Novel substituted pyrazine-carboxamide-imidazopyridine derivatives

Abstract

The present invention relates to compounds of formula (I), processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, in particular their use in the treatment and / or prevention of conditions associated with metabotropic glutamate receptor subtype 4 (mGluR4) function. 1 and R 6 has the meaning given herein. JPEG2025540259000130.jpg3059

Description

[Technical Field]

[0001] The present invention relates to substituted pyrazine-carboxamide derivatives, pharmaceutical compositions containing them, and their use in therapy, in particular in the treatment and / or prevention of neurological and non-neurological conditions associated with mGluR4 function. [Background technology]

[0002] L-glutamate (herein referred to as glutamate) is the most abundant excitatory neurotransmitter in the vertebrate brain. Dysfunction of the brain glutamate system often leads to neurological and psychiatric disorders. Therefore, modulation of the glutamatergic system is considered an attractive therapeutic strategy. Glutamate acts through various types of glutamate receptors located on the cell surface. Glutamate receptors include AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) exert their effects through G protein coupling and activation of second messenger systems. mGluR subtypes are classified into three groups (distinguished by sequence homology, pharmacology, and second messenger systems), with group III being the largest group (mGluR4, mGluR6, mGluR7, and mGluR8) [Conn and Pin, Annu Rev Pharmacol Toxicol, 1997, 37: 205-237]. Group III mGlu receptors share predominantly presynaptic expression (Schoepp, Pharmacol Exp Ther, 2001, 299: 12-20), and they regulate glutamatergic and GABAergic transmission. Activation of group III receptors (including mGluR4) causes attenuation of adenylate cyclase activity, which, through activation of Gαi / o receptors, reduces transmitter release.

[0003] mGluR4 receptors are primarily located at the presynaptic terminals of nerve endings. Expression of mGluR4 has been verified in multiple brain regions, with high expression in the basal ganglia and cerebellum, among other brain regions. Due to its role in regulating mGluR4 expression within relevant brain circuits and transmitter release, mGluR4 modulators are thought to have implications for motor control (including Parkinson's disease), impulse control, learning and memory, anxiety, pain, cerebellar function, epilepsy, and the regulation of excitation / inhibition balance, which is crucial for information processing (Marino et al. Ann NY Acad Sci, 2003, 1003: 435-437; Isherwood et al. Neuropharmacology 2017, 123: 249-260; Makoff et al. Mol Brain Res, 1996, 37: 239-248; Davis et al. Neuropharmacology 2013, 66: 365-372; Iscru et al. Genes Brain Behav. 2013, 12: 615-625; Szczurowska and Mares, Physiol Res, 2012, 61: 619-628), but is not limited to these effects. Because mGluR4 has also been reported to be expressed in peripheral tissues, such as (but not limited to) the islets of Langerhans, antagonists of mGluR4 function may also have therapeutic value in disorders including, but not limited to, metabolic diseases, digestive disorders, and cancer (Chang et al. Clin Cancer Res. 2005, 11: 3288-3295; Uhera et al. Diabetes 2004, 53: 998-1006; Nunez-Salces et al. Neurogastroenterol Motil 2020, 32).

[0004] Because mGluR4 has also been reported to be expressed in vagal afferents and in central satiety pathways and brain circuits, antagonists of mGluR4 function may also have therapeutic value in disorders including, but not limited to, overweight and obesity (Blackshow et al. Front Neurosci 2011, 5: 40; 1-7; Page et al. Br J Pharmacol. 2012, 166: 1537-1558). WO21028512 describes arylsulfonamides as mGluR4 NAMs. However, the activity of these compounds is considered too low to be applicable as medicines, especially because acidic arylsulfonamides may also be affected by efflux at the blood-brain barrier, limiting their brain exposure for CNS applications.

[0005] Detailed Description of the Invention The present invention provides novel substituted pyrazine-carboxamide derivatives of formula I or physiologically acceptable salts thereof. [ka] (In the formula, A represents C1-C6-alkyl, C3-C6-cycloalkyl, C3-C5-cycloalkyl-C1-C2-alkyl-, C1-C3-alkyl-O-C1-C3-alkyl-, 4-6-membered heterocycloalkyl-, 4-6-membered heterocycloalkyl-C1-C3-alkyl-, where the latter group is optionally substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, fluoro; Xa is N or CR 2 represents; Xb is N or CR 3 represents; Xc is N or CR 4 represents; Xd is CR 5 represents; provided that one of Xa, Xb, and Xc represents N; R1 represents C1-C7-alkyl, C1-C3-alkyl-O—C1-C3-alkyl-, C3-C7-cycloalkyl, 4- to 6-membered heterocycloalkyl, C3-C7-cycloalkyl-C1-C3-alkyl-, 4- to 6-membered heterocycloalkylmethyl-, C5-C6-heterocycloalkylethyl-, the latter group optionally being substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkoxy, hydroxy, fluoro; R 2 , R 3 , R 4 and R 5 represent, independently of one another, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C3-alkyl-O—C1-C3-alkyl-, C3-C6-cycloalkyl, 4- to 6-membered C4-C6-heterocycloalkyl, C1-C4-alkoxy-, C3-C6-cycloalkoxy-, the last six groups being optionally substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, fluoro; R 6 represents halogen, C1-C3-alkyl optionally substituted with 2 to 3 fluorine atoms.

[0006] In another embodiment, the present invention provides compounds of the general formulae Ia, Ib and Ic, or physiologically acceptable salts thereof: [ka] (In the formula, A represents C1-C6-alkyl, C3-C6-cycloalkyl, C3-C5-cycloalkyl-C1-C2-alkyl-, C1-C3-alkyl-O-C1-C3-alkyl-, 4-6-membered heterocycloalkyl-, 4-6-membered heterocycloalkyl-C1-C3-alkyl-, where the latter group is optionally substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, fluoro; R 1represents C1-C7-alkyl, C1-C3-alkyl-O—C1-C3-alkyl-, C3-C7-cycloalkyl, 4- to 6-membered heterocycloalkyl-, C3-C7-cycloalkyl-C1-C3-alkyl-, 4- to 6-membered heterocycloalkylmethyl-, C5-C6-heterocycloalkylethyl-, the latter group optionally being substituted by 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkoxy, hydroxy, fluoro; R 2 , R 3 , R 4 and R 5 represent, independently of one another, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C3-alkyl-O—C1-C3-alkyl-, C3-C6-cycloalkyl, 4- to 6-membered C4-C6-heterocycloalkyl, C1-C4-alkoxy-, C3-C6-cycloalkoxy-, the last six groups being optionally substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, fluoro; R 6 represents halogen, C1-C3-alkyl optionally substituted with 2 to 3 fluorine atoms.

[0007] In another embodiment, in general formula I according to any one of the preceding embodiments, A represents C1-C3-alkyl, C3-C6-cycloalkyl, C3-C5-cycloalkylmethyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, tetrahydrofuranylmethyl, tetrahydropyranylmethyl, 1,4-dioxanylmethyl, C1-C2-alkyl-O—C1-C3-alkyl, which latter group may optionally be substituted by 1 to 4 substituents selected from methyl, methoxy, hydroxy, fluoro.

[0008] In a further embodiment, in general formula I according to any one of the preceding embodiments, R 1represents C1-C3-alkyl, C1-C2-alkyl-O-C1-C3-alkyl-, C3-C4-cycloalkyl, C4-C5-heterocycloalkyl-, C3-C4-cycloalkyl-O-C1-C3-alkyl-, the latter group optionally being substituted by 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, C3-C4-cycloalkoxy, hydroxy, fluoro.

[0009] In a further embodiment, in general formula I according to any one of the preceding embodiments, R 2 , R 3 , R 4 and R 5 are each independently hydrogen, fluoro, chloro, bromo, cyano, methyl, cyclopropyl, or methoxy, and the latter three groups may optionally be substituted with 2 to 3 fluorine substituents.

[0010] In a further embodiment, in general formula I according to any one of the preceding embodiments, R 6 represents C1-C3-alkyl optionally substituted with 2 to 3 fluorine atoms.

[0011] In another embodiment, in general formula I according to any one of the preceding embodiments, A, [ka] represents a group selected from the group comprising:

[0012] In another embodiment, in general formula I according to any one of the preceding embodiments, R 1 represents a substituent selected from the group consisting of ethyl, —CH2—CHF2, and isopropyl. In another embodiment, in general formula I according to any one of the preceding embodiments, R 2 represents hydrogen. In another embodiment, in general formula I according to any one of the preceding embodiments, R 3 represents hydrogen, methyl and trifluoromethyl. In another embodiment, in general formula I according to any one of the preceding embodiments, R 4 represents hydrogen, fluoro, chloro, bromo, cyano, methyl and trifluoromethyl. In another embodiment, in general formula I according to any one of the preceding embodiments, R 5 represents hydrogen, methyl and methoxy. In another embodiment, in general formula I according to any one of the preceding embodiments, R 6 represents methyl, trifluoromethyl and -CH2H.

[0013] The compounds of the present invention are potent mGluR4 negative modulators, which inhibit the function of mGluR4, thereby suppressing glutamine-induced intracellular cAMP decrease. The present invention therefore provides compounds for use in the treatment of mGluR4-mediated disorders. The present invention further provides a method of treating an mGluR4-mediated disorder in a human subject, said method comprising administering to the subject a compound or composition of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, the present invention relates to a method for treating a condition in which a decrease in mGluR4 activity can reduce the severity of the condition by administering a compound that inhibits mGluR4 function, e.g., a compound described herein that inhibits glutamate-induced intracellular cAMP decrease. The compounds described herein are antagonists of mGluR4 function and have a measured IC for inhibition of mGluR4 of 50 nanomolar or less. 50 It has. In another aspect, the compounds described herein that are antagonists of mGluR4 function can be used to inhibit mGluR4 function. For example, they can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction. In some embodiments, the compounds described herein can be used in vitro to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction, for example, in cultured cells. In other embodiments, the compounds described herein can be used in vivo to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction.

[0015] definition Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give them in light of the disclosure and the context.

[0016] The terms "negative regulator," "antagonist," and "inhibitor" are used interchangeably and refer to agents that reduce or suppress biological activity (e.g., reduced receptor activity) and include negative allosteric modulators (NAMs). mGluR4 receptors described herein include homomultimeric and heteromultimeric structures (e.g., homomultimeric mGluR4 and heteromultimeric mGluR4-mGluR2). Inhibitors of mGluR4 function include inhibitors having any combination of the structural and / or functional properties described herein. With respect to inhibitory or therapeutic methods, an "effective amount" (of an mGluR4 antagonist) refers to the amount of antagonist in a formulation that, when administered as part of a desired dosing regimen, produces a desired clinical or functional result. Without being bound by theory, an effective amount of an mGluR4 antagonist for use in the methods of the present invention includes an amount of mGluR4 antagonist effective to reduce one or more in vitro or in vivo functions of the mGluR4 receptor. Exemplary functions include, but are not limited to, alterations in intracellular cAMP, synaptic transmitter release, alterations in neuronal activity, or modulation of impulsive behavior. Compounds that antagonize mGluR4 function include compounds that antagonize the in vitro or in vivo functional activity of mGluR4. When a particular functional activity is readily observable only in an in vitro assay, the ability of a compound to inhibit mGluR4 function in that in vitro assay serves as a reasonable surrogate for the compound's activity. In certain embodiments, an effective amount is an amount sufficient to inhibit an mGluR4-mediated cellular function. mGluR4 antagonists for use in the methods of the present invention can be characterized by their activity, or lack of activity, at one or more receptors. When referring to other receptors, inhibition of the function of such other receptors is similarly defined. For example, receptor inhibition or receptor activity means that the antagonist inhibits one or more functional activities of the other receptors. Such functions include, for example, signal transduction across intracellular membranes and / or changes in the intracellular concentration of intracellular substances such as cAMP mediated by specific receptors and subsequent functions, such as neurotransmitter release.

