, for example in the context of the definition of “C1-C4-alkyl”, “C1-C4-halogenoalkyl”, “C1-C4-hydroxyalkyl”, “C1-C4-alkoxy” or “C1-C4-halogenoalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 4, i.e.1, 2, 3 or 4 carbon atoms.
  • C3-C6 as used in the present text, for example in the context of the definition of “C3-C6-cycloalkyl” or C3-C6-halogenocycloalkyl, means a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e.3, 4, 5 or 6 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range.
  • C1-C4 encompasses C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3, and C3-C4
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6
  • C3-C4" encompasses C3, C4, and C3-C4
  • C 3 -C 10 encompasses C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 3 -C 10 , C 3 -C 9 , C 3 -C 8 , C 3 -C 7
  • 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).
  • 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.
  • 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 “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes examples include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, respectively.
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”).
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful, for example, 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 18 F or 11 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 13 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.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 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.
  • 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.
  • 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 0.015%. 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 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s).
  • 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 [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J.
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (for example Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • 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.
  • Deuterated drugs showing this effect may have reduced dosing requirements (for example 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.
  • 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 for example cytochrome P450.
  • cytochrome P450 cytochrome P450
  • 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.
  • 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. In certain instances, it is possible that asymmetry may also be present due to restricted rotation around a double bond or due to a ring structure, wherein the rotation of bonds is restricted or prevented.
  • These geometric isomers may be indicated as cis- or trans- isomers or as (E)- and (Z)-isomers.
  • Preferred compounds are those which produce the more desirable biological activity.
  • 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.
  • 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 (for example, 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, for example, 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.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, for example, (R)- or (S)- stereoisomers, (E)- or (Z)-isomers, cis- or trans-isomers, in any ratio.
  • Isolation of a single stereoisomer, for example, 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.
  • 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.
  • 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.
  • polar solvents in particular water
  • stoichiometric solvates for example 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.
  • the compounds of the present invention may exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or 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.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in 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, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • 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
  • 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.
  • 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.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound – wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_1 and E2_1 wherein n is 0; E1_2 and E2_1 wherein n is 0; E1_3 and E2_1 wherein n is 0; E1_6 and E2_1 wherein n is 0; E1_7 and E2_2 wherein n is 0; or wherein E1 and E2 form the following pair when the compound of formula I is a compound of formula I.2: E1_7 and E2_2 wherein n is 0; in
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_2 and E2_1 wherein n is 0; E1_4 and E2_1 wherein n is 0; E1_7 and E2_2 wherein n is 0.
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound, wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_2 and E2_1’ wherein n is 0; E1_4 and E2_1’’ wherein n is 0; E1_7 and E2_2 wherein n is 0; in which E1_2 is wherein R2 is selected from the group consisting of hydrogen, halogen, cyano, -COOH, C1-C4-alkoxy-C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4- alkyl), -C(O)-N(C1-C4-alkyl)
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound, wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_2 and E2_1’ wherein n is 0; E1_4 and E2_1’’ wherein n is 0; E1_7 and E2_2 wherein n is 0; in which E1_2 is wherein R2 is selected from the group consisting of hydrogen, halogen, cyano, -COOH, C1-C4-alkoxy- C(O)-, -C(O)-NH2, -C(O)-NH(C1-C4-alkyl), -C(O)-N(C1-C4-alkyl)
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound, wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_2 and E2_1’ wherein n is 0; E1_4 and E2_1’’ wherein n is 0; E1_7 and E2_2 wherein n is 0; in which E1_2 is wherein R2 is selected from the group consisting of hydrogen, halogen, –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; C1-C4-alkyl, C3-C6-cycloalkyl, C2-C4-alkenyl or C3
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound, wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_2 and E2_1’ wherein n is 0; E1_4 and E2_1’’ wherein n is 0; E1_7 and E2_2 wherein n is 0; in which E1_2 is wherein R2 is selected from the group consisting of hydrogen, chlorine, fluorine, bromine; –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, propenyl, cyclopentenyl, cyclohexenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound wherein E1 and E2 are selected from the following pairs when the compound of formula I is a compound of formula I.1: E1_7 and E2_1’’ wherein n is 0; E1_4 and E2_1’’ wherein n is 0; in which E1_4 is wherein R4 is methyl; Q is optionally substituted phenyl, wherein the optional substituent of phenyll is selected from the group consisting of halogen, alkyl optionally substituted with halogen, alkoxy optionally substituted with halogen, and -SF5; R2 is selected from the group consisting of alkyl, cycloalkyl optionally subsituted with halogen, CN,
  • the compounds of this embodiment are particularly suitable for the long-term prevention and/or treatment of a disease, in particular for the long-term prevention and/or treatment of a helminthic infection in an animal.
  • PCT/EP2022/074866 In one embodiment, the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of PCT/EP2022/074866. The disclosure of PCT/EP2022/074866 is incorporated herein by reference in its entirety.
  • the compound for use in the long-term prevention and/or treatment of a disease according to the invention is a compound according to the following aspects of PCT/EP2022/074866: Aspect I of PCT/EP2022/074866: A compound of general formula (I): in which: A is A1 or A2; o is 0, 1, 2, 3 or 4; R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1- C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)- C1-C4-al
  • PCT/EP2022/074866 The compound according to Aspect I of PCT/EP2022/074866, wherein: A is A1 or A2; o is 0, 1, 2, 3 or 4; R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C 1 -C 4 -alkyl, C 1 -C 4 - halogenoalkyl having 1 to 5 halogen atoms, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy having 1 to 5 halogen atoms, C 3 -C 6 -cycloalkyl, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , -S-C 1 -C 4 -alkyl, -S(O)- C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4
  • Aspect III of PCT/EP2022/074866 The compound according to Aspect 1 or 2 of PCT/EP2022/074866, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl and C1-C4-alkoxy, cyano, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, Rp is selected from the group consisting of hydrogen, C1-C4-alkyl, X, Y are independently selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , wherein at least one of X and Y is CR 7 R 8 , R 1 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 4 - alkenyl, C3-C4-alkynyl, C1-C4-
  • Aspect IV of PCT/EP2022/074866 The compound according to any one of Aspects 1, 2 or 3 of PCT/EP2022/074866, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, and cyano, Rp is selected from the group consisting of hydrogen, C1-C4-alkyl, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 or O, R 1 is hydrogen or C1-C4-alkyl, R 2 is selected from the group consisting of 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2- thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan
  • R 1 is hydrogen or methyl
  • R 2 is selected from the group consisting of 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2- thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido- 1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3- yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-methylpyrrolidine-2-yl, 1-methylpyrrolidine
  • Aspect VI of PCT/EP2022/074866 The compound according to Aspect 1, 2, 3, 4 or 5 of PCT/EP2022/074866, wherein: A is selected from the group consisting of , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of 2-oxocyclobutyl, 3-oxocyclobutyl, 3-thietanyl, 2- thietanyl, 1-oxidothietan-3-yl, 1-oxidothietan-2-yl, 1-imino-1-oxido-1-thietan-3-yl, 1-imino-1-oxido- 1-thietan-2-yl, 1,1-dioxidothietan-3-yl, 1,1-dioxidothietan-2-yl, 4-oxoazetidin-2-yl, 2-oxoazetidin-3- yl, 2-hydroxycyclobutyl, 3-hydroxycyclobutyl, 2-fluorocyclobutyl, 3-flu
  • Aspect VII of PCT/EP2022/074866 The compound according to Aspect 1, 2, 3, 4, 5, or 6 of PCT/EP2022/074866, wherein: R 2 is selected from the group consisting of 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1- imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3- fluorocyclobutyl, 3,3-difluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidine-2-yl, 1- methylpyrrolidine-3-yl, 5-oxopyrrolidine-3-yl, 2-oxopyrrolidine-3-yl, 5-oxopyrrolidine-2-yl, tetrahydropyran-4-yl, 3-oxopiperazin-1-yl
  • Aspect VIII of PCT/EP2022/074866 The compound according to Aspect 1, 2, 3, 4, 5, 6, or 7 of PCT/EP2022/074866, wherein: R 2 is selected from the group consisting of 3-oxocyclobutyl, 3-thietanyl, 1-oxidothietan-3-yl, 1- imino-1-oxido-1-thietan-3-yl, 1,1-dioxidothietan-3-yl, 2-oxoazetidin-3-yl, 3-hydroxycyclobutyl, 3- fluorocyclobutyl, tetrahydrofuran-3-yl, 1-methylpyrrolidine-2-yl, 1-methylpyrrolidine-3-yl, 5- oxopyrrolidine-3-yl, 2-oxopyrrolidine-3-yl, 5-oxopyrrolidine-2-yl, tetrahydropyran-4-yl, 2-oxa-5- azabicyclo[4.1.0]heptan-5-yl, 3,
  • Aspect IX of PCT/EP2022/074866 The compound according to Aspect 1, 2, 3, 4, 5, 6, 7, or 8 of PCT/EP2022/074866, wherein: R 2 is 3-hydroxycyclobutyl, 3-fluorocyclobutyl, tetrahydrofuran-3-yl or 3-oxocyclobutyl, Q is 2,3,5-trifluorophenyl or 3,5-dichlorophenyl
  • E1_1, E2_1, n and R1 are as defined in PCT/EP2022/074866.
