Novel substituted pyrazinecarboxamide derivatives

Abstract

The present invention relates to compounds of formula I, processes for their manufacture, pharmaceutical compositions comprising them and their use in therapy, in particular in the treatment and / or prevention of conditions associated with the function of the metabotropic glutamate receptor subtype 4 (mGluR4). A, R1, R2, R3, R4, R5 and R6 have the meanings given in the specification. # imgabs0 #

Description

FIELD OF THE INVENTION

[0001] The present invention relates to substituted pyrazine-carboxamide derivatives, pharmaceutical compositions comprising them and their use in therapy, in particular in the treatment and / or prevention of neuronal and non-neuronal disorders associated with mGluR4 function. BACKGROUND OF THE INVENTION

[0002] L-Glutamic acid (referred to herein as glutamate) is one of the most abundant excitatory neurotransmitters in the vertebrate brain. Dysfunction of the brain glutamate system typically gives rise to neurological or psychiatric disorders. Thus, modulation of the glutamatergic system is regarded as an attractive therapeutic approach.

[0003] Glutamate acts via different 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 action by coupling to G proteins and activating second messenger systems.

[0004] mGluR subtypes are divided into three groups (distinguished by sequence homology, pharmacology, second messenger systems), where Group III is the largest group (mGluR4, mGluR6, mGluR7, mGluR8) (Conn and Pin, Annu Rev Pharmacol Toxicol, 1997, 37:205-237). Group III mGlu receptors are mainly expressed presynaptically (Schoepp, Pharmacol Exp Ther, 2001, 299:12-20), where the receptors modulate glutamatergic as well as GABAergic transmission. Activation of Group III receptors, including mGluR4, reduces