[0017] The terms "compound" and "agent" are used interchangeably to refer to the negative regulators of the present invention. In the groups, radicals or moieties defined below, the number of carbon atoms is often specified before the group, for example, C1-6-alkyl means an alkyl group or radical having from 1 to 6 carbon atoms. Generally, for groups containing more than one subgroup, the last specified subgroup is the point of attachment of the radical, for example, the substituent "aryl-C1-3-alkyl-" means that the aryl group is attached to a C1-3-alkyl-group and that the C1-3-alkyl-group is attached to the group or nucleus to which the substituent is attached. When a compound of the invention is described by chemical name and formula, in the event of a conflict, the formula shall prevail. An asterisk may be used in a subformula to indicate the bond that connects to the core molecule being defined.

[0018] Stereochemistry / Solvation / Hydration The compounds described herein can be chiral (e.g., possessing one or more stereocenters). All stereoisomers are intended, unless otherwise specified, to be enantiomers and diastereomers. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional crystallization using "chiral resolving agents" of optically active, salt-forming organic acids. Suitable resolving agents for fractional crystallization include, for example, optically active acids (e.g., D- and L-tartaric acid, D- and L-diacetyltartaric acid, D- and L-dibenzoyltartaric acid, D- and L-mandelic acid, D- and L-malic acid, D- and L-lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid). Other resolving agents suitable for fractional crystallization include stereomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art. The compounds of the present invention also include tautomeric forms, e.g., keto-enol tautomers. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.), as well as racemates thereof, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the above forms of such isomers and enantiomers, where such isomers and enantiomers exist. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. For example, compounds of the invention can contain radioactive isotopes, such as tritium ( 3 H) or carbon-14 ( 14 C), can be radiolabeled. All isotopic varieties, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0019] salt The phrase "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds where the parent compound forms acid or base salts. Examples of acids that form pharmaceutically acceptable salts with a parent compound containing a basic moiety include inorganic or organic acids, such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, or tartaric acid, as well as salts of amino acids, such as arginates, and organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). The neutral forms of the compounds of the present invention are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. Certain physical properties of the parent form of the compound, such as solubility in polar solvents, may differ from those of the various salt forms, but the salts are otherwise equivalent to the parent form of the compound for purposes of this invention.

[0020] halogen The term "halogen" generally refers to fluorine, chlorine, bromine and iodine. Alkyl The term "Ci-n-alkyl", alone or in combination with another radical, means an acyclic, saturated, branched or straight-chain hydrocarbon radical having from 1 to n carbon atoms, where n is an integer from 2 to n. For example, the term "C 1-5"-Alkyl" encompasses the radicals HC-, HC-CH-, HC-CH-CH-, HC-CH(CH)-, HC-CH-CH-CH-, HC-CH(CH)-, HC-CH(CH)-CH-, HC-C(CH)-, HC-CH-CH-CH-, HC-CH-CH-CH-, HC-CH-CH-CH(CH)-, HC-CH-CH(CH)-, HC-CH-CH(CH)-CH-, HC-CH-C(CH)-, HC-C(CH)-CH-, HC-CH(CH)-CH(CH)- and HC-CH-CH(CHCH)-. cycloalkyl The term "C3-n-cycloalkyl," alone or in combination with another radical, means a cyclic, saturated, unbranched hydrocarbon radical having from 3 to n carbon atoms, where n is an integer from 4 to n. For example, the term "C3-7-cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Heterocycloalkyl: The term "heterocycloalkyl" means a saturated or unsaturated mono- or polycyclic ring system, including aromatic ring systems, containing one or more heteroatoms selected from N, O, or S(O)r, where r=0, 1, or 2, consisting of 3 to 14 ring atoms, and wherein the heteroatoms are not part of an aromatic ring. Many of the terms given above may be used repeatedly in the definitions of formulae or groups and may at each occurrence have, independently of one of the meanings given above.

[0021] According to the invention, the compounds of general formula (I) are obtained by methods known per se, for example by the following method: (a) The preparation of compounds of general formula (I) is described in the Examples or can be carried out, for example, according to the following formula Scheme 1. [ka] (In the formula, A, Xa, Xb, Xc, Xd and R 1 From R6 is defined as described in embodiment 1, and optionally the amino, hydroxy, carboxy or thiol group may be protected with a common protecting group, such as those described in TW Greene, PGM Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, which can be cleaved by methods known in the literature.

[0022] Scheme 1 [ka]

[0023] [ka] wherein Q is a leaving group or a group that can be converted into a leaving group in situ, such as a halogen atom, hydroxy, C 1-4 -alkyloxy, alkyloxycarbonyloxy, 4-pentafluorophenyloxy, nitrophenyloxy, trichloromethyl or acyloxy radical, or Q together with the carbonyl radical represents an alkylcarboxylate radical, R11 denotes a protecting group for the carboxylate function known in the literature, for example a tert.-butyl, methyl, ethyl, allyl or benzyl group, and R12 denotes a protecting group for the amino function known in the literature, for example a tert.-butoxycarbonyl, benzyloxycarbonyl or trifluoroacetyl group, and R13 represents a leaving group for the alkylation reaction, for example an iodine or bromine atom, or a tosylate or mesylate group; and R14 represents a leaving group for an aromatic nucleophilic substitution reaction, for example a fluorine or chlorine atom.

[0024] [ka] Reaction step i (substitution) shown in scheme 1 can be carried out as described in the examples or according to conditions known in the literature, for example as follows: A compound of general formula II is mixed with a compound of general formula XIII in a solvent (e.g., methylene chloride, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution or sulfolane), optionally in the presence of an inorganic or organic base (e.g., potassium carbonate, sodium hydride, triethylamine or Hunig's base), at a temperature between -20°C and 200°C, preferably between -10°C and 100°C.

[0025] [ka] Reaction step ix (substitution followed by nitro reduction) shown in scheme 1 can be carried out as described in the examples or according to conditions known in the literature, for example as follows: Displacement of substrate IX with amine XII as described above, followed by nitro reduction as described below: Nitro reduction to an amine group can be accomplished in an aqueous solvent (e.g., water, isopropanol / water, tetrahydrofuran / water or dioxane / water) or in a solvent (e.g., diethyl ether, tetrahydrofuran, dioxane, benzene, toluene) in the presence of an acid (e.g., trifluoroacetic acid, hydrochloric acid or sulfuric acid) and a reducing metal (e.g., zinc, iron, magnesium or calcium) or reducing agent (e.g., triphenylphosphine or lithium alanate) at a temperature between -40°C and 100°C, preferably between -10°C and 50°C. Alternatively, the reduction may be achieved using hydrogen in the presence of a catalyst (e.g., palladium on charcoal, Raney nickel or platinum), in a solvent (e.g., tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid), optionally with the addition of an acid, e.g., hydrochloric acid, at a temperature between -20°C and 50°C, but preferably 0°C to ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar.

[0026] [ka] [ka] Reaction steps ii and iv (acylation) can be carried out as described in the Examples or according to conditions known in the literature, for example as follows: By acylation of an amine (III or IV) with an optionally activated carboxylic acid (XI): The acylation can be conveniently carried out using the corresponding halide or anhydride in a solvent (e.g., methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, aqueous sodium hydroxide, or sulfolane), optionally in the presence of an inorganic or organic base (e.g., potassium carbonate, sodium hydride, triethylamine, or Hunig's base), at a temperature between -20°C and 200°C, preferably between -10°C and 100°C.

[0027] Acylation can also be carried out, however, using the free acid, optionally in the presence of an acid activating or dehydrating agent (e.g., ethyl-1-ethoxy-1,2-dihydroquinoline-1-carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, diphosphorus pentoxide, propanephosphonic acid cyclic anhydride, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexyl N,N'-Dicyclohexylcarbodiimide / Camphorsulfonic acid, N,N'-Dicyclohexylcarbodiimide / N-Hydroxysuccinimide or 1-Hydroxy-benzotriazole, N,N'-Carbonyldiimidazole, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate / N-methylmorpholine, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate The reaction may be carried out in the presence of, for example, fluoroborate / N-ethyldiisopropylamine, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate / N-methylmorpholine, O-pentafluorophenyl-N,N,N',N'-tetramethyluronium-hexafluorophosphate / triethylamine, N,N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally with the addition of an auxiliary base such as aqueous sodium hydroxide, cesium carbonate, potassium carbonate or sodium carbonate, or cesium bicarbonate, potassium bicarbonate or sodium bicarbonate, or an amine base (e.g., pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine), at a temperature between -20°C and 200°C, preferably between -10°C and 160°C. Other methods of amide coupling are described, for example, in P.D. Bailey, I.D. Collier, K.M. Morgan in "Comprehensive Functional Group Interconversions", Vol. 5, page 257ff., Pergamon 1995 or in the Houben-Weyl Supplementary Volume 22, Thieme Publishing, 2003, and in the references cited therein.

[0028] [ka] Reaction step viii (acylation followed by deprotection) can be carried out as described in the examples or according to conditions known in the literature, for example as follows: Acylation of the amine-containing substrate VIII with reagent XI as described above, followed by cleavage of the protecting group as described below: Any protecting groups used may optionally subsequently be cleaved, for example, by hydrolysis in an aqueous solvent (for example, water, isopropanol / water, tetrahydrofuran / water or dioxane / water) in the presence of an acid (for example, trifluoroacetic acid, hydrochloric acid or sulfuric acid) or an alkali metal base (for example, lithium hydroxide, sodium hydroxide or potassium hydroxide), or by ether cleavage, for example, in the presence of iodotrimethylsilane, at temperatures between 0°C and 100°C, preferably between 10°C and 50°C. However, benzyl, methoxybenzyl or benzyloxycarbonyl groups can be cleaved, for example, hydrogenolytically using hydrogen in the presence of a catalyst, for example palladium on charcoal, in a solvent (for example tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid), optionally with the addition of an acid, for example hydrochloric acid, at a temperature between 0°C and 50°C, preferably ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably 1 to 5 bar. However, the protecting groups can also be cleaved by the method described by TW Greene, PGM Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

[0029] [ka] [ka] Reaction steps iii and v (acylation followed by cyclization) can be carried out as described in the examples or according to conditions known in the literature, for example as follows: Acylation of an amine-containing substrate V with reagents VI or VII as described above, followed by cyclization as described below: The cyclization can be conveniently carried out in a solvent or mixture of solvents (e.g., ethanol, isopropanol, acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin, dimethyl sulfoxide, methylene chloride, chloroform, carbon tetrachloride), for example, at a temperature between 0°C and 250°C, preferably between 20°C and 100°C, optionally in the presence of a condensing agent (e.g., phosphoryl chloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N'-dicyclohexylcarbodiimide), or optionally in the presence of a base (e.g., potassium methoxide or potassium tert-butoxide), or in the presence of a metal salt (e.g., lithium bromide, aluminum bromide, zinc bromide, or aluminum-containing montmorillonite clay). However, the cyclization can also be carried out without a solvent and / or a condensing agent.