  • E1_1, E2_1, n and R1 are as defined in the above-described aspects of PCT/EP2022/074866.
  • the compound of general formula (I) is a compound of formula I.1 wherein E1_1, E2_1, and R1, are as defined in the above-described aspects of PCT/EP2022/074866 and n is 0.
  • WO 2018/087036 A1 In one embodiment, the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of WO 2018/087036 A1. The disclosure of WO 2018/087036 A1 is incorporated herein by reference in its entirety.
  • the compound for use in the long-term prevention and/or treatment of a disease according to the invention is a compound according to the following aspects of WO 2018/087036 A1: Aspect I of WO 2018/087036 A1: A compound of general formula (I): in which : A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1- C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)- C1-C4-alky
  • Aspect II of WO 2018/087036 A1 The compound according to Aspect 1 of WO 2018/087036 A1, wherein: A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C 1 -C 4 -alkyl, C 1 - C 4 -halogenoalkyl having 1 to 5 halogen atoms, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy having 1 to 5 halogen atoms, C 3 -C 6 -cycloalkyl, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , -S-C 1 -C 4 -alkyl, -S(O)- C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -al
  • Aspect III of WO 2018/087036 A1 The compound according to Aspect 1 or 2 of WO 2018/087036 A1, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, cyano, C 1 -C 4 - halogenoalkyl having 1 to 5 halogen atoms, R p is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, X, Y are independently selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , wherein at least one of X and Y is CR 7 R 8 , R 1 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 4 - alkenyl, C 3 -C 4 -alkyn
  • Aspect IV of WO 2018/087036 A1 The compound according to Aspect 1, 2 or 3 of WO 2018/087036 A1, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-alkoxy, R p is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 or O, R 1 is hydrogen or C 1 -C 4 -alkyl, R 2 is selected from the group consisting of hydrogen, halogen, -C(O)-N(C 1 -C 4 -alkyl) 2 ; –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO 2 R 15 ; C 1 -C 4 -alkyl,
  • Aspect V of WO 2018/087036 A1 The compound according to Aspect 1, 2, 3 or 4 of WO 2018/087036 A1, wherein: A is selected from the group consisting of , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of hydrogen, chlorine, iodine, -C(O)-N(CH3)2, –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, cyclopentenyl, cyclohexenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting of -OH, cyano, ethoxy-C(O)-, -C(O)-NH 2
  • each Z 21 is independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and Z 22 is hydrogen, methyl, or Q is selected from the group consisting of (Q7-6) (Q7-7) (Q7-8) (Q7-9) in which: each Z 23 is independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, or Q is selected from the group consisting of , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • Aspect VI of WO 2018/087036 A1 The compound according to Aspect 1, 2, 3, 4 or 5 of WO 2018/087036 A1, wherein: A is selected from the group consisting of , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of chlorine, iodine, -C(O)-N(CH 3 ) 2 , –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, ethenyl, propenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting of -OH, cyano, ethoxy-C(O)-, -C(O)-NH2, methoxy, NH2, N(CH3)2, N(CH3)(C(O)CH
  • E1_1, E2_1, n and R1 are as defined in WO 2018/087036 A1. In one embodiment, E1_1, E2_1, n and R1 are as defined in the above-described aspects of WO 2018/087036 A1. In one embodiment, the compound of general formula (I) is a compound of formula I.1 wherein E1_1, E2_1 and R1 are as defined in the above-described aspects of WO 2018/087036 A1 and n is 0. WO 2019/025341 A1 In one embodiment, the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of WO 2019/025341 A1.
  • the compound for use in the long-term prevention and/or treatment of a disease according to the invention is a compound according to the following aspects of WO 2019/025341 A1: Aspect I of WO 2019/025341 A1: A compound of general formula (I): in which : A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1- C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1
  • Aspect II of WO 2019/025341 A1 The compound according to Aspect 1 of WO 2019/025341 A1, wherein: A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C1-C4-alkyl, C1- C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy, C1-C4-halogenoalkoxy having 1 to 5 halogen atoms, C3-C6-cycloalkyl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -S-C1-C4-alkyl, -S(O)- C1-C4-alkyl, -SO2-C1-C4-alkyl, –S-C1-C4-halogenoalkyl, —S(O)
  • Aspect III of WO 2019/025341 A1 The compound according to Aspect 1 or 2 of WO 2019/025341 A1, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, cyano, C 1 -C 4 -halogenoalkyl having 1 to 5 halogen atoms, X, Y are independently selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , wherein at least one of X and Y is CR 7 R 8 , R 1 is selected from the group consisting of hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C4- alkenyl, C3-C4-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-cycloal
  • Aspect IV of WO 2019/025341 A1 The compound according to Aspect 1, 2 or 3 of WO 2019/025341 A1, wherein: A is A1 or A2, , o is 0 or 1, R is selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-alkoxy, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 , R 1 is hydrogen or C1-C4-alkyl, R 2 is selected from the group consisting of hydrogen, halogen, –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 4 -alkenyl or C 3 -C 6 -cycloalkenyl, each of which is optionally substituted
  • Aspect V of WO 2019/025341 A1 The compound according to Aspect 1, 2, 3 or 4 of WO 2019/025341 A1, wherein: A is selected from the group consisting of , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of hydrogen, chlorine, –NR 12 R 13 ; –OR 14 ; -SR 15 , -S(O)R 15 , -SO2R 15 ; methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclohexyl, propenyl, cyclopentenyl, cyclohexenyl, each of which is optionally substituted by 1 or 2 substituents independently selected from the group consisting of cyano, ethoxy-C(O)-, and -C(O)-NH2; and a monocyclic or a bicyclic heterocycle selected from the group consisting of azetidine, pyrrolidine, pyrazolidine, imidazol
  • Aspect VI of WO 2019/025341 A1 The compound according to Aspect 1, 2, 3 or 4 of WO 2019/025341 A1, wherein: A is A1 , o is 0 or 1, R is selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of hydrogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, methyl, ethyl, and morpholin-4-yl; R 3 is hydrogen, R 4 is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy and trifluoromethyl, R 5 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl, R 6 is selected from
  • Aspect VII of WO 2019/025341 A1 The compound according to Aspect 1, 2, 3 or 4 of WO 2019/025341 A1, wherein: , o is 0 or 1, R is selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of hydrogen, amino, methylamino, ethylamino, dimethylamino, diethylamino, methyl, ethyl, isopropyl, and morpholin-4-yl; R 3 is hydrogen, R 4 is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy and trifluoromethyl, R 5 is selected from the group consisting of hydrogen, chlorine, fluorine and methyl, R 6 is
  • Aspect VIII of WO 2019/025341 A1 The compound according to any one of Aspects 1, 2, 3, 4, 5, 6 or 7 of WO 2019/025341 A1, wherein in the definition of the substituent R 2 the meaning of hydrogen is excluded.
  • E1_1, E2_1’, n and R1 are as defined in WO 2019/025341 A1.
  • E1_1, E2_1’, n and R1 are as defined in the above-described aspects of WO 2019/025341 A1.
  • the compound of general formula (I) is a compound of formula I.1 wherein E1_1, E2_1’ and R1 are as defined in the above-described aspects of WO 2019/025341 A1 and n is 0.
  • the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of WO 2019/215182 A1.
  • the disclosure of WO 2019/215182 A1 is incorporated herein by reference in its entirety.
  • the compound for use in the long-term prevention and/or treatment of a disease according to the invention is a compound according to the following aspects of WO 2019/215182 A1: Aspect I of WO 2019/215182 A1: A compound of general formula (I): in which : A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C 1 -C 4 -alkyl, C 1 - C 4 -halogenoalkyl having 1 to 5 halogen atoms, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy having 1 to 5 halogen atoms, C 3 -C 6 -cycloalkyl, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , -S-C 1 -C 4 -al
  • Aspect II of WO 2019/215182 A1 The compound according to Aspect 1 WO 2019/215182 A1, wherein: A is A1 or A2, o is 0, 1, 2, 3 or 4, R is selected from the group consisting of hydrogen, halogen, cyano, nitro, -OH, C 1 -C 4 -alkyl, C 1 - C 4 -halogenoalkyl having 1 to 5 halogen atoms, C 1 -C 4 -alkoxy, C 1 -C 4 -halogenoalkoxy having 1 to 5 halogen atoms, C 3 -C 6 -cycloalkyl, -NH 2 , -NH(C 1 -C 4 -alkyl), -N(C 1 -C 4 -alkyl) 2 , -S-C 1 -C 4 -alkyl, -S(O)- C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -alkyl,
  • Aspect III of WO 2019/215182 A1 The compound according to Aspect 1 or 2 of WO 2019/215182 A1, wherein: o is 0, 1 or 2, R is selected from the group consisting of halogen, C1-C4-alkyl and C1-C4-alkoxy, cyano, C1-C4- halogenoalkyl having 1 to 5 halogen atoms, Rp is selected from the group consisting of hydrogen, C1-C4-alkyl, X, Y are independently selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , wherein at least one of X and Y is CR 7 R 8 , R 1 is selected from the group consisting of hydrogen, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C4- alkenyl, C3-C4-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C3-
  • Aspect IV of WO 2019/215182 A1 The compound according to Aspect 1, 2 or 3 of WO 2019/215182 A1, wherein: A is A1 or A2, o is 0, 1 or 2, R is selected from the group consisting of halogen, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, R p is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, X is selected from the group consisting of CR 7 R 8 , O, S, and N-R 9 , Y is CR 7 R 8 or O, R 1 is hydrogen or C1-C4-alkyl, R 2 is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6 dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R 3 is hydrogen or C1-C4-alkyl, R 4 is selected from the group consisting of hydrogen, hal
  • R 1 is hydrogen or methyl
  • R 2 is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6 dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl
  • R 3 is hydrogen or methyl
  • R 4 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy and NH2, preferably hydrogen, fluorine, chlorine, methoxy and isopropoxy
  • R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl, methoxy and trifluoromethyl
  • R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy
  • Q is 2,3,5-trifluorophenyl, wherein a compound according to the formula is excluded; or a stereoi
  • A is selected from the group consisting of , R 1 is hydrogen or methyl, R 2 is selected from the group consisting of tetrahydro-2H-pyran-4-yl, 3,6 dihydro-2H-pyran-4-yl, ethyl and 3-fluoroazetidin-1-yl, R 3 is hydrogen or methyl, R 4 is selected from the group consisting of hydrogen, chlorine, fluorine, methyl, methoxy, isopropoxy and trifluoromethyl, preferably chlorine, fluorine, methoxy and isopropoxy, R 5 is selected from the group consisting of hydrogen, chlorine, fluorine, -OH, cyano, methyl, trifluoromethoxy and NH2, R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, cyano, methyl and methoxy, Q is 2,3,5
  • Aspect VII of WO 2019/215182 A1 The compound according to any one of Aspects 1-6 of WO 2019/215182 A1, wherein: R 2 is tetrahydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • Aspect VIII of WO 2019/215182 A1 The compound according to any one of Aspects 1-6, wherein: R 2 is 3,6-dihydro-2H-pyran-4-yl, Q is 2,3,5-trifluorophenyl, or a stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • Aspect IX of WO 2019/215182 A1 The compound according to any one of Aspects 1-6, wherein: R 2 is ethyl, R 4 is selected from the group consisting of hydrogen, halogen, -OH, cyano, C1-C4-alkyl, C3-C6- cycloalkyl, C1-C4-halogenoalkyl having 1 to 5 halogen atoms, C1-C4-alkoxy-C1-C4-alkyl, C1-C4- alkoxy, C 1 -C 4 -halogenoalkoxy having 1 to 5 halogen atoms, C 1 -C 4 -alkyl-C(O)-, -NH 2 , -NH(C 1 -C 4 - alkyl), -N(C 1 -C 4 -alkyl) 2 , -S-C 1 -C 4 -alkyl, -S(O)-C 1 -C 4 -al
  • Aspect X of WO 2019/215182 A1 The compound according to any one of Aspects 1-6, wherein: R 2 is 3-fluoroazetidin-1-yl, Q is 2,3,5-trifluorophenyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • E1_1, E2_1, n and R1 are as defined in WO 2019/215182 A1.
  • E1_1, E2_1, n and R1 are as defined in the above-described aspects of WO 2019/215182 A1.
  • the compound of general formula (I) is a compound of formula I.1 wherein E1_1, E2_1 and R1 are as defined in the above-described aspects of WO 2019/215182 A1 and n is 0.
  • WO 2020/131631 A1 In one embodiment, the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of WO 2020/131631 A1. The disclosure of WO 2020/131631 A1 is incorporated herein by reference in its entirety.
  • the compound for use in the long-term prevention and/or treatment of a disease according to the invention is a compound according to the following aspects of WO 2020/131631 A1: Aspect I of WO 2020/131631 A1: A compound of compounds of formula (I): wherein n is 0 or 1; X1 is selected from the group consisting of N and CR1; X 2 is selected from the group consisting of N and CR 2 ; X 3 is selected from the group consisting of N and CR 3 ; X4 is selected from the group consisting of N and CR4; X5 is selected from the group consisting of N and CR5; X6 is selected from the group consisting of N and CR6; G is the group ; Y1 is selected from the group consisting of CR8R9, O, S, and NR10; Y2 is selected from the group consisting of CR8R9, O, S, and NR10; wherein at least one of the groups Y1 or Y2
  • Aspect VI of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 5 of WO 2020/131631 A1 wherein X1 is CR1; X2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is CR6; or a salt thereof.
  • Aspect VII of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 5 of WO 2020/131631 A1, wherein X 1 is CR 1 ; X 2 is CR2; X3 is CR3; X4 is CR4; X5 is CR5; and X6 is N; or a salt thereof.
  • Aspect VIII of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 5 of WO 2020/131631 A1, wherein X 1 is N; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is CR 4 ; X 5 is CR 5 ; and X 6 is N; or a salt thereof.
  • Aspect IX of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 5 of WO 2020/131631 A1, wherein X 1 is N; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is CR 4 ; X 5 is CR 5 ; and X 6 is N; or a salt thereof.
  • Aspect X of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 9 of WO 2020/131631 A1, wherein Q is a 6- or 10 membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 al
  • Aspect XI of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 9 of WO 2020/131631 A1, wherein Q is 6-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, - S
  • Aspect XII of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 9 of WO 2020/131631 A1, wherein Q is a 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group O, S, and N and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, -NH 2 , -NH(C 1 -C 4 alkyl), and -N(C 1 -C 4 alkyl) 2 and any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl; or a salt
  • Aspect XIII of WO 2020/131631 A1 A compound according to any one of Aspects 1 to 9 of WO 2020/131631 A1, wherein Q is a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group O, S, N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2 and any N in the heterocyclalkyl is optionally substituted with a substituent selected
  • Aspect XIV of WO 2020/131631 A1 The compound according to any one of Aspects 1 to 13 of WO 2020/131631 A1, wherein n is 1; or a salt thereof.
  • Aspect XV of WO 2020/131631 A1 The compound according to any one of Aspects 1 to 14 of WO 2020/131631 A1, wherein Y1 is CR8R9 and Y2 is O; or a salt thereof.
  • Aspect XVI of WO 2020/131631 A1 The compound according to any one of Aspects 1 to 15 of WO 2020/131631 A1, wherein R 4 is selected from the group consisting of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -N(C 1 -C 4 alkyl) 2 , and 4- to 7-membered heterocycloalkyl; or a salt thereof.
  • a compound of Aspect 1 wherein the compound is selected from the group consisting of (4R)-N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]chromane-4-carboxamide; (4S)-N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]chromane-4-carboxamide; (1R)-N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]tetralin-1-carboxamide (1S)-N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]tetralin-1-carboxamide; (4R)-N-[4-cyclopropyl-8-(3,5-dichlorophenyl)-3-quinolyl]chroman
  • E1_7, E2_1’’, n and R1 are as defined in WO 2020/131631 A1. In one embodiment, E1_7, E2_1’’, n and R1 are as defined in the above-described aspects of WO 2020/131631 A1. In one embodiment, the compound of general formula (I) is a compound of formula I.2 wherein E1_7, E2_1’’ and R1 are as defined in the above-described aspects of WO 2020/131631 A1 and n is 0. WO 2022/117783 A1 In one embodiment, the compound for use in the long-term prevention and/or treatment of a disease is a compound according to the disclosure of WO 2022/117783 A1.