[0030] [ka] Reaction step vi (acylation followed by deprotection and cyclization) can be carried out as described in the Examples or according to conditions known in the literature, for example as follows: Acylation of an amine-containing substrate VI with reagent X as described above, followed by cleavage of the protecting group as described above, followed by cyclization as described above.

[0031] [ka] Reaction step x (acylation followed by deprotection) shown in Scheme 1 can be carried out as described in the Examples or according to conditions known in the literature, for example as follows: Acylation of substrate VI with a carboxylic acid or carboxylic acid derivative X as described above, followed by deprotection as described above.

[0032] [ka] Reaction step xi (acylation followed by cyclization) shown in scheme 1 can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows: Acylation of substrate VIV with a carboxylic acid or carboxylic acid derivative XI as described above, followed by cyclization as described above.

[0033] The terms "mGluR4," "mGluR4 protein," and "mGluR4 receptor" are used interchangeably throughout this application. Unless otherwise indicated, the term "mGluR4" includes homomultimeric structures (e.g., homomultimeric mGluR4) and heteromultimeric structures (e.g., heteromultimeric mGluR4-mGluR2).

[0034] Biological assays The biological activity of the compounds is measured by the following methods: A. In vitro testing of mGluR4 potency The in vitro activity of the compounds of the present invention is investigated as follows. HEK293 cells overexpressing the human metabotropic glutamate 4 receptor were thawed at 37°C and immediately diluted with cell culture medium. After centrifugation, the cell pellet was resuspended in medium and then dispensed from the spinner flask into the wells of an assay plate. After incubating the plate at room temperature for 1 hour, they were incubated at 37°C / 5% CO2 for 24 hours. After washing the cells in the plate three times with 80 μL of HBSS / HEPES buffer (leaving 10 μL of buffer in the well after washing), 5 μL of compound diluted in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) and 1 mM IBMX (final concentration: 0.5 mM) was added to the wells of the assay plate. Then, 5 μL per well of L-glutamic acid (final concentration: 10 μM), forskolin (final concentration: 1 μM), and 1 mM IBMX (final concentration: 0.5 mM) dissolved in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) are added to the assay plate (final DMSO concentration: 1%). Several wells of the assay plate are used for positive and negative controls or for a cAMP standard curve. The assay plate is incubated at room temperature for 30 minutes. Then, 5 μL of anti-cAMP antibody d2 solution and 5 μL of cAMP-europium cryptate dilution are added per well to all wells of the plate, and the plate is protected from light and incubated for an additional 60 minutes at room temperature. Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) are measured using an EnVision™ reader (PerkinElmer). The ratio between the emissions at 615 nm and 665 nm is calculated by the reader. All assays are performed in the dark or under green light.

[0035] cAMP standards were prepared by diluting the cAMP stock solution with HBSS / Hepes buffer: 5 μl / well of the cAMP dilution (containing 1 mM IBMX and 0.2% BSA in HBSS / Hepes buffer for a final concentration of 0.5 mM IBMX and 0.1% BSA) was added to wells of an assay plate, along with 10 μl / well of HBSS / Hepes buffer and 5 μl / well of 4% DMSO in HBSS / Hepes with 0.2% BSA (final DMSO concentration: 1%, the same as for compound-containing wells). The final cAMP concentrations in the assay plate were 0, 0.17, 0.69, 2.78, 11.1, 44.5, 178, and 712 nM (two wells / cAMP concentration). Each assay microtiter plate also contained wells with a vehicle control instead of compound as a control for L-glutamate-induced signal (negative control; 100% CTL; 10 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO), and wells with a vehicle control without L-glutamate (positive control; 0% CTL; 0 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO) as a control for nonspecific changes in signal. The data is analyzed by calculating the ratio between the emission at 665 nm and the emission at 615 nm (Em665 / Em615 ratio). The compound signal is then normalized using the positive and negative controls according to the following formula: PoC = 100 x ((signal sample - positive control) / (negative control - positive control))

[0036] B. Evaluation of metabolic stability in human liver microsomes (human MST) The metabolic stability of the compounds of the invention can be investigated as follows: Metabolic degradation of test compounds is analyzed using pooled liver microsomes at 37°C. A final incubation volume of 100 μL per time point contains TRIS buffer (0.1 M) at pH 7.6, MgCl (5 mM), microsomal protein (1 mg / mL), and test compound at a final concentration of 1 μM at room temperature. After a short preincubation period at 37°C, the reaction is initiated by the addition of β-nicotinamide adenine dinucleotide phosphate reduced form (NADPH, 1 mM) and terminated after various time points by transferring aliquots to solvent. After centrifugation (10,000 g, 5 min), aliquots of the supernatant are analyzed for the amount of parent compound by LC-MS / MS. Half-lives (t 1 / 2 ) is determined by the slope of a semi-logarithmic plot of the concentration-time profile.

[0037] C. Evaluation of efflux in Madin-Darby canine kidney (MDCK) cells transfected with the human MDR1 gene The apparent permeability coefficient (PE) of a compound across an MDCK-MDR1 cell monolayer is measured in the apical-to-basolateral (AB) and basolateral-to-apical (BA) transport directions (pH 7.4, 37°C). Through both passive and active transport mechanisms, AB permeability (PEAB) indicates drug absorption from the blood to the brain, and BA permeability (PEBA) indicates drug efflux from the brain back to the blood. Both passive and active transport mechanisms are mediated by efflux and uptake transporters expressed in MDCK-MDR1 cells, primarily by overexpressed human MDR1 P-gp. Compounds are classified into permeability / absorption classes by comparing AB permeability with that of reference compounds with known in vitro permeability and oral absorption in humans. Identical or similar permeability in both transport directions indicates passive transport, while vectorial permeability indicates an additional active transport mechanism. A higher PEBA than PEAB indicates the involvement of active efflux mediated by MDR1 P-gp. Active transport is concentration-dependent and saturable. MDCK-MDR1 cells (1-2 x 10e5 cells / cm2 area) are seeded onto filter inserts (Costar Transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 7 days. MDR1 expression is then promoted by culturing the cells in complete medium with 5 mM sodium butyrate for 2 days. Compounds are dissolved in an appropriate solvent (e.g., DMSO, 1-20 mM stock solution). The stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO, 1.8 mM CaCl, 4.17 mM NaHCO, 1.19 mM NaHPO x 7H2O, 0.41 mM NaHPO x 7H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare transport solution (0.1-300 μM compound, final DMSO <= 0.5%). Transport solution (TL) is applied to the apical or basolateral donor side (filter triplicate measurements) to measure AB or BA permeability, respectively. The receiver side contains the same buffer as the donor side. Samples are collected from the donor at the beginning and end of the experiment, and from the receiver at various time intervals up to 2 hours, for concentration measurement by HPLC-MS / MS or scintillation counter. The collected receiver volume is replaced with fresh receiver solution.

[0038] D. Evaluation of efficacy on impulsive behavior tested in the rat 5-choice serial reaction time task (5-CSRTT) Evaluation of effectiveness on motor impulsive behavior can be investigated as follows: Training for the 5-CSRTT task was performed according to a standard protocol (Isherwood et al. Neuropharmacology 2017, 123: 249-260). Briefly, rats were trained to nose-poke at a light cue presented at one of five locations on the curved wall of the operant box (Med Associates Inc, St. Albans, Vermont). If a rat nose-poked at the illuminated location during or up to 1 s after the stimulus presentation, a sugar pellet was delivered to a reward port on the opposite side of the chamber. Infrared beams at each choice hole and reward port allowed for accurate detection of rats in the operanda associated with this task. Motor impulsive behavior was defined as a response at any nose-poke port before the onset of the light cue (premature response). After stable performance was reached, a new analytical approach was applied, revealing trait-like (long-term) stability in the number of premature responses made by individual animals over several months. In general, this analysis allowed us to reliably stratify animals into high- and low-impulse groups based on longitudinal assessment of the number of premature responses they made during training. The study was conducted as a crossover, with all subjects receiving both vehicle and compound on separate days, approximately 2 weeks apart. The order of vehicle and compound administration was randomized within subjects, while a third group served as a technical control and received atomoxetine on both experimental days. Using a standardized numerical threshold for impulsivity level, animals with more than 40 premature responses (out of 200 trials) were classified as high-impulsive, and animals with fewer than 40 premature responses were classified as low-impulsive. Importantly, classification based on this numerical threshold showed greater than 80% agreement with the longitudinal analysis of training data (described above). The high agreement between these two approaches to stratification allowed us to reliably compare compound effects in stable high-impulsive and stable low-impulsive rats in the 5-CSRTT.

[0039] Biological data [Table 1]

[0040] The compounds of the present invention are structurally distinct from the structurally closest compound in the prior art (i.e., intermediate 213 in WO 2019 / 138017). In the compounds of the present invention, the heteromonocycle attached to the carboxamide is a substituted pyrazine (6-membered heteroaryl) rather than a pyrazole moiety (5-membered heteroaryl). While the compounds disclosed in WO 2019 / 138017 are immunomodulators (IL-17 modulators), the compounds of the present invention are unexpectedly highly potent mGluR4 negative modulators (see Table 2). The structurally closest compound disclosed in WO 2019 / 138017 was tested in Assay A and found to exhibit no therapeutically relevant activity as an mGluR4 modulator (Table 1). Unexpectedly, the compounds of the present invention are more than 100-fold more potent in Assay A (comparison data in Tables 1 and 2).

[0041] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0042] Therapeutic Use / Method of Use The present invention relates to compounds useful for the treatment and / or prevention of diseases, disorders, and conditions in which inhibition of mGluR4 activity is therapeutically beneficial, including, but not limited to, the treatment of psychiatric and neurological conditions associated with impulse control deficits or maladaptive impulsivity. Such impulse control deficits are found in addictions, including substance use disorders; personality disorders, e.g., borderline personality disorder and antisocial personality disorder; behavioral disorders, eating disorders, e.g., binge eating disorder and attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, e.g., post-traumatic stress disorder; tic disorders, e.g., Tourette's syndrome; and other movement disorders, e.g., restless legs disorder. In a further aspect of the present invention, the compounds of the present invention are useful for the treatment of mGluR4-related pathophysiological disorders, including cognitive function, motivational behavior / reward, mood and stress, and aggression. Additionally, they are of therapeutic benefit in cancer and related disorders associated with maladaptive tumorigenesis, e.g., osteosarcoma.