  • Aspect VII of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 6 of WO 2022/117783 A1, wherein Q is a 6- or 10 membered aryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, -C(O)NH 2 , -C(O)R 17 , -NH 2 , -NH(C 1 -C 4 alkyl), -N(C 1 - C 4 alkyl) 2 , -NH(C 3 -C 6 cycloalkyl), -N(C 1 -C 4 alkyl)(C 3 -C 6 -cycloalkyl), -NHSO 2 (C 1 -C 4
  • Aspect VIII of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 6 of WO 2022/117783 A1, wherein Q is a 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group O, S, and N and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, -OH, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, -SC1-C4, C(O)R17, -NH2, -NH(C1-C4 alkyl), and -N(C1- C4 alkyl)2 and any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, and C3-C6 cycl
  • Aspect X of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 9 of WO 2022/117783 A1, wherein G is ; and M is O; or a stereoisomer or salt thereof.
  • Aspect XI of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 10 of WO 2022/117783 A1, wherein G is ; M is O; and R7 is hydrogen or C1-C9 alkyl, preferably R7 is hydrogen or nonyl; or a stereoisomer or salt thereof.
  • Aspect XII of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 11 of WO 2022/117783 A1, wherein R4 is selected from the group consisting of B(OH)2, C2-C4 alkenyl, C3-C6-cycloalkyl, C1-C4 halogenoalkyl, C1-C4-alkoxy substituted C1-C4 alkyl, -N(C1-C4 alkyl)2, -N(C1-C4 alkyl)(C1-C4 alkoxy), -N(C1-C4 alkyl)(C1-C4 alkoxy substituted C1-C4 alkyl), -N(C1-C4 alkoxy substituted C1-C4 alkyl)2, - N(C(O)C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)(C3-
  • Aspect XIII of WO 2022/117783 A1 The compound of formula (I’) according to any one of Aspects 1 to 12 of WO 2022/117783 A1, or a stereoisomer or salt thereof, having formula (Ia-5”), wherein R 1 , R 4 , R 11 , and Q are as defined in any one of Aspects 1 to 12.
  • Aspect XIV of WO 2022/117783 A1 The compound of formula (Ia-5”) according to Aspect 13 of WO 2022/117783 A1, or a stereoisomer or salt thereof, wherein R 1 is hydrogen, halogen, cyano or C 1 -C 9 alkyl.
  • Aspect XV of WO 2022/117783 A1 The compound of formula (Ia-5”) according to Aspect 13 or 14 of WO 2022/117783 A1, or a stereoisomer or salt thereof, wherein R 4 is selected from:
  • Aspect XVI of WO 2022/117783 A1 The compound of formula (Ia-5”) according to any one of Aspects 13 to 15, or a stereoisomer or salt thereof, wherein R 11 is hydrogen or halogen.
  • Aspect XVII of WO 2022/117783 A1 The compound of formula (Ia-5”) according to any one of Aspects 13 to 16, or a stereoisomer or salt thereof, wherein Q is a 6-membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, C1-C4 halogenoalkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -C(O)NH2, -C(O)R17, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NH(C3-C6 cycloalkyl), -N(C1-C4 alkyl)(C3-C6-cycloalkyl), -NHSO2(C1-C4 alkyl), -SC1-C4 alky
  • Aspect XVIII of WO 2022/117783 A1 The compound of formula (Ia-5”) according to any one of Aspects 13 to 17, or a stereoisomer or salt thereof, wherein Q is selected from: Aspect XIX of WO 2022/117783 A1: The compound of formula (I’) according to any one of Aspects 1 to 18 selected from the group consisting of: N-[8-(3,5-dichlorophenyl)-4-(dimethylamino)-3-quinolyl]-2,3-dihydro-1,4-benzoxazine-4- carboxamide; (Example 1.1) 8-(3,5-dichlorophenyl)-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-(dimethylamino)-1,7-naphthyridine-3- carboxamide; (Example 2.1) 8-(3,5-dichlorophenyl)-N-(
  • E1_7, E2_2, n and R1 are as defined in WO 2022/117783 A1. In one embodiment, E1_7, E2_2, n and R1 are as defined in the above-described aspects of WO 2022/117783 A1. In one embodiment, the compound of general formula (I) is a compound of formula I.2 wherein E1_7, E2_2 and R1 are as defined in the above-described aspects of WO 2022/117783 A1 and n is 0.
  • Long-term prevention and/or treatment of a disease The claimed invention concerns compounds for use in the long-term prevention and/or treatment of a disease.
  • the compound for use in the long-term prevention and/or treatment of a disease has a half-life of at least 20 hours, preferably at least 30 hours, more preferably at least 35 hours, and most preferably at least 40 hours.
  • Compounds for use according to the invention with such a half-life are particularly suitable in the long-term prevention and/or treatment of a disease, in particular in the long-term prevention and/or treatment of an helminthic infection in an animal, preferably in a cat or a dog.
  • Methods to determine the half-life of a given compound are part of the common general knowledge of the skilled person.
  • the compound for use in the long-term prevention and/or treatment of a disease has a plasma clearance of less than 2 L/h/kg, preferably less than 1.5 L/h/kg and most preferably less than 1 L/h/kg.
  • Compounds for use according to the invention with such a plasma clearance are particularly suitable in the long-term prevention and/or treatment of a disease, in particular in the long- term prevention and/or treatment of an helminthic infection in an animal, preferably in a cat or a dog. Methods to determine the plasma-clearance of a given compound are part of the common general knowledge of the skilled person.
  • the term “long-term” means a period of time of at least one month, preferably at least two months, even more preferably at least three months and most preferably at least six months. It was surprising that the compounds for use according to the claimed invention have this long-term effect of preventing and/or treating a disease, in particular an helminthic infection in an animal, preferably in a cat or a dog.
  • the term “long-term” means that the prevention and/or treatment of a disease is held for a period of time of at least one month, preferably at least two months, even more preferably at least three months and most preferably at least six months with an efficacy of at least 40%, preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, still more preferably at least 80% and most preferably at least 90%.
  • efficacy as used herein means the power to produce any effect on the prevention and/or treatment a disease. It belongs to the skilled person’s common general knowledge to choose and apply a suitable standard technique to determine the efficacy in preventing and/or treating a given disease when using a compound according to the claimed invention.
  • the term “for use in the long-term prevention and/or treatment of a disease” means that the compound prevents and/or treats the onset of a disease occurring or arising at least one month after its administration, preferably at least one and a half months after its administration, more preferably at least two months after its administration, even more preferably at least three months after its administration and most preferably at least six months after its administration.
  • the compounds of the claimed invention are particularly effective to prevent and/or treat the onset of a disease, in particular the onset of an helmintic infection in an animal, preferably in a cat or a dog, when the disease occurs in these time intervals after administration of the compound.
  • the terms "treating” or “preventing“ of a disease or disorder includes preventing or protecting against the disease or disorder (that is, causing the clinical symptoms not to develop), inhibiting the disease or disorder (i.e., arresting or suppressing the development of clinical symptoms), and/or relieving the disease or disorder (i.e., causing the regression of clinical symptoms). It is not always possible to distinguish between researchingpreventing" and proceedingssuppressing" a disease or disorder since the ultimate inductive event or events may be unknown or latent.
  • the term termed herein can also be understood to constitute a type of explicates both strictlypreventing" and proceedingssuppressing".
  • the term termed can thus include whilprophylaxis".
  • the compound for use according to the invention i.e. the active compound
  • the compound for use according to the invention is formulated in a form that enables a sustained release of the compound when administered to a subject.
  • This has the advantage that the long-term properties of the compounds for use according to the invention can be further modulated and/or enhanced so that a particularly efficient long-term effect regarding the prevention and/or treatment of a disease is achieved, in particular in the long-term prevention and/or treatment of an helminthic infection in an animal, preferably in a cat or a dog.
  • sustained release means in particular “ensures a sustained release”.
  • sustained release is known by the skilled person and refers to the delivery of a compound at a programmed rate that leads to a compound delivery for a prolonged period of time compared the delivery of a compound formulated in a conventional rapid-release formulation, in particular a conventional rapid-release tablet or suspension administered orally.
  • the “sustained release” is effected by a subcutaneous injection that has sustained release relative to the PO administration. Such sustained release is derived from the inherent solubility characteristics of the molecule and the route of administration.
  • a conventional rapid-release tablet or suspension is one that is not formulated to release the compound in a modified way.
  • Rapid-release tablets or suspensions are in particular those which, according to the USP release method using apparatus 2 (paddle), have a Q value (30 minutes) of 75 %.
  • the skilled person knows and/or can readily identify by standard techniques suitable formulations that allow a sustained release of the administered compound. For example, micro-encapsulation could be used. Another strategy could be to use compound-polymer conjugates (for example hydrogels) to ensure a sustained-release of the active compound.
  • Disease The claimed invention concerns compounds for use in the long-term prevention and/or treatment of a disease.
  • the disease is a helminithic infection.
  • the compounds according to the claimed invention are particularly efficient in the long-term prevention (i.e.
  • helminthic infections preferably gastro-intestinal and extra-intestinal helminthic infections.
  • helminthic infections preferably gastro-intestinal and extra-intestinal helminthic infections.
  • helminths pathogenic for humans or animals include, for example, acanthocephala, nematodes, pentastoma and platyhelmintha (e.g.
  • helminths include, but are not limited to: Monogenea: for example Dactylogyrus spp., Gyrodactylus spp., Microbothrium spp., Polystoma spp., Troglocephalus spp. Cestodes: from the order of the Pseudophyllidea, for example: Bothridium spp., Diphyllobothrium spp., Diplogonoporus spp., Ichthyobothrium spp., Ligula spp., Schistocephalus spp., Spirometra spp.
  • Cyclophyllida for example: Andyra spp., Anoplocephala spp., Avitellina spp., Bertiella spp., Cittotaenia spp., Davainea spp., Diorchis spp., Diplopylidium spp., Dipylidium spp., Echinococcus spp., Echinocotyle spp., Echinolepis spp., Hydatigera spp., Hymenolepis spp., Joyeuxiella spp., Mesocestoides spp., Moniezia spp., Paranoplocephala spp., Raillietina spp., Stilesia spp., Taenia spp., Thysaniezia spp., Thysanosoma spp.
  • Trematodes from the class of the Digenea, for example: Austrobilharzia spp., Brachylaima spp., Calicophoron spp., Catatropis spp., Clonorchis spp.
  • Collyriclum spp. Cotylophoron spp., Cyclocoelum spp., Dicrocoelium spp., Diplostomum spp., Echinochasmus spp., Echinoparyphium spp., Echinostoma spp., Eurytrema spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Fischoederius spp., Gastrothylacus spp., Gigantobilharzia spp., Gigantocotyle spp., Heterophyes spp., Hypoderaeum spp., Leucochloridium spp., Metagonimus spp., Metorchis spp., Nanophyetus spp., Notocotylus spp., Opisthorchis spp., Or
  • Nematodes from the order of the Trichinellida, for example: Capillaria spp., Eucoleus spp., Paracapillaria spp., Trichinella spp., Trichomosoides spp., Trichuris spp. from the order of the Tylenchida, for example: Micronema spp., Parastrongyloides spp., Strongyloides spp.
  • Aelurostrongylus spp. Amidostomum spp., Ancylostoma spp., Angiostrongylus spp., Bronchonema spp., Bunostomum spp., Chabertia spp., Cooperia spp., Cooperioides spp., Crenosoma spp., Cyathostomum spp., Cyclococercus spp., Cyclodontostomum spp., Cylicocyclus spp., Cylicostephanus spp., Cylindropharynx spp., Cystocaulus spp., Dictyocaulus spp., Elaphostrongylus spp., Filaroides spp., Globocephalus spp., Graphidium spp., Gyalocephalus s
  • Spirurida from the order of the Spirurida, for example: Acanthocheilonema spp., Anisakis spp., Ascaridia spp.; Ascaris spp., Ascarops spp., Aspiculuris spp., Baylisascaris spp., Brugia spp., Cercopithifilaria spp., Crassicauda spp., Dipetalonema spp., Dirofilaria spp., Dracunculus spp.; Draschia spp., Enterobius spp., Filaria spp., Gnathostoma spp., Gongylonema spp., Habronema spp., Heterakis spp.; Litomosoides spp., Loa spp., Onchocerca spp., Oxyuris spp., Parabronema spp
  • Acantocephala from the order of the Oligacanthorhynchida, for example: Macracanthorhynchus spp., Prosthenorchis spp.; from the order of the Moniliformida, for example: Moniliformis spp. from the order of the Polymorphida, for example: Filicollis spp.; from the order of the Echinorhynchida, for example: Acanthocephalus spp., Echinorhynchus spp., Leptorhynchoides spp. Pentastoma: from the order of the Porocephalida, for example: Linguatula spp.
  • compositions for use in the long-term prevention and/or treatment of a disease comprising at least one compound according the claimed invention and at least one further ingredient.
  • the pharmaceutical composition comprises 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.
  • active ingredient refers to an ingredient that has a pharmaceutical effect, in particular a pharmaceutical effect related to the prevention and/or treatment of an endo- and/or ectoparasiticidal infection.
  • endoparasite as used herein is known to the skilled person and refers in particular to helminths.
  • ectoparasite as used herein is known to the skilled person and refers in particular to arthropods, particularly insects or acarids.
  • the present invention covers a pharmaceutical composition for use in the long- term treatment and/or prevention of a disease comprising: ⁇ one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and ⁇ one or more further active ingredients, in particular one or more endo- and/or ectoparasiticides.
  • Such pharmaceutical compositions have the advantage that they are particularly efficient to prevent and/or treat endo- and ectoparasitic infections simulateneously.
  • ectoparasiticides and/or endoparasiticides are insecticides, acaricides and nematicides, and include in particular: (1) Acetylcholinesterase (AChE) inhibitors, such as, for example, carbamates, for example alanycarb, aldicarb, bendiocarb, benfuracarb, butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb, methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox, triazamate, trimethacarb, XMC and xylylcarb; or organophosphates, for example acephate, azamethiphos, azinphos-e
  • GABA-gated chloride channel blockers such as, for example, cyclodiene-organochlorines, for example chlordane and endosulfan or phenylpyrazoles (fiproles), for example ethiprole and fipronil.
  • Sodium channel modulators such as, for example, pyrethroids, e.g.
  • Nicotinic acetylcholine receptor (nAChR) competitive modulators such as, for example, neonicotinoids, e.g. acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid and thiamethoxam or nicotine or sulfoxaflor or flupyradifurone.
  • Nicotinic acetylcholine receptor (nAChR) allosteric modulators such as, for example, spinosyns, e.g. spinetoram and spinosad.
  • Glutamate-gated chloride channel (GluCl) allosteric modulators such as, for example, avermectins/milbemycins, for example abamectin, emamectin benzoate, lepimectin and milbemectin.
  • Juvenile hormone mimics such as, for example, juvenile hormone analogues, e.g. hydroprene, kinoprene and methoprene or fenoxycarb or pyriproxyfen.
  • Modulators of Chordotonal Organs such as, for example pymetrozine or flonicamid.
  • Mite growth inhibitors such as, for example clofentezine, hexythiazox and diflovidazin or etoxazole.
  • Inhibitors of mitochondrial ATP synthase such as, ATP disruptors such as, for example, diafenthiuron or organotin compounds, for example azocyclotin, cyhexatin and fenbutatin oxide or propargite or tetradifon.
  • Uncouplers of oxidative phosphorylation via disruption of the proton gradient such as, for example, chlorfenapyr, DNOC and sulfluramid.
  • Nicotinic acetylcholine receptor channel blockers such as, for example, bensultap, cartap hydrochloride, thiocylam, and thiosultap-sodium.
  • Inhibitors of chitin biosynthesis type 0, such as, for example, bistrifluron, chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron and triflumuron.
  • Inhibitors of chitin biosynthesis type 1, for example buprofezin.
  • Moulting disruptor in particular for Diptera, i.e. dipterans
  • Moulting disruptor such as, for example, cyromazine.
  • Ecdysone receptor agonists such as, for example, chromafenozide, halofenozide, methoxyfenozide and tebufenozide.
  • Octopamine receptor agonists such as, for example, amitraz.
  • Mitochondrial complex III electron transport inhibitors such as, for example, hydramethylnone or acequinocyl or fluacrypyrim.
  • Mitochondrial complex I electron transport inhibitors such as, for example from the group of the METI acaricides, e.g.
  • Voltage-dependent sodium channel blockers such as, for example indoxacarb or metaflumizone.
  • Inhibitors of acetyl CoA carboxylase such as, for example, tetronic and tetramic acid derivatives, e.g. spirodiclofen, spiromesifen and spirotetramat.
  • Mitochondrial complex II electron transport inhibitors such as, for example, beta-ketonitrile derivatives, e.g.
  • cyenopyrafen and cyflumetofen and carboxanilides such as, for example, pyflubumide.
  • Ryanodine receptor modulators such as, for example, diamides, e.g. chlorantraniliprole, cyantraniliprole and flubendiamide, further active ingredients such as, for example, Afidopyropen, Afoxolaner, Azadirachtin, Benclothiaz, Benzoximate, Bifenazate, Broflanilide, Bromopropylate, Chinomethionat, Chloroprallethrin, Cryolite, Cyclaniliprole, Cycloxaprid, Cyhalodiamide, Dicloromezotiaz, Dicofol, epsilon-Metofluthrin, epsilon-Momfluthrin, Flometoquin, Fluazaindolizine, Fluensulfone,
  • Active ingredients with unknown or non-specific mode of action e.g., fentrifanil, fenoxacrim, cycloprene, chlorobenzilate, chlordimeform, flubenzimine, dicyclanil, amidoflumet, quinomethionate, triarathene, clothiazoben, tetrasul, potassium oleate, petroleum, metoxadiazone, gossyplure, flutenzin, bromopropylate, cryolite; Active ingredients from other classes, e.g.