[0043] In view of their pharmacological action, the compounds of the present invention are suitable for use in the treatment of diseases or conditions selected from the list consisting of the following (1) to (8): (1) disorders related to dysfunctional impulse control; for example, pathological gambling, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, shopping addiction, internet addiction, sexual compulsive behavior, sexual disorders, sexual dysfunction, psychological disorders, eating disorders such as binge eating disorder, bulimia nervosa, anorexia nervosa, other specified eating and eating disorders, obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi syndrome, bulimia nervosa, appetite / taste disorders, bipolar disorder, post-traumatic stress disorder; (2) Drug Abuse / Dependence / Craving or addiction and relapse prevention (including, but not limited to, drugs, e.g., cocaine, opioids such as morphine, barbiturates, benzodiazepines, amphetamines, nicotine / tobacco and other psychostimulants), alcoholism and alcohol-related disorders, drug abuse or addiction or relapse, drug tolerance or withdrawal; (3) Psychiatric and neurological symptoms For example, attention deficit hyperactivity disorder, conduct disorders, attention problems and related disorders, sleep disorders, anxiety disorders, e.g. generalized anxiety disorder, panic disorder, phobias, post-traumatic stress disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease and Tourette's syndrome, restless legs syndrome, dementia, dysnezia, severe mental retardation, neurodegenerative disorders (including nosological entities, e.g. disinhibition-dementia-Parkinson's disease-muscle atrophy complex), pallidal-pontine-nigral degeneration, mood disorders, bipolar disorder, mania, manic-depression, borderline personality disorder, antisocial personality disorder, aggression, e.g. impulsive aggression, suicidal tendencies dementia, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neuroses / disorders, antidepressant neuroses / disorders, anxiety neuroses, dysthymic disorders, neurological diseases such as cerebral edema and angioedema, cerebral dementia such as Parkinson's and Alzheimer's disease, senile dementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, seizure disorders, stroke, myasthenia gravis, brain and meningeal infections such as encephalomyelitis, meningitis, HIV, and schizophrenia, delusional disorder, autism, affective disorders, and tic disorders (including, but not limited to, Tourette's syndrome and other movement disorders), dpilepsia, chronic pain; (4) cognitive impairment in psychiatric or neurological disorders; Cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; (5) personality disorder, For example, borderline personality disorder, antisocial personality disorder, paranoid personality disorder, schizoid and schizotypal personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, other specified and non-specified personality disorders; (6) Sleep disorders, For example, sleep disorders related to narcolepsy, jet lag, sleep apnea, insomnia, parasomnia, disturbed biological and circadian rhythms, psychiatric and neurological disorders; (7) non-neurological symptoms, wherein the non-neurological conditions include metabolic conditions such as diabetes, insulin resistance, metabolic syndrome, overweight, obesity, and use for weight loss, cosmetic weight loss, prevention of relapse during or after obesity treatment, weight maintenance, vomiting, disorders related to cardiovascular dysfunction, and disorders related to blood pressure dysregulation (e.g., hypertension or hypotension); (8) Cancer and related disorders; Here, said cancer and related disorders are related to maladaptive tumorigenesis, for example, osteosarcoma, breast cancer, ependymoma, bladder cancer, colon cancer.

[0044] The applicable daily dose of the compounds of the invention may vary from 0.1 mg to 2000 mg. The actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease, etc. In any case, the active ingredient will be administered in a dose and manner that will deliver a pharmaceutically effective amount appropriate to the patient's condition.

[0045] Pharmaceutical Composition Suitable compositions for administering the compounds of the present invention will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, syrups, elixirs, sachets, injections, inhalants, and powders. The content of the pharmaceutically active compound may vary from 0.1 to 95% by weight, preferably from 5.0 to 90% by weight, based on the total composition. Suitable tablets can be obtained, for example, by mixing the compounds of the present invention with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants, and compressing the resulting mixture into tablets.

[0046] Combination therapy The compounds of the present invention may be combined with other therapeutic options known in the art for use in connection with the treatment of any of the indications treated by the present invention. Such active ingredients or treatment options that may be suitable for combination with the compounds and treatments of the present invention include antidepressants, mood stabilizers, typical and atypical antipsychotics, tranquilizers, antiepileptics, antiparkinsonian drugs, hypnotics, cognitive enhancers, stimulants, medications for attention deficit hyperactivity disorder, additional psychotropic medications, anti-inflammatory drugs, analgesics, chemotherapeutic drugs, and combinations with treatment options used for metabolic disorders, liver disease, and kidney disease.

[0047] Experimental Section List of abbreviations: [Table 3] JPEG2025540259000029.jpg182146

[0048] method: HPLC-MS method: Method 1 Method 2 [Table 4] [Table 5]

[0049] Method 3 [Table 6] Table 7

[0050] Method 4 Table 8 Table 9

[0051] キラルSFC analysis method I_C2_10_MEOH_NH3_002 Table 10

[0052] I_C2_20_MEOH_NH3_002 Table 11

[0053] I_C4_10_MEOH_NH3_002 Table 12

[0054] I_C4_15_MEOH_NH3_002 Table 13

[0055] I_C4_20_MEOH_NH3_001 Table 14

[0056] I_IA_15_ETOH_NH3_001 Table 15

[0057] I_IG_10_MEOH_NH3_002

Table 16

[0058] I_IG_15_IPA_NH3_001

Table 17

[0059] I_IG_15_MEOH_NH3_001

Table 18

[0060] I_IG_25_IPA_NH3_001

Table 19

[0061] I_IG_25_MeOH_NH3_001

Table 20

[0062] I_SA_10_IPA_NH3_001

Table 21

[0063] I_SA_10_MEOH_NH3_001

Table 22

[0064] I_SA_15_MEOH_NH3_001 Table 23

[0065] I_SB_10_IPA_NH3_001 Table 24

[0066] I_SB_20_MEOH_NH3_001 Table 25

[0067] I_SC_05_IPA_NH3_001 Table 26

[0068] I_SC_10_IPA_NH3_001 Table 27

[0069] I_SC_10_MEOH_NH3_001 Table 28

[0070] I_SC_15_IPA_NH3_001 Table 29

[0071] I_SC_20_IPA_NH3_001 Table 30

[0072] I_SC_20_MEOH_NH3_001 [Table 31]

[0073] I_SC_25_MEOH_NH3_001 [Table 32]

[0074] NMR Methods: NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2 pl6 software. Chemical shifts are given in parts per million (ppm) downfield from the internal trimethylsilane standard, δ. Selected data are reported in the following format: chemical shift (multiplicity, coupling constant (J), number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad). MS(ESI + ):(M+H) + 170 HPLC: RT=0.23min, method F [Example]

[0075] Example 1: [ka]

[0076] Step 1: 5-Bromo-2-chloro-4-methyl-3-nitropyridine (2.0 g, 7.9 mmol) is mixed with isopropylamine (10 mL, 117 mmol) and stirred at ambient temperature for 16 hours. The mixture is concentrated in vacuo. The residue is washed with water, filtered, washed with water, and dried in vacuo. Yield: 2.17 g (7.9 mmol; quantitatively obtained) Int-1a MS(ESI+ ):(M+H) + 274 / 276(Br);HPLC:RT=1.22min, method:Z018_S04 Step 2: Int-1a (1.0 g, 3.6 mmol) was mixed with 150 mg of Raney nickel in 20 mL of THF and hydrogenated at 50 psi for 19 hours at ambient temperature, filtered, and the filtrate was concentrated in vacuo. Yield: 870 mg (3.6 mmol; 98%) Int-1b MS(ESI + ):(M+H) + 244 / 246(Br);HPLC:RT=0.94min, Method:Z011_S03

[0077] Step 3: Int-1b (245 mg, 1.00 mmol) was stirred with Zn(CN) (200 mg, 1.70 mmol) and X-Phos G1 (70 mg, 0.10 mmol) in 2.0 mL of NMP under argon at 110 °C for 16 h. ACN was then added, the mixture was filtered, and the filtrate was purified via preparative HPLC (C-18 X-Bridge, 50 °C, eluent gradient (water + 0.15% NH):ACN 79:21 → 59:41). Product-containing fractions were combined and lyophilized. Yield: 160 mg (0.84 mmol; 84%) Int-1c MS(ESI + ):(M+H) + 191;HPLC:RT=0.61min, method:Z018_S04 Step 4: 2-N-Boc-amino-3-methoxy-3-methyl-butanoic acid (186 mg, 0.75 mmol) and Int-1c (130 mg, 0.68 mmol) in 1.5 mL of pyridine were cooled to 0 °C, and PPA (50% in EtOAc, 1.05 mL, 1.71 mmol) was added under stirring. After stirring at ambient temperature for 2 h, the mixture was concentrated in vacuo. The residue was dissolved in water and EtOAc (1:1), extracted with EtOAc, and the combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was treated with diethyl ether, filtered, and dried in vacuo. Yield: 260 mg (0.62 mmol; 91%) Int-1d MS(ESI + ):(M+H) + 420;HPLC:RT=1.04min, method:Z011_S03

[0078] Step 5: Int-1d (270 mg, 0.64 mmol) is mixed with 5 mL of 4 M HCl in dioxane, and the mixture is stirred at ambient temperature for 2 hours. The mixture is then concentrated in vacuo. Yield: 229 mg (0.64 mmol; quantitatively obtained) Int-1 e HPLC: RT=0.86min, method: Z011_S03 Step 6: To a mixture of 5-(difluoromethyl)pyrazine-2-carboxylic acid (109 mg, 0.63 mmol), TBTU (201 mg, 0.63 mmol), and TEA (0.40 mL, 2.85 mmol) in 3.0 mL of DMF was added Int-1e (203 mg, 0.57 mmol) at ambient temperature, and the mixture was stirred for 3 h. 100 μL of water was added, and the mixture was purified by basic preparative HPLC. The product-containing fractions were combined and lyophilized. Yield: 170 mg (0.36 mmol; 63%) Int-1f MS(ESI + ):(M+H) + 476; HPLC: RT=1.01 min, Method: Z011_S03

[0079] Step 7: Int-1f (70 mg, 0.15 mmol) is stirred in 4.0 mL of AcOH at 97 °C for 8 days. The mixture is then concentrated in vacuo, dissolved in THF / water, adjusted to basic pH by the addition of aqueous NH3, and purified by basic preparative HPLC. Product-containing fractions are combined and lyophilized. The mixture is then separated by chiral SFC. Yield: 34 mg (0.074 mmol; 49%) Example 1

[0080] [Table 33]

[0081] The following products are obtained analogously to Example 1: [Table 34]

[0082] [Table 35]

[0083] [Table 36]

[0084] [Table 37]

[0085] [Table 38]

[0086] [Table 39]

[0087] [Table 40]

[0088] Table 41

[0089] Table 42

[0090] Table 43

[0091] Table 44

[0092] Table 45

[0093] Table 46

[0094] Table 47

[0095] Table 48

[0096] Table 49

[0097] Table 50

[0098] [Table 51]

[0099] [Table 52]

[0100] [Table 53]

[0101] [Table 54]

[0102] [Table 55]

[0103] [Table 56]

[0104] [Table 57]

[0105] [Table 58]

[0106] Example 5: [ka]