  • organs butacarb, dimetilan, cloethocarb, phosphocarb, pirimiphos (-ethyl), parathion (-ethyl), methacrifos, isopropyl o-salicylate, trichlorfon, sulprofos, propaphos, sebufos, pyridathion, prothoate, dichlofenthion, demeton-S-methylsulphone, isazofos, cyanofenphos, dialifos, carbophenothion, autathiofos, aromfenvinfos (-methyl), azinphos (-ethyl), chlorpyrifos (- ethyl), fosmethilan, iodofenphos, dioxabenzofos, formothion, fonofos, flupyrazofos, fensulfothion, etrimfo
  • camphechlor lindane, heptachlor; or phenylpyrazoles, e.g. acetoprole, pyrafluprole, pyriprole, vaniliprole, sisapronil; or isoxazolines, e.g. sarolaner, afoxolaner, lotilaner, fluralaner; pyrethroids, e.g.
  • nithiazine dicloromezotiaz, triflumezopyrim
  • macrocyclic lactones e.g. nemadectin, ivermectin, latidectin, moxidectin, selamectin, eprinomectin, doramectin, emamectin benzoate; milbemycin oxime; triprene, epofenonane, diofenolan; Biologicals, hormones or pheromones, for example natural products, e.g. thuringiensin, codlemone or neem components; dinitrophenols, e.g.
  • Anthelmintically active compounds including, without limitation, the following nematicidally, trematicidally and/or cestocidally active compounds: from the class of macrocyclic lactones, for example: eprinomectin, abamectin, nemadectin, moxidectin, doramectin, selamectin, lepimectin, latidectin, milbemectin, ivermectin, emamectin, milbemycin; from the class of benzimidazoles and probenzimidazoles, for example: oxibendazole, mebendazole, triclabendazole, thiophanate, parbendazole, oxfendazole, netobi
  • Antiprotozoal active ingredients in the present invention including, without limitation, the following active ingredients: from the class of triazines, for example: diclazuril, ponazuril, letrazuril, toltrazuril; from the class of polylether ionophore, for example: monensin, salinomycin, maduramicin, narasin; from the class of macrocyclic lactones, for example: milbemycin, erythromycin; from the class of quinolones, for example: enrofloxacin, pradofloxacin; from the class of quinines, for example: chloroquine; from the class of pyrimidines, for example: pyrimethamine; from the class of sulfonamides, for example: sulfaquinoxaline, trimethoprim, sulfaclozin; from the class of thiamines, for example: amprolium; from the class of lincosamides, for example: amp
  • the pharmaceutical composition is a fixed combination.
  • the term “fixed combination” is 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.
  • 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.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • the pharmaceutical composition is a non-fixed combination or a kit-of-parts.
  • the terms “non-fixed combination” or “kit-of-parts” are known to persons skilled in the art and are defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • 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 claimed compounds are used for long-term prevention and/or treatment of a disease in a subject in need thereof.
  • Subject as used herein in particular means a human and a non-human animal.
  • the term “animal” as used herein refers to a “non-human animal”.
  • the non- human animal is an animal, in particular an animal selected from the group consisting of cattle, poultry, swine and companion animals such as cats and dogs.
  • the non-human animal is a mammal.
  • the subject is a dog.
  • the compounds for use according to the invention have particularly good long-lasting properties in preventing and/or treating a disease such as a helminthic infection in an animal.
  • the claimed invention also concerns the use of a compound according to the invention for long-term prevention and/or treatment of a disease, in particular a helminthic infection in animals.
  • the compound or the pharmaceutical composition for use according to the invention, as described supra are used for the long-term prevention and/or treatment of a disease, in particular of a helminthic infection, particularly of a gastro-intestinal and a extra-intestinal helminth infection, more particularly of a gastro-intestinal and a extra-intestinal infections with nematodes.
  • the compound or the pharmaceutical composition for use according to the invention are used for the preparation of a medicament suitable for the long-term prevention and/or treatment of a disease, in particular of a helminthic infection, particularly of a gastro-intestinal and a extra-intestinal helminth infection, more particularly of a gastro-intestinal and a extra-intestinal infections with nematodes.
  • a disease in particular of a helminthic infection, particularly of a gastro-intestinal and a extra-intestinal helminth infection, more particularly of a gastro-intestinal and a extra-intestinal infections with nematodes.
  • the compound or the pharmaceutical composition for use according to the invention are used as a long-term anthelmintic agent, in particular as a long-term nematicidal agent, a long-term platyhelminthicidal agent, a long-term acanthocephalicidal agent, or a long-term pentastomicidal agent.
  • Method of treatment also concerns a method for long-term prevention and/or treatment of a disease comprising the administration of a compound or a pharmaceutical composition according to the invention at an effective dose to a subject in need thereof.
  • a variety of administration routes are available for administering the compounds and the pharmaceutical composition according to the invention.
  • the particular mode selected will depend upon the particular subject group selected, the age and general health status of the subject, the particular condition being treated and the dosage required for therapeutic and/or prophylactic efficacy.
  • the methods of this invention may be practiced using any mode of administration that produces effective levels of prevention and/or treatment of a disease, in particular a helminthic infection, without causing clinically unacceptable adverse effects.
  • the method comprises administering an effective amount of the compound or the pharmaceutical composition according to the invention to the subject in need thereof.
  • Such effective amount is any amount that causes a prevention and/or treatment of a disease such as an helminthic infection.
  • the skilled person knows methods to assess the presence and progression of an helminthic infection.
  • the effective amount depends on the subject such as the animal species, age, weight, stage of disease, as well as other factors known in the art. It is possible for the compounds and the pharmaceutical composition 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. It is possible for the compounds and the pharmaceutical composition for use according to the invention to be administered in suitable administration forms. In one embodiment, the compound or the pharmaceutical composition for use according to the invention is administered orally.
  • the compounds and the pharmaceutical composition according to the invention for oral administration, it is possible to formulate the compounds and the pharmaceutical composition 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.
  • tablets uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble
  • orally-disintegrating tablets for example, films/wafers, films/lyophylisates
  • capsules for example hard or soft gelatine capsules
  • sugar-coated tablets granules
  • the compound or the pharmaceutical composition for use according to the invention is administered parenterally.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with inclusion of absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • absorption step for example intravenously, intraarterially, intracardially, intraspinally or intralumbally
  • absorption for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • the compound or the pharmaceutical composition for use according to the invention is administered subcutanteously.
  • Administration forms which are suitable for parenteral administration are, for example, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • the compound or the pharmaceutical composition for use according to the invention is administered subcutaneously in a form enabling a sustained release of the compound or the active compound in the pharmaceutical composition. This has the advantage that a particularly efficient long-term effect regarding the prevention and/or treatment of a disease is achieved, in particular in the long-term prevention and/or treatment of an helminthic infection in an animal, preferably in a cat or a dog.
  • Suitable administration routes are, for example, 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.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual,
  • compositions according to the invention can be incorporated into suitable administration forms. This can be effected in a manner known by the skilled person, in particular by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, ⁇ fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), ⁇ ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), ⁇ bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), ⁇ solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid poly
  • the total amount of the compound for use according to the invention is administered in ranges from about 0.001 mg/kg to about 200 mg/kg body weight per day, preferably from about 0.005 mg/kg to about 100 mg/kg body weight per day and most preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day.
  • these administration characteristics ensure that the long-term prevention and/or treatment of a disease, in particular the long-term prevention and/or treatment of an helminthic infection in animals, is particularly effective.
  • the dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques is from 0.01 to 200 mg/kg of total body weight.
  • the dosage for rectal administration is from 0.01 to 200 mg/kg of total body weight. In one embodiment, the dosage for vaginal administration is from 0.01 to 200 mg/kg of total body weight. In one embodiment, the dosage for topical administration is from 0.1 to 200 mg of total body weight. In one embodiment, the dosage for transdermal administration is 0.01 to 200 mg/kg of total body weight. In one embodiment, the dosage for administration by inhalation is from 0.01 to 100 mg/kg of total body weight. In one embodiment, the compound or the pharmaceutical composition for use according to the invention is administered at most once every month, preferably at most once every one and a half months, more preferable at most once every two months, even more preferably at most once every three months and most preferably at most once every six months.
  • the compound or the pharmaceutical composition for use according to the invention is administered once every month, preferably once every one and a half months, more preferable once every two months, even more preferably once every three months and most preferably once every six months.
  • This has the advantage that an effective long-term prevention and/or treatment of a disease, in particular of a helminthic infection in animals, is achieved while at the same time a convenient dosage regimen is applied.