[0107] Step 1: A mixture of 2-chloro-4-hydroxy-3-nitro-pyridine (2.00 g; 11.5 mmol) and isopropylamine (3.6 mL, 41.9 mmol) in 20 mL of n-butanol is stirred in an autoclave at 110 °C for 18 h. The mixture is concentrated in vacuo, dissolved in MeOH, and acidified with AcOH. The mixture is filtered. The filtrate is purified by column chromatography (C18 Sunfire, 50 °C, eluent gradient: (H2O + 0.1% TFA):ACN 95:5 -> 75:25). The fractions containing the product are combined and lyophilized. The lyophilized product is combined with the solid obtained after filtration and dried under vacuum. Yield: 1.59 g (8.06 mmol; 70%) Int-5a MS(ESI + ):(M+H) + 198;HPLC:RT=0.61min, method:Z018_S04 Step 2: A mixture of Int-5a (1.59 g, 8.06 mmol) and POCl (2 mL, 21 mmol) in 20 mL of ACN is stirred at 80 °C for 30 min. The mixture is then concentrated in vacuo, the residue is dissolved in DCM and water, the mixture is basified with aqueous NaCO (2 N), and the aqueous layer is extracted with DCM. The combined organic layers are dried over MgSO and concentrated in vacuo, and the residue is used without further purification. Yield: 1.74 g (8.07 mmol; quantitatively obtained) Int-5b MS(ESI + ):(M+H) + 216 / 218(Cl);HPLC:RT=1.13min, method:Z018_S04

[0108] Step 3: A mixture of Int-5b (1.74 g, 8.07 mmol) and sodium methoxide (5.4 N in MeOH, 2.25 mL, 12.2 mmol) in 15 mL of MeOH and 15 mL of THF is stirred at ambient temperature for 3 days. The mixture is then concentrated in vacuo, and the residue is treated with water and filtered. The solid is washed with ACN and dried in vacuo. Yield: 1.62 g (7.67 mmol; 95%) Int-5c MS(ESI + ):(M+H) + 212;HPLC:RT=0.84min, method:Z018_S04 Step 4: A mixture of Int-5c (1.62 g, 7.67 mmol) and NBS (1.40 g, 7.87 mmol) in 30 mL of ACN is stirred at ambient temperature for 6 h, then at 45° C. for 20 min. The mixture is then concentrated in vacuo, the residue is dissolved in NaCO (0.5 N) and DCM, the aqueous layer is extracted with DCM, and the combined organic layers are dried over MgSO and concentrated in vacuo. Yield: 2.23 g (7.67 mmol; quantitatively obtained) Int-5d MS(ESI + ):(M+H) + 290 / 292(Br);HPLC:RT=1.18min, method:Z018_S04

[0109] Step 5: Int-5d (400 mg, 1.38 mmol) was mixed with Raney nickel (100 mg) in 20 mL of THF and hydrogenated at 50 psi hydrogen pressure for 20 hours, after which the mixture was filtered and concentrated in vacuo. Yield: 350 mg (1.35 mmol; 98%) Int-5e MS(ESI + ):(M+H) + 260 / 262(Br);HPLC:RT=0.65min, Method:Z018_S04 Step 6: PPA (50% wt. in AcOH, 1.5 mL, 2.45 mmol) was added to Int-5e (350 mg, 1.35 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (300 mg, 1.39 mmol) in 5 mL of pyridine at 0 °C, followed by stirring at 0 °C for 1 h. Water and ACN were added, and the mixture was purified by column chromatography (XBridge C18, 50 °C, eluent gradient: (HO + 0.1% NH):ACN 55:45 -> 35:65). Product-containing fractions were combined and lyophilized. Yield: 440 mg (0.96 mmol; 72%) Int-5f MS(ESI + ):(M+H) + 457 / 459(Br);HPLC:RT=0.92min, method:Z018_S04

[0110] Step 7: Int-5f (440 mg, 0.96 mmol) in HCl in dioxane (4 M, 4 mL) is stirred at ambient temperature for 1 h. The mixture is concentrated in vacuo, and the residue is dissolved in saturated aqueous NaHCO (1 N) and DCM. The aqueous layer is extracted with DCM, and the combined organic layers are dried over MgSO and concentrated in vacuo. Yield: 310 mg (0.87 mmol; 90%) Int-5 g MS(ESI + ):(M+H) + 357 / 359(Br);HPLC:RT=0.66min, method:Z018_S04 Step 8: Int-5g (310 mg, 0.26 mol) and ZnBr (400 mg, 1.78 mmol) in 5 mL of n-butyl acetate are stirred at 100 °C for 3 h, then at ambient temperature for 16 h. The mixture is then concentrated in vacuo, and the residue is dissolved in ACN, acidified by adding AcOH, some water is added, and filtered. The filtrate is purified by column chromatography (Sunfire C-18, 50 °C, eluent gradient: (H O + 0.15% TFA):ACN 80:20 -> 60:40). The product-containing fractions are combined and lyophilized. Yield: 230 mg (0.51 mmol; 58%) Int-5h MS(ESI + ):(M+H) + 339 / 341(Br);HPLC:RT=0.83min, method:Z018_S04 Step 9: To a mixture of Int-5h (230 mg, 0.51 mmol), 5-methyl-pyrazine-carboxylic acid (100 mg, 0.72 mmol), and TEA (400 mg, 3.95 mmol) in 4 mL of DMF, TBTU (180 mg, 0.56 mmol) was added and the mixture was stirred at ambient temperature for 15 min. Water was added, and the mixture was purified by column chromatography (XBridge C18, 50 °C, eluent gradient: (HO + 0.15% NH3):ACN 46:54 → 26:74). The product-containing fractions were combined and lyophilized. Yield: 210 mg (0.46 mmol; 90%) Example 5

[0111] [Table 59]

[0112] Example 6: [ka]

[0113] Step 1: A mixture of 2-chloro-3-nitro-5-trifluoromethyl-pyridine (1.50 g; 6.62 mmol) and isopropylamine (2.0 mL, 23.5 mmol) in 10 mL of THF is stirred at ambient temperature for 10 minutes. The mixture is concentrated in vacuo, the residue is treated with water, filtered, the solid is washed with water and dried in vacuo. Yield: 1.55 g (6.22 mmol; 94%) Int-6a MS(ESI + ):(M+H) + 250;HPLC:RT=1.17min, method:Z018_S04 Step 2: Int-6a (1.55 g, 6.22 mmol) was mixed with Raney nickel (200 mg) in 30 mL of THF and hydrogenated at ambient temperature for 17 hours at 50 psi hydrogen pressure, after which the mixture was filtered and concentrated in vacuo. Yield: 1.32 g (6.02 mmol; 97%) Int-6b MS(ESI+ ):(M+H) + 220;HPLC:RT=0.94min, method:Z011_S03

[0114] Step 3: N-2-Boc-amino-3-cyclopropyl-propionic acid (20 g, 87 mmol) is mixed with HCl in dioxane (4 N, 150 mL, 600 mmol) at 0° C., and the mixture is stirred at 0° C. for 15 min and at ambient temperature for 3 days. The mixture is concentrated in vacuo, and the residue is dissolved in dioxane and concentrated in vacuo again. Yield: 14.4 g (87 mmol; quantitatively obtained) Int-6c MS(ESI + ):(M+H) + 130 Step 4: To Int-6c (14.4 g, 87 mmol) in 150 mL of MeOH was added thionyl chloride (8.0 mL, 110 mmol) under stirring at ambient temperature, and the mixture was stirred for 5 h. The mixture was concentrated in vacuo, the residue was dissolved in dioxane, concentrated in vacuo, the residue was dissolved in ACN, and concentrated in vacuo again. Yield: 15.6 g (87 mmol; quantitatively obtained) Int-6d MS(ESI + ):(M+H) + 144

[0115] Step 5: A mixture of Int-6d (7.00 g, 39.0 mmol) and 5-methyl-pyrazine-2-carboxylic acid (7.00 g, 50.7 mmol) in 400 mL of THF is stirred at 0 °C, TEA (15 mL, 108 mmol) is added, followed by CIP (11.5 g, 41.3 mmol), and the mixture is stirred at 0 °C for 20 min. Water is added, and the mixture is concentrated in vacuo. The residue is dissolved in water and DCM, the aqueous layer is extracted with DCM, and the organic layers are combined, dried over MgSO4, and concentrated in vacuo. Yield: 23 g (content: 45%; 39 mmol; quantitatively obtained) Int-6e MS(ESI + ):(M+H) +264;HPLC:RT=0.91min, method:Z018_S04 Step 6: Int-6e (23 g, content: 45%, 39 mmol) in 150 mL of MeOH is mixed with 1 N aqueous NaOH (40 mL, 40 mmol) and stirred at ambient temperature for 1 h. 4 N NaOH (10 mL, 40 mmol) is then added, and the mixture is stirred at ambient temperature for 1.5 h. The mixture is concentrated in vacuo, the residue is dissolved in water, acidified to pH 1 with 4 N aqueous HCl, and the aqueous layer is extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo, and the residue is purified by preparative HPLC (C-18 Sunfire, 50 °C, eluent gradient (water + 0.15% TFA):ACN 83:17 -> 63:37). The product-containing fractions are combined and concentrated in vacuo, the aqueous layer is extracted with DCM, and the combined organic layers are dried over MgSO4 and concentrated in vacuo. Yield: 7.07 g (28.4 mmol, 72%) Int-6f MS(ESI + ):(M+H) + 250;HPLC:RT=0.80min, method:Z018_S04

[0116] Step 7: Int-6b (100 mg, 0.46 mmol), Int-6f (100 mg, 0.40 mmol), and NMM (265 μL, 2.41 mmol) in 5 mL of DCM were stirred at 0 °C, and PPA (50% in EtOAc; 470 μL, 0.80 mmol) was added. After stirring at 0 °C for 1 h, the cooling was removed, and the mixture was stirred at ambient temperature for 16 h. Water and 5 mL of AcOH were added, and the mixture was stirred at 90 °C for 45 min, then at 100 °C for 3 h, then at ambient temperature for 3 days, and then at 100 °C for 2 h. The mixture was diluted with MeOH, filtered, and the filtrate was purified by HPLC (C-18 Sunfire, 50 °C, eluent gradient (water + 0.15% TFA):ACN 45:55 -> 25:75). The product-containing fractions were combined and lyophilized. The residue is dissolved in MeOH, loaded onto an ion exchange cartridge (Agilent PL-HCO3 MP SPE) and concentrated in vacuo. The residue is purified by chiral SFC. Yield: 54 mg (0.12 mmol; 59%) Example 6

[0117] [Table 60]

[0118] [Table 61] The following products are obtained analogously to Example 6:

[0119] [Table 62]

[0120] [Table 63]

[0121] Example 8: [ka]

[0122] Step 1: To a mixture of 3-bromo-6-trifluoromethyl-pyridin-2-amine (2.00 g, 8.30 mmol) and aqueous NH3 (30%; 5.45 mL, 41.5 mmol) in 12 mL of DMF, acetylacetone (342 μL, 3.32 mmol) and copper acetylacetonate (217 mg, 0.83 mmol) are added under argon, and the mixture is stirred at 90 °C for 18 h. 100 mL of EtOAc and 60 mL of water are added, and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo. The residue is purified by column chromatography on a silica column (eluent: DCM:MeOH 98:2), and the product-containing fractions are combined and concentrated in vacuo. Yield: 1.51 g (content: 98%; 8.30 mol; quantitatively obtained) Int-8a MS(ESI +):(M+H) + 178;HPLC:RT=0.69min, method:Z011_S03 Step 2: To Int-8a (453 mg, 2.56 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (500 mg, 2.33 mmol) in 10 mL of DCM was added NMM (894 μL, 8.05 mmol) and PPA (50% by weight in AcOH, 2.7 mL, 4.41 mmol) at 0 °C, followed by stirring at 0 °C for 4.5 h. DCM and 5% aqueous NaHCO were added, and the mixture was stirred vigorously. The organic layer was dried over NaSO and concentrated in vacuo, and the residue was dissolved in diethyl ether and concentrated in vacuo. Yield: 1.00 g (content: 96%; 2.56 mmol; quantitatively obtained) Int-8b MS(ESI + ):(M+H) + 375;HPLC:RT=0.97min, method:Z011_S03

[0123] Step 3: A mixture of Int-8b (900 mg, 2.41 mmol), ZnBr (1.08 g, 4.81 mmol), and n-butyl acetate is stirred at 110 °C for 2.5 days. EtOAc and 5% aqueous NaHCO are added, and the mixture is stirred vigorously. The mixture is filtered, and the solid is dried at ambient temperature and used without further purification. Yield: 1.20 g (content: 50%; 2.34 mmol; 97%) Int-8c MS(ESI + ):(M+H) + 257;HPLC:RT=0.64min, method:Z011_S03 Step 4: Int-8c (50%; 1.74 g, 3.40 mmol) and 2-methyl-pyrazine-5-carboxylic acid (100 mg, 0.40 mmol) in 30 mL of DCM were stirred at 0 °C, and NMM (1.50 mL, 14.4 mmol) and PPA (50% in EtOAc; 4.0 mL, 3.40 mmol) were added. After stirring at 0 °C for 1 h, the cooling was reduced to reach ambient temperature over 16 h. EtOAc and 5% aqueous NaHCO3 were added, and the mixture was stirred vigorously. The mixture was filtered, and the solid was dried at ambient temperature. Yield: 1.36 g (content: 94%; 3.40 mmol; quantitatively obtained) Int-8d MS(ESI + ):(M+H) + 377;HPLC:RT=0.69min, method:Z011_S03

[0124] Step 5: To Int-8d (600 mg, 1.60 mmol) in 7.0 mL of DMF was added CsCO (779 mg, 2.39 mmol) and isopropyl methanesulfonate (100 μL, 3.19 mmol), and the mixture was stirred at 90 °C for 17 h. Subsequently, additional isopropyl methanesulfonate (385 μL, 0.83 mmol) was added, and the mixture was stirred at 90 °C for 8 h. EtOAc was then added, and the mixture was filtered. The filtrate was concentrated in vacuo, the residue was dissolved in MeOH, filtered, and the filtrate was purified via preparative HPLC (C-18 X-Bridge, 60 °C, eluent (water + 0.15% NH):ACN mixture). The product-containing fractions were combined and lyophilized. Yield: 107 mg (0.26 mmol; 16%) Example 8

[0125] [Table 64]

[0126] Example 11: [ka] Step 1: To isopropylamine (60 mL, 704 mmol) is added 5-bromo-2-chloro-4-methyl-3-nitropyridine (20.0 g, 79.5 mmol) over 2 minutes with stirring, and the mixture is stirred at ambient temperature for 17 hours. The mixture is then concentrated in vacuo, the residue is treated with water, filtered, the solid is washed with water, dissolved in ACN, and dried in vacuo at 45°C. Yield: 21.2 g (77.3 mmol; 97%) Int-11a MS(ESI + ):(M+H) + 274 / 276(Br);HPLC:RT=1.22min, method:Z018_S04 Step 2: Int-11a (10.0 g, 36.5 mmol) was mixed with Raney nickel (200 mg) in 150 mL of THF and hydrogenated at ambient temperature for 18 hours at 50 psi hydrogen pressure, after which the mixture was filtered and concentrated to dryness in vacuo. Yield: 9.00 g (content: 98%; 36.1 mmol; 99%) Int-11b MS(ESI + ):(M+H) + 244 / 246(Br);HPLC:RT=0.94min, Method:Z011_S03

[0127] Step 3: To a mixture of Int-11b (27.6 g, 111 mmol) and Zn(CN) (13.3 g, 113 mmol) in 100 mL of NMP under argon, tetrakis(triphenylphosphine)-palladium(0) (6.40 g, 5.54 mmol) was added, and the mixture was stirred at 115 °C for 45 min. 300 mL of DCM and 300 mL of water were then added, and the mixture was vigorously stirred and filtered. The organic layer was washed with water, dried over MgSO, and concentrated in vacuo. The residue was dissolved in DCM, mixed with extrelut, concentrated in vacuo, and purified via column chromatography on silica gel (eluent gradient: PE: EtOAc 85:15 -> 55:45). The aqueous layer after quenching was extracted with EtOAc, and the combined organic layer was washed with aqueous NaCl, dried over MgSO, and concentrated in vacuo. The residue is purified by column chromatography on silica gel (eluent gradient: PE: EtOAc 85:15 -> 55:45). The product-containing fractions are combined and concentrated in vacuo to give a residue. Yield: 13.6g (71.5mmol; 65%) Int-11c MS(ESI + ):(M+H) + 191;HPLC:RT=0.81min, method:Z011_S03 Step 4: A mixture of Int-11c (13.6 g, 71.5 mmol), (S)-2-(Boc-amino)-3-cyclopropyl-propionic acid, and NMM (38.5 mL, 350 mmol) in 1.0 L of DCM is cooled to -10 °C, and PPA (50% in EtOAc; 84.6 mL, 144 mmol) is added within 8 min under stirring. The cooling is reduced to reach ambient temperature within 16 h under stirring. 200 mL of 5% aqueous NaHCO3 is added, and the organic layer is washed with water. 250 mL of water is added, and the mixture is acidified to pH 4 with 0.5 N aqueous KHSO4 and stirred vigorously. The organic layer is washed with water, dried over MgSO4, and concentrated in vacuo. The residue is treated with diisopropyl ether and concentrated in vacuo at 45 °C. Yield: 20.6 g (51.4 mmol; 73%) Int-11d MS(ESI + ):(M+H)+ 402;HPLC:RT=1.06min, method:Z011_S03

[0128] Step 5: A mixture of Int-11d (20.2 g, 50.2 mmol) and K2CO3 (8.33 g, 60.3 mmol) in 300 mL of 2-propanol is stirred at 85 °C for 22 h and at 90 °C for 34 h. 200 mL of DCM is added, filtered, and the filtrate is concentrated in vacuo. The residue is dissolved in DCM / MeOH, silica gel is added, and the mixture is concentrated in vacuo. The residue is used for purification via column chromatography on silica gel (eluent DCM:EtOH 98:2). The product-containing fractions are combined and concentrated in vacuo. Yield: 16.0 g (41.7 mmol; 83%) Int-11e MS(ESI + ):(M+H) + 384;HPLC:RT=1.16min, method:Z011_S03 Step 6: To Int-11e (16.0 g, 41.7 mmol) in 250 mL of DCM is slowly added a solution of HCl in dioxane (4 N; 52.2 mL, 209 mmol). The mixture is stirred at ambient temperature for 16 h and concentrated in vacuo. Yield: 14.9 mg (41.7 mmol; quantitatively obtained) Int-11f MS(ESI + ):(M+H) + 284;HPLC:RT=0.95min, method:Z011_S03 Step 7: A mixture of Int-11f (300 mg, 0.84 mmol), 5-difluoromethyl-pyrazine-2-carboxylic acid (188 mg, 1.08 mmol), and pyridine (2.1 mL, 26 mmol) was stirred at 0 °C. PPA (50% in EtOAc; 0.7 mL, 1.2 mmol) was added, and the mixture was stirred at 0 °C for 30 min and at ambient temperature for 16 h. THF and water were added, and the mixture was purified by preparative HPLC (C-18 X-Bridge 10 μm, eluent gradient (water + 0.1% NH3):ACN 52:48 -> 42:58). The product-containing fractions were combined and concentrated in vacuo. The residue was dissolved in ACN and water and lyophilized. Yield: 125 mg (284 μmol; 42%) Example 11

[0129] [Table 65]

[0130] The following products are obtained analogously to Example 11: [Table 66]

[0131] Example 16: [ka]

[0132] Step 1: To 2-methyl-6-trifluoromethyl-pyridin-3-amine (20 g, 108 mmol) in 230 mL of ACN is added NBS (20.2 g, 113 mmol) portionwise within 3 minutes under stirring at ambient temperature. Stirring is continued for 2.5 hours. The mixture is then concentrated in vacuo, and the residue is dissolved in DCM and washed with water. The organic layer is dried over MgSO4 and concentrated in vacuo. Yield: 27.2 g (107 mmol; 99%) Int-16a MS(ESI + ):(M+H) +255; HPLC: RT=0.99 min, Method: Z018_S04 Step 2: In an autoclave, Int-16a (27.0 g, 106 mmol) is mixed with isopropylamine (91.4 mL, 1.06 mol), 169 mL of water, CuI (1.21 g, 6.35 mmol), and 1-pyridin-2-yl-ethanone oxime (1.19 g, 8.47 mmol). The mixture is stirred at 90 °C for 24 h. THF and water are then added, and the mixture is concentrated in vacuo. The residue is extracted with EtOAc, and the combined organic layers are dried over MgSO and concentrated in vacuo. The residue is mixed with DCM, TFH, and extrelut, the mixture is concentrated in vacuo, and the residue is purified by column chromatography on silica gel (eluent gradient: PE:EtOAc 67:33 -> 37:63). The product-containing fractions are combined and concentrated in vacuo. Yield: 10.1g (43.3mol; 41%) Int-16b MS(ESI + ):(M+H) + 234;HPLC:RT=0.92min, method:Z011_S03

[0133] Step 3: A mixture of Int-16b (10.1 g, 42 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (9.95 g, 46 mmol) in 100 mL of pyridine is cooled to −10° C. Under stirring, PPA (50% in EtOAc, 37.1 mL, 63 mmol) is added over 8 min, and the mixture is stirred at −5° C. for 1 h. The mixture is poured into water at 0° C., stirred vigorously, adjusted to pH 8 by adding concentrated aqueous NH3, and stirred vigorously again. The formed solid is filtered, washed with water, and dried in vacuo at 60° C. Yield: 17.0 g (39.6 mmol; 94%) Int-16c MS(ESI + ):(M+H) + 431;HPLC:RT=1.06min, method:Z011_S03 Step 4: Int-16c (17.0 g, 37.5 mmol) and ZnBr (18.6 g, 82.5 mmol) in n-butyl acetate are stirred at 115 °C for 21 h and at 135 °C for 2 h. The mixture is poured into ice water and stirred. The pH is adjusted to 8.5 by adding concentrated aqueous NH, and Celite is added, stirred, and filtered. The solid is washed with EtOAc. The organic layer is washed with aqueous NaCl, dried over MgSO, and concentrated in vacuo. The residue is dissolved in EtOAc and purified by column chromatography on silica gel (eluent gradient: EtOAc:(EtOH + 5% concentrated aqueous NH 97:3 -> 80:20). Fractions containing the product are collected and concentrated in vacuo. Yield: 11.5 g (36.9 mmol; 98%) Int-16d. MS(ESI + ):(M+H) + 313;HPLC:RT=0.93min, method:Z011_S03