  • "drug holidays" are possible, in which a subject is not dosed with a drug for a certain period of time. Such drug holidays can be beneficial to the overall balance between pharmacological effect and tolerability.
  • M+1 means the molecular ion peak, plus or minus 1 a.m.u. (atomic mass unit) respectively, as observed in mass spectroscopy by electrospray ionization (ESI + or -).
  • LC-MS Method 0 Measurement of logP values was performed according to EEC directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on reversed phase columns with the following methods, instrument(s): Agilent 1100 LC system, Agilent MSD system, HTS PAL; Waters IClass Acquity UPLC, SQD2 (MS), PDA (UV).
  • [ a] logP value is determined by measurement of LC-UV, in an acidic range, with 0.1% formic acid in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile).
  • [ b] logP value is determined by measurement of LC-UV, in a neutral range, with 0.001 molar ammonium acetate solution in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile). Calibration was done with straight-chain alkan-2-ones (with 3 to 16 carbon atoms) with known logP values (measurement of logP values using retention times with linear interpolation between successive alkanones).
  • Lambda-max-values were determined using UV-spectra from 200 nm to 400 nm and the peak values of the chromatographic signals.
  • Method L1 Instrument type: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLC HSS T31.8 ⁇ 50 x 1 mm; eluent A: 1 l water + 0.25 ml formic acid, eluent B: 1 l acetonitrile + 0.25 ml formic acid; gradient: 0.0 min 90% A ⁇ 1.2 min 5% A ⁇ 2.0 min 5% A oven: 50°C; flow: 0.40 ml/min; UV-detection: 208 – 400 nm.
  • Method L2 MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 50x2.1mm, 3.5 ⁇ ); flow: 0.8 mL/min; column temp: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin.
  • Method L1.1 MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 30x2.1mm, 3.5 ⁇ ); flow: 1 mL/min; column temp: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin.
  • Method L2.1 MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 50x2.1mm, 3.5 ⁇ ); flow: 0.8 mL/min; column temp: 35°C; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin.
  • the injection volume was 0.1 ⁇ L.
  • the run was performed at a temperature of 40 oC and a flow rate of 0.6 mL/min, with a gradient elution.
  • Method info (Time (min) and B %): 0-5; 0.3-5; 2.5-95; 3.7-95; 4-5; 4.6-5.
  • LC-MS LC-MS Method 5 Instrument type: UPLC with SQD2 and Sample Manager from Waters, column: Zorbax Eclipse Plus C18, 50 mm x 2,1 mm, 1,8 ⁇ m, eluent A: 1 l acetonitrile + 1 ml formic acid, eluent B: 1 l water + 0.9 ml formic acid; gradient 0.0 min 90% B ⁇ 1.7 min 5% B ⁇ 2.4 min 5% B DAD A: 210 ⁇ 4 nm, reference 360 ⁇ 50 nm, DAD A: 270 ⁇ 2 nm, reference 550 ⁇ 50 nm (only ketones), MSD, 100-1000 Amu, ES-ionisation, positive or negative.
  • NMR peak lists 1 H-NMR data of selected examples are written in form of 1 H-NMR peak lists. To each signal peak are listed the ⁇ -value in ppm and the signal intensity in round brackets. Between the ⁇ -value – signal intensity pairs are semicolons or commas as delimiters.
  • the peak list of an example has therefore the form: ⁇ 1 (intensity1); ⁇ 2 (intensity2);........; ⁇ i (intensityi); hence; ⁇ n (intensityn) or ⁇ 1 (intensity1), ⁇ 2 (intensity2),........; ⁇ i (intensityi), whil, ⁇ n (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.
  • tetramethylsilane peak can occur but not necessarily.
  • the 1 H-NMR peak lists are similar to classical 1 H-NMR prints and contains therefore usually all peaks, which are listed at classical NMR-interpretation. Additionally they can show like classical 1 H-NMR prints signals of solvents, stereoisomers of the target compounds, which are also object of the invention, and/or peaks of impurities.
  • peaks of solvents for example peaks of DMSO in DMSO-D6 and the peak of water are shown in our 1 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 >90%).
  • 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”.
  • Example 1 N-[(4S)-3,4-Dihydro-2H-chromen-4-yl]-4-ethyl-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide Under argon a flask was charged with 8-bromo-N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-ethyl-7- fluoroquinoline-3-carboxamide (13.0 g, 30.3 mmol), 2,3,5-trifluorobenzene boronic acid (2.67 g, 15.2 mmol), potassiumcarbonate (8.37 g, 60.6 mmol) and (2'-aminobiphenyl-2-yl)(chloro)palladium - dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (1:1) (477 mg, 606 ⁇ mol).
  • Example 2 (S)-3-(3,5-dichloro-4-fluorophenyl)-N-(2,3-dihydro-1H-inden-1-yl)-7-isopropyl-2- methylpyrazolo[1,5-a]pyrimidine-6-carboxamide
  • Example 2 was prepared analogously to Example 130 of WO 2017/178416.
  • Example 5 was prepared analogously to Example 655 of WO 2018/087036.
  • Example 6 8-[2-chloro-6-(trifluoromethyl)-pyrimidin-4-yl]-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino- quinoline-3-carboxamide
  • Example 6 was prepared analogously to Example 5.1 of WO 2022/117783.
  • Example 8 N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-4-(1,1-dioxidothietan-3-yl)-7-fluoro-8-(2,3,5- trifluorophenyl)quinoline-3-carboxamide N-[(4S)-3,4-dihydro-2H-chromen-4-yl]-7-fluoro-4-(thietan-3-yl)-8-(2,3,5-trifluorophenyl)-quinoline- 3-carboxamide (400 mg, 0.76 mmol) was supended in DCM (9 ml).
  • the reaction mixture was stirred for 16 hour 100 °C under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was treated with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurred with petroleum ether. The precipitated solids were collected by filtration and washed with petroleum ether to afford ethyl 7-fluoranyl-4-oxidanyl-8-[2,3,5- tris(fluoranyl)phenyl]quinoline-3-carboxylate (4.00 g, 10.95 mmol, 34.40% yield) as a black solid.
  • Step 2 Ethyl 4-bromo-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylate To a solution of ethyl 7-fluoranyl-4-oxidanyl-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3-carboxylate (3.93 g, 10.76 mmol) in DCM (40 mL) and DMF (8 mL) was added POBr 3 (4.63 g, 16.14 mmol) in portions at 0 °C.
  • Step 3 Ethyl 4-(3,3-dimethoxy-1-(methoxycarbonyl)cyclobutyl)-7-fluoro-8-(2,3,5-trifluorophenyl)quinoline- 3-carboxylate To a solution of methyl 3,3-di(methoxy)cyclobutanecarboxylate (2.00 g, 11.46 mmol) in THF (20 mL) were added LiHMDS (15.3 mL, 15.27 mmol, 1M in THF) dropwise at -78 °C under nitrogen atmosphere.
  • Step 4 7-fluoro-4-(3-oxocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid
  • ethyl 4-[3,3-di(methoxy)-1-methoxycarbonyl-cyclobutyl]-7-fluoranyl-8-[2,3,5- tris(fluoranyl)phenyl]quinoline-3-carboxylate (2.85 g, 5.47 mmol) in DME (30 mL)
  • NaOH 874 mg, 21.86 mmol
  • water 2.4 mL
  • Step 5 7-fluoro-4-((1r,3r)-3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3-carboxylic acid
  • 7-fluoranyl-4-(3-oxidanylidenecyclobutyl)-8-[2,3,5-tris(fluoranyl)phenyl]quinoline-3- carboxylic acid (2.50 g, 6.42 mmol) in MeOH (20 mL) was added sodium borohydride (364 mg, 9.63 mmol) in portions at 0 °C.
  • Step 6 N-((S)-chroman-4-yl)-7-fluoro-4-((1R,3S)-3-hydroxycyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide
  • 4S-chroman-4-amine 488 mg, 3.27 mmol
  • HATU 932.81 mg, 2.45 mmol
  • DIEA 634 mg, 4.91 mmol
  • Step 7 N-((S)-chroman-4-yl)-7-fluoro-4-((1R,3S)-3-fluorocyclobutyl)-8-(2,3,5-trifluorophenyl)quinoline-3- carboxamide
  • N-[(4S)-chroman-4-yl]-7-fluoro-4-(3-hydroxycyclobutyl)-8-(2,3,5- trifluorophenyl)quinoline-3-carboxamide (272 mg, 520.58 ⁇ mol) in DCM (3 mL) was added BAST (346 mg, 1.56 mmol) dropwise at 0 °C under nitrogen atmosphere.
  • the resulting mixture was stirred for 0.5 hour at 0 °C under nitrogen atmosphere.