[0134] Step 5: Under nitrogen, Int-16d (60.0 g, 192 mmol) was added to 5-methyl-pyrazine-2-carboxylic acid (188 mg, 1.08 mmol) and TEA (80 mL, 576 mmol) in 500 mL of EtOAc, and the mixture was cooled to −5 °C. PPA (50% in EtOAc; 149 mL, 250 mmol) was added with stirring and cooling, maintaining the temperature below 0 °C. The cooling was then removed, and the mixture was stirred at ambient temperature for 45 min. 1.0 L of water was added, and the mixture was stirred for 5 min. The organic layer was washed twice with 500 mL of half-concentrated aqueous NaCl solution containing 5 mL of concentrated aqueous NH3. 10 g of charcoal was added, and the mixture was stirred for 10 min, after which it was filtered, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DCM and diethyl ether, each of which was again concentrated in vacuo, and then dried in vacuo at ambient temperature. The residue is dissolved in 80 mL of diisopropyl ether, and then n-heptane is added in portions, a total of 320 mL, with vigorous stirring between additions. The solid is filtered, washed with 200 mL of n-heptane, and dried under vacuum at 55°C. The solid is then added to 1.46 L of water, stirred at ambient temperature for 22 hours, filtered, washed with 1.5 L of water, and dried under nitrogen at 65°C for 22 hours. Yield: 69.6 g (162 mmol; 84%) Example 16

[0135] [Table 67]

[0136] The following products are obtained analogously to Example 16: [Table 68]

[0137] [Table 69]

[0138] [Table 70]

[0139] [Table 71]

[0140] [Table 72]

[0141] Example 27: [ka]

[0142] Step 1: A mixture of 4,5-diamino-2-(trifluoromethyl)-pyridine (605 mg, 3.42 mmol), (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (700 mg, 3.26 mmol), and NMM (1.25 mL, 11 mmol) in 40 mL of DCM is cooled to -10 °C, and PPA (50% in EtOAc, 3.8 mL, 6.60 mmol) is added under stirring. After 1.25 h, the ice bath is removed, DCM and 5% aqueous NaHCO are added, and the mixture is stirred vigorously at ambient temperature. The organic layer is dried over NaSO and concentrated in vacuo. The residue is dissolved in diethyl ether and concentrated in vacuo. Yield: 1.50 g (content: 75%; 3.01 mmol; 92%) Int-27a MS(ESI + ):(M+H) + 375;HPLC:RT=0.88min, method:Z011_S03 Step 2: A mixture of Int-27a (810 mg, 2.3 mmol) and ZnBr (974 mg, 4.33 mmol) in 15 mL of n-butyl acetate is stirred at 110 °C for 19 h. EtOAc and 5% aqueous NaHCO are added, the mixture is stirred vigorously, and the aqueous layer is extracted with EtOAc. The combined organic layers are washed with water, dried over NaSO, and concentrated in vacuo. Yield: 600 mg (2.3 mmol; quantitatively obtained) Int-27b MS(ESI + ):(M+H) + 257;HPLC:RT=0.58min, method:Z011_S03

[0143] Step 3: To a mixture of Int-27b (221 mg, 0.86 mmol), 5-(difluoromethyl)-pyrazine-2-carboxylic acid (150 mg, 0.86 mmol), and NMM (379 μL, 2.72 mmol) in 10 mL of DCM cooled to 0 °C, PPA (50% in EtOAc, 1.0 mL, 1.74 mmol) is added under stirring. The ice bath is removed, and stirring is continued at ambient temperature for 17 h. DCM and 5% aqueous NaHCO3 are added, and the mixture is stirred vigorously at ambient temperature. The organic layer is dried over Na2SO4 and concentrated in vacuo. Yield: 304 mg (0.74 mmol; 86%) Int-27c MS(ESI + ):(M+H) + 413;HPLC:RT=0.72min, method:Z011_S03 Step 4: To a mixture of Int-27c (304 mg, 0.74 mmol), triphenylphosphine (290 mg, 1.11 mmol), and isopropanol (284 μL, 3.69 mmol) in 5 mL of THF, diisopropyl azodicarboxylate (40% in toluene, 543 μL, 1.11 mmol) was added at 0 °C and stirred for 3.5 h at 0 °C and 17 h at ambient temperature. Then, triphenylphosphine (100 mg, 0.38 mmol) and diisopropyl azodicarboxylate (40% in toluene, 543 μL, 0.41 mmol) were added at 0 °C and stirred for 5.5 h until the mixture reached ambient temperature. Water was added, the mixture was stirred vigorously, and the mixture was extracted with EtOAc. The combined organic layer was dried over Na SO and concentrated in vacuo. The residue was dissolved in DCM and purified by column chromatography on silica gel (eluent DCM:MeOH 98:2). The product-containing fractions are combined and concentrated in vacuo, and the residue is further purified by chiral SFC. Yield: 68 mg (0.15 mmol, 20%) Example 27

[0144] [Table 73]

[0145] The following products are obtained analogously to Example 27: [Table 74]

[0146] Example 28: [ka]

[0147] Step 1: A mixture of Int-11c (365 mg, 1.82 mmol), (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (471 mg, 2.19 mmol), and NMM (1.2 mL, 10.9 mmol) in 25 mL of DCM was cooled to -5 °C, and PPA (50% in EtOAc, 2.1 mL, 3.65 mmol) was added under stirring. After 10 min, the cooling was removed, and the mixture was stirred at ambient temperature for 3.5 days. Water was added, and the organic layer was concentrated in vacuo. The residue was dissolved in THF and MeOH and purified via preparative HPLC (XBridge C-18 10 μm, eluent gradient (HO + 0.1% NH):ACN 61:39 -> 41:59). Product-containing fractions were combined and lyophilized. Yield: 518 mg (1.34 mmol, 73%) Int-28a MS(ESI + ):(M+H) + 388;HPLC:RT=1.00min, method:Z011_S03 Step 2: To Int-28a (515 mg, 1.33 mmol) in 6.7 mL of dioxane containing 250 μL of MeOH was added HCl in dioxane (4 N, 6.6 mL, 26.6 mmol) at ambient temperature for 2.25 h. The mixture was concentrated in vacuo, and the residue was dissolved in ACN and concentrated in vacuo. Yield: 520 mg (1.31 mmol, 99%) Int-28b MS(ESI + :(M+H) + 288;HPLC:RT=0.79min, method:Z011_S03

[0148] Step 3: To a mixture of Int-28b (255 mg, 0.64 mmol), 5-methyl-pyrazine-2-carboxylic acid (93 mg, 0.66 mmol), and TEA (403 μL, 2.89 mmol) in 10 mL of ACN, CIP (188 mg, 0.68 mmol) was added and the mixture was stirred at ambient temperature for 25 min. The mixture was concentrated in vacuo, and the residue was dissolved in DCM, washed with water, dried over MgSO, and concentrated in vacuo. Yield: 189 mg (0.46 mmol, 72%) Int-28c MS(ESI + ):(M+H) + 408;HPLC:RT=0.90min, method:Z011_S03 Step 4: To Int-28c (185 mg, 0.45 mmol) in 3.0 mL of isopropanol was added KCO (75 mg, 0.55 mmol), and the mixture was stirred at 85 °C for 39 h. 5 mL of THF was then added, the resulting mixture was filtered, and the filtrate was purified via preparative HPLC (X-Bridge C-18 10 μm, eluent gradient (HO + 0.1% NH):ACN 61:39 -> 41:59). Product-containing fractions were combined and concentrated in vacuo. The residue was further purified by chiral SFC. Yield: 72 mg (0.19 mmol, 42%) Example 28

[0149] [Table 75]

[0150] The following products are obtained analogously to Example 28: [Table 76]

[0151] [Table 77]

[0152] Example 33: [ka]

[0153] Step 1: To 3-bromo-6-chloro-2-methyl-5-nitropyridine (0.60 g, 2.39 mmol) in 5 mL of DCM, add 0.56 g (9.54 mmol) of isopropylamine, and the mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated in vacuo, water is added, the mixture is filtered, and the solid is dried. Yield: 0.66 g (2.39 mmol; quantitatively obtained) Int-33a MS(ESI + ):(M+H) + 274 Step 2: Int-33a (0.38 g, 1.39 mmol) was mixed with Raney nickel (70 mg) in 5 mL of MeOH and hydrogenated at ambient temperature for 17 hours at 50 psi hydrogen pressure, after which the mixture was filtered and concentrated to dryness in vacuo. Yield: 0.36 g (1.48 mmol; quantitatively obtained) Int-33b MS(ESI + ):(M+H) + 244 / 246(Br); HPLC: RT=1.02 min, Method: Z011_S03

[0154] Step 3: To a mixture of Int-33b (0.36 g, 1.48 mmol) and Zn(CN) (0.29 g, 2.43 mmol) in 10 mL of NMP under argon, chloro(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]-palladium(II) (0.10 g, 0.135 mmol) was added, and the mixture was stirred at 110 °C for 18 h. Water was then added, and the mixture was vigorously stirred and filtered. The solid was dried at ambient temperature. Yield: 0.17 g (0.87 mmol; 59%) Int-33c MS(ESI + ):(M+H)+ 191;HPLC:RT=0.88min, method:Z011_S03 Step 4: Int-33c (165 mg, 0.87 mmol), Int-6f (216 mg, 0.87 mmol), and NMM (158 mg, 1.56 mmol) in 10 mL of DCM are stirred at 0 °C, and PPA (50% in EtOAc; 580 mg, 0.91 mmol) is added. After stirring at 0 °C for 1 h, the cooling is removed and the mixture is stirred at ambient temperature for 16 h. The mixture is concentrated in vacuo, and the residue is dissolved in semiconcentrated aqueous NaHCO and extracted with DCM. The combined organic layers are concentrated in vacuo. Yield: 150 mg (0.36 mmol; 41%) Int-33d MS(ESI + ):(M+H) + 422; HPLC: RT=1.01 min, Method: Z011_S03 Step 5: Int-33d (150 mg, 0.36 mmol) and ZnBr (160 mg, 0.71 mmol) in 5 mL of n-butyl acetate are stirred at 100 °C for 20 h, EtOAc and 5% aqueous NaHCO are added, filtered, and the organic layer is concentrated in vacuo. The residue is purified by preparative HPLC. Yield: 8 mg (0.02 mmol; 6%) Example 33

[0155] [Table 78]

[0156] Example 47: [ka]

[0157] Step 1: NaHCO3 (18.6 g, 221 mmol) is added to (2S)-2-Boc-amino-2-cyclopropyl-acetic acid in 160 mL of DMF under stirring at ambient temperature, followed by benzyl bromide (10.6 mL, 88.5 mmol). The mixture is stirred for 22 hours, then filtered, and the filtrate is concentrated in vacuo. The residue is mixed with 500 mL of water and extracted with tert-butyl-methyl-ether. The combined organic layers are washed with water, dried over MgSO4, and concentrated in vacuo. Yield: 25.9 g (84.8 mmol, 96%) Int-47a MS(ESI + ):(M+H) + 306 Step 2: To Int-47a (25.8 g, 84.5 mmol) in 63 mL of dioxane and 63 mL of MeOH is added HCl in dioxane (4 M, 127 mL, 507 mmol) under stirring at 10° C. The mixture is stirred at ambient temperature for 1.5 hours, then concentrated in vacuo, dissolved in DCM, MeOH, and diethyl ether, respectively, and each concentrated again in vacuo. Yield: 20.4 g (84.4 mmol; quantitatively obtained) Int-47b MS(ESI + ):(M+H) + 206;HPLC:RT=0.87min, method:Z011_S03