  • the resulting mixture was treated with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 10 (S)-3-(2-chloro-6-fluorophenyl)-N-(chroman-4-yl)-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6- carboxamide
  • Example 10 was prepared analogously to Example 130 of WO 2017/178416.
  • the catalyst 10% palladium on charcoal (125 mg), was added, argon replaced by hydrogen and the mixture stirred under atmospheric pressure of hydrogen for 18 h.
  • the reaction mixture was filtered over celite, rinsed with ethyl acetate and concentrated in vacuo.
  • the residue (560 mg, a crude mixture of different reduction products) was dissolved in DMSO (4.5 ml) and treated with ammoniumcerium-nitrate (2 M solution in water, 1.9 ml, 3.8 mmol) resulting in a brownish suspension, with was stirred over night at ambient temperature.
  • the mixture was dissolved by addition of more DMSO, acetonitrile and some 5 M formic acid and directly purified via prep.
  • HPLC C18, gradient: 0.1% aq.
  • Step 2 Ethyl 7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1C-1) A solution of 3-amino-5-methylpyrazole (12.95 g, 133 mmol) and ethyl 2-(ethoxymethylene)-4- methyl-3-oxopentanoate (28.56 g, 133 mmol) in absolute ethanol (400 mL) was stirred at reflux for 48 h.
  • Step 3 Ethyl 3-bromo-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (1D-1) To a stirring solution of ethyl 7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (32.38 g, 131 mmol) in acetonitrile (1.3 L) was added N-bromosuccinimide (23.71 g, 133 mmol). After 20 minutes the reaction mixture was concentrated in vacuo, to afford 71.20 g of a solid, which was triturated in diethyl ether (0.4 L). The solids were filtered off and washed with diethyl ether.
  • the filtrate was concentrated in vacuo to yield 46.50 g of a solid.
  • the material was triturated in diisopropyl ether (1.0 L). The solids were filtered off and the filtrate was treated with active charcoal (6.4 g). The charcoal was filtered off over kieselguhr and the filtrate was concentrated in vacuo to afford 42.06 g (126 mmol; 97% of theory) of the title compound.
  • Step 4 3-Bromo-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (1E-1)
  • ethyl 3-bromo-7-isopropyl-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate 42.0 g, 129 mmol
  • lithium hydroxide monohydrate 42.0 g, 1001 mmol
  • water 800 mL
  • the mixture was stirred at room temperature for 5 h.
  • the organic solvent was removed in vacuo.
  • the basic aqueous layer was washed with ethyl acetate (2x400 mL).
  • the organic extracts were set aside.
  • the aqueous layer was acidified with a solution of concentrated hydrochloric acid (50 mL) in water (500 mL) and was extracted with ethyl acetate (2x400 mL).
  • the aqueous layer was further acidified with hydrochloric acid (4N; 200 mL) and was extracted with ethyl acetate (2x400 mL).
  • the combined organic layers were washed with water (400 mL) and brine (400 mL) and were dried with sodium sulfate. Solvents were removed in vacuo and the residue was co- evaporated with toluene and ethyl acetate to afford 26.0 g (84 mmol) of the title compound.
  • Step 6 (S)-N-(2,3-Dihydro-1H-inden-1-yl)-3-(3-fluorophenyl)-7-isopropyl-2-methylpyrazolo[1,5- a]pyrimidine-6-carboxamide
  • a solution of (S)-3-bromo-N-(2,3-dihydro-1H-inden-1-yl)-7-isopropyl-2-methylpyrazolo[1,5- a]pyrimidine-6-carboxamide 101 mg, 0.24 mmol
  • 3-fluorophenylboronic acid 38 mg, 0.27 mmol
  • sodium carbonate 78 mg, 0.73 mmol
  • Formulations The compound of Example 9 was prepared in the following two exemplary formulations: Formulation for intravenous administration: Compound of Example 9 in PEG300 (90%): EtOH (10%) The compound of Example 9 was weighed out in concentration ranges of 0.5-1mg/mL and the stock PEG300 (90%): EtOH (10%) solution was added. The resulting suspension was stirred until a full solution was obtained.
  • Formulation for subcutaneous administration Compound of Example 9 in 0.5% cellulose (HPMC 5cP, Mantocel), 1% Lutrol F68 (Poloxamer 188), 0.9% NaCl, water
  • the compound of Example 9 was weighed out in concentration ranges of 5-50mg/mL and the stock 0.5% cellulose (HPMC 5cP, Mantocel), 1% Lutrol F68 (Poloxamer 188), 0.9% NaCl, water was added.
  • the resulting suspension was stirred. Particle size reduction of the active compound was achieved using a probe sonicator for 30-90 minutes.
  • Table 2 Results of modified Knott and adult heartworm antigen testing conducted 150, 180 and 210 days after experimental Dirofilaria immitis infection in dogs of treatment groups 1 and 2 Test Type and Number of Days Compound of Example 9 at after 1 st Infection Negative Control 30 mg/kg Modified 150 - - Knott Test 180 + - 210 + - 150 - - + + - Heartworm Antigen Test 180 - + + + + - 210 + - Circulating microfilaria were detected in all negative control dogs 180 days post-infection. All negative control dogs also had a positive heartworm antigen test 210 days post- infection.
  • Heartworm antigen test results were positive for all negative control dogs (Group 1) 149 days after the second Dirofilaria immitis infection. In contrast, only 50% of the dogs which had been treated with 30 mg/kg of the compound of Example 9 prior to the second Dirofilaria immitis infection (Group 2) had a positive heartworm antigen test result. All negative control dogs were heavily infected with Dirofilaria immitis with a geometric group mean count of 60.9 worms (range 50-82 worms per dog) in the heart and lungs. All dogs which had been treated with 30 mg/kg of the compound of Example 9 prior to the second Dirofilaria immitis infection (Group 2) exhibited ⁇ 80% reduction in worm burden relative to the negative control group in the heart and lungs.
  • Example 9 Treatment efficacy and residual protection efficacy of the compound of Example 9 hookworm infections
  • the cohorts were treated as follows: – Cohort A: The compound of Example 9 or the vehicle solution was administered 15 days after infection with Ancylostoma caninum – Cohort B: The compound of Example 9 or the vehicle solution was administered 30 days prior to infection with Ancylostoma caninum – Cohort C: The compound of Example 9 or the vehicle solution was administered 60 days prior to infection with Ancylostoma caninum Fecal egg counts (FECs, eggs per gram of feces) were obtained from each dog 15, 20, 25 and 30 days after hookworm infection. Following the final FEC, dogs were dewormed with a commercial anthelmintic and feces were collected for 48 hours.
  • FECs Fecal egg counts
  • Fecal output from each dog was soaked in water for a minimum of 30 minutes and processing through 250 ⁇ m, 150 ⁇ m and 38 ⁇ m sieves to recover expelled adult and immature hookworms. Expelled hookworms were preserved in fixative (5% formalin) and counted.
  • Test for treatment of an existing infection Cohort A was designed to evaluate effectiveness against patent adult hookworm infections present at the time of treatment with the compound of Example 9. Results of the test for treatment of an existing infection: All four dogs developed an infection prior to the treatment. Fecal egg count reduction was >90% upon treatment with the compound of Example 9 (see Table 3). Residual efficacy test: Cohorts B, and C were designed to evaluate residual efficacy and protection from infections occurring 30 and 60 days after treatment with the compound of Example 9.
  • Results of the residual efficacy test The combination of FECs and expelled worm counts indicated that the compound of Example 9 provided 100% protection from infections with hookworm larvae for at least 60 days (Table 3) in cohorts B and C.
  • Table 3 Results of fecal egg counts for Cohorts A (treatment of an existing infection) as well as B and C (residual efficacy test) Mean Fecal Egg Count (EPG) at the Indicated Mean Number of Day After Infection Recovered Cohort Group 15 days 20 days 25 days 30 days Hookworms Therapeutic Treatment / Control of an Existing Infection Control 750 225 400 200 6.0

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Abstract

La présente invention concerne des inhibiteurs du canal potassique activé par le calcium Slo-1 d'endoparasites et des compositions pharmaceutiques contenant de tels inhibiteurs destinés à être utilisés dans la prévention et/ou le traitement à long terme d'une maladie. En outre, l'invention concerne l'utilisation d'un inhibiteur de Slo-1 ou d'une composition pharmaceutique pour la prévention et/ou le traitement à long terme d'une maladie ainsi qu'un procédé de prévention et/ou de traitement à long terme d'une maladie comprenant l'administration d'un inhibiteur de Slo-1 ou d'une composition pharmaceutique comprenant un tel inhibiteur à une dose efficace à un sujet en ayant besoin.
PCT/EP2024/060054 2023-04-14 2024-04-12 Prévention et/ou traitement à long terme d'une maladie par des inhibiteurs de slo-1 WO2024213752A1 (fr)

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