[0158] Step 3: PPA (50% in EtOAc; 33 mL, 55.4 mmol) is added to a mixture of Int-47b (10.3 g, 42.6 mmol) and 2-methylpyrazine-5-carboxylic acid (6.69 g, 46.0 mmol) in 33 mL of pyridine under stirring at −15° C. The mixture is stirred at 0° C. for 20 minutes and at ambient temperature for 1.5 hours. Then, 5 mL of water is added, and the mixture is concentrated in vacuo. The residue is dissolved in 150 mL each of water and tert-butyl-methyl-ether, and the aqueous layer is extracted with tert-butyl-methyl-ether. The combined organic layers are washed with semiconcentrated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent gradient: PE / EtOAc 80:20->45:55). Yield: 10.4 g (30.4 mmol; 71%) Int-47c MS(ESI + ):(M+H) + 326; HPLC: RT=0.99 min, Method: Z011_S03 Step 4: To Int-47c (10 g, 30.7 mmol) in 76 mL of dioxane, aqueous LiOH (1 N; 38.4 mL, 38.4 mmol) is added, and the mixture is stirred at ambient temperature for 1 h. The mixture is then adjusted to pH 3 by the addition of aqueous HCl (4 N, 9.6 mL, 38.4 mmol) and lyophilized. The residue is dissolved in water, filtered, and the solid is washed with water and dried under vacuum. Yield: 5.82 g (24.7 mmol; 80%) Int-47d MS(ESI + ):(M+H) + 236;HPLC:RT=0.73min, method:Z018_S04

[0159] Step 5: NMM (752 μL, 6.84 mmol) and PPA (50% in EtOAc; 1.4 mL, 2.35 mmol) are added to a mixture of 4,5-diamino-2-trifluoromethyl-pyridine (416 mg, 2.35 mmol) and Int-47d (460 mg, 1.96 mmol) in 40 mL of DCM under stirring at −10° C. The mixture is stirred at 0° C. for 3 h. DCM is then added and the mixture is extracted with 5% aqueous NaHCO solution. The aqueous layer is extracted with DCM, and the combined organic layers are dried over NaSO and concentrated in vacuo. Yield: 579 mg (1.47 mmol; 75%) Int-47e MS(ESI + ):(M+H) + 395;HPLC:RT=0.79min, method:Z011_S03 Step 6: Int-47e (579 mg, 1.47 mmol) is stirred in 5 mL of AcOH at 85° C. for 4 days. The mixture is concentrated in vacuo, the residue is dissolved in MeOH, filtered, and the filtrate is purified by HPLC (XBridge C18, 10 μm, free: (HO+0.15% NH):ACN 91:9). The product-containing fractions are combined and concentrated in vacuo. Yield: 224 mg (0.60 mmol; 40%) Int-47f MS(ESI + ):(M+H) + 377;HPLC:RT=0.69min, method:Z011_S03 Step 7: To Int-47f (223 mg, 0.59 mmol) in 5.0 mL of DMF was added CsCO (290 mg, 0.89 mmol) and iodoethane (57 μL, 0.71 mmol), and the mixture was stirred at 60 °C for 4.5 h. Afterwards, additional iodoethane (20 μL, 0.21 mmol) was added, and the mixture was stirred at 60 °C for 1.5 h. ACN was added, filtered, and concentrated in vacuo. The residue was purified via preparative HPLC (XBridge C-18 10 μm, 60 °C, eluent (HO + 0.1% NH):MeOH 61:39 -> 41:59). Fractions containing the product were combined and concentrated in vacuo. The residue was further purified by chiral SFC. Yield: 10 mg (0.025 mmol, 4.2%)

[0160] [Table 79]

[0161] The following products are obtained analogously to Example 47: [Table 80]

[0162] [Table 81]

Claims

1. A compound of formula I or a physiologically acceptable salt thereof. 【Chemistry 1】 (In the formula, A is C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 5 -cycloalkyl-C 1 -C 2 -Alkyl-, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, 4- to 6-membered heterocycloalkyl-, 4- to 6-membered heterocycloalkyl-C 1 -C 3 -alkyl-, the latter group optionally being C 1 -C 4 -Alkyl, C 1 -C 4 - optionally substituted with 1 to 4 substituents selected from alkoxy, hydroxy, fluoro; Xa is N or C—R 2 represents; Xb is N or C—R 3 represents; Xc is N or C—R 4 represents; Xd is C-R 5 represents; provided that one of Xa, Xb, and Xc represents N; R 1 is C 1 -C 7 -Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 7 -cycloalkyl, 4-6 membered heterocycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkyl-, 4- to 6-membered heterocycloalkylmethyl-, C 5 -C 6 -heterocycloalkylethyl-, the latter group optionally being C 1 -C 4 -Alkyl, C 1 -C 4 -alkoxy, C 3 -C 7 - optionally substituted with 1 to 4 substituents selected from cycloalkoxy, hydroxy, fluoro; R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, cyano, C 1 -C 4 -Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 6 -cycloalkyl, 4-6 membered C 4 -C 6 -heterocycloalkyl, C 1 -C 4 -alkoxy-, C 3 -C 6 -cycloalkoxy-, the last six groups optionally being C 1 -C 4 -Alkyl, C 1 -C 4 - optionally substituted with 1 to 4 substituents selected from alkoxy, hydroxy, fluoro; R 6 is a C optionally substituted with halogen, 2 to 3 fluorine atoms 1 -C 3 represents alkyl.)

2. 2. The compound of claim 1, which is a compound of formula Ia, formula Ib or Ic, or a physiologically acceptable salt thereof. 【Chemistry 2】 (In the formula, A is C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 5 -cycloalkyl-C 1 -C 2 -Alkyl-, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, 4- to 6-membered heterocycloalkyl-, 4- to 6-membered heterocycloalkyl-C 1 -C 3 -alkyl-, the latter group optionally being C 1 -C 4 -Alkyl, C 1 -C 4 - optionally substituted with 1 to 4 substituents selected from alkoxy, hydroxy, fluoro; R 1 is C 1 -C 7 -Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 7 -cycloalkyl, 4-6 membered heterocycloalkyl-, C 3 -C 7 -cycloalkyl-C 1 -C 3 -alkyl-, 4- to 6-membered heterocycloalkylmethyl-, C 5 -C 6 -heterocycloalkylethyl-, the latter group optionally being C 1 -C 4 -Alkyl, C 1 -C 4 -alkoxy, C 3 -C 7 - optionally substituted with 1 to 4 substituents selected from cycloalkoxy, hydroxy, fluoro; R 2 , R 3 , R 4 and R 5 are each independently hydrogen, halogen, cyano, C 1 -C 4 -Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 6 -cycloalkyl, 4-6 membered C 4 -C 6 -heterocycloalkyl, C 1 -C 4 -alkoxy-, C 3 -C 6 -cycloalkoxy-, the last six groups optionally being C 1 -C 4 -Alkyl, C 1 -C 4 - optionally substituted with 1 to 4 substituents selected from alkoxy, hydroxy, fluoro; R 6 is a C optionally substituted with halogen, 2 to 3 fluorine atoms 1 -C 3 represents alkyl.)

3. A is C 1 -C 3 -Alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 5 -cycloalkylmethyl-, tetrahydrofuranyl-, tetrahydropyranyl-, 1,4-dioxanyl, tetrahydrofuranylmethyl-, tetrahydropyranylmethyl-, 1,4-dioxanylmethyl-, C 1 -C 2 -Alkyl-O-C 1 -C 3 3. The compound according to claim 1 or 2, wherein the group represents -alkyl-, which group is optionally substituted with 1 to 4 substituents selected from methyl, methoxy, hydroxy, and fluoro.

4. R 1 But C 1 -C 3 -Alkyl, C 1 -C 2 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 4 -cycloalkyl, C 4 -C 5 -heterocycloalkyl-, C 3 -C 4 -cycloalkyl-O-C 1 -C 3 -alkyl-, the latter group optionally being C 1 -C 4 -Alkyl, C 1 -C 4 -alkoxy, C 3 -C 4 The compound according to any one of claims 1 to 3, which is optionally substituted with 1 to 4 substituents selected from -cycloalkoxy, hydroxy, and fluoro.

5. R 2 , R 3 , R 4 and R 5 are each independently hydrogen, fluoro, chloro, bromo, cyano, methyl, cyclopropyl, or methoxy, and the latter three groups may optionally be substituted with 2 to 3 fluorine atoms.

6. R 6 C optionally substituted with 2 to 3 fluorine atoms 1 -C 3 6. A compound according to any one of claims 1 to 5, wherein - represents alkyl.

7. A is, 【Transformation 3】 7. A compound according to any one of claims 1 to 6, wherein R represents a group selected from the group comprising:

8. R 1 is ethyl, -CH 2 -CHF 2 8. The compound according to claim 1, wherein the substituents are selected from the group consisting of , and isopropyl.

9. R 2 represents hydrogen; R 3 represents hydrogen, methyl and trifluoromethyl; R 4 represents hydrogen, fluoro, chloro, bromo, cyano, methyl and trifluoromethyl; R 5 represents hydrogen, methyl and methoxy; 9. A compound according to any one of claims 1 to 8.

10. R 6 is methyl, trifluoromethyl and —CF 2 10. A compound according to any one of claims 1 to 9, wherein R represents H. 【Request Item 11】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 11. The compound according to any one of claims 1 to 10, which is a compound selected from the group consisting of:

12. 12. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 11.

13. 13. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12 for use as a pharmaceutical.

14. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12.

15. 13. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12 for use in the treatment or prevention of a disease or disorder in which inhibition of metabotropic glutamate receptor subtype 4 (mGluR4) activity is of therapeutic benefit.

16. 16. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12, for use according to claim 15, wherein the mGluR4 mediated condition or disorder is a psychiatric, neurological, neurodegenerative, non-neurological or metabolic disease, cancer or a related disorder.

17. 16. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt according to claim 12, for use according to claim 16, wherein the disease or disorder is selected from the group consisting of impulse control deficits or maladaptive impulsivity; substance use disorders; personality disorders, such as borderline personality disorder, antisocial personality disorder, behavioral disorders; eating disorders, such as binge eating disorder; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, such as post-traumatic stress disorder; tic disorders, such as Tourette's syndrome; movement disorders, such as restless legs disorder; cognitive decline in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancer and related disorders associated with maladaptive tumorigenesis, such as osteosarcoma.

18. 13. A method for treating an mGluR4-mediated disorder in a subject, the method comprising administering to the subject an effective amount of a compound described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof described in claim 12.

19. 19. The method of claim 18, wherein the mGluR4-mediated condition or disorder is a psychiatric, neurological, neurodegenerative, non-neurological or metabolic disease, cancer or a related disorder.

20. 20. The method of claim 19, wherein the psychiatric, neurological, neurodegenerative, non-neurological disease, cancer or related disorder is selected from the group consisting of impulse control deficits or maladaptive impulsivity; substance use disorders; personality disorders, such as borderline personality disorder, antisocial personality disorder, behavioral disorders; eating disorders, such as binge eating disorder; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, such as post-traumatic stress disorder; tic disorders, such as Tourette's syndrome; movement disorders, such as restless legs disorder; cognitive decline in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancer and related disorders associated with maladaptive tumorigenesis, such as osteosarcoma.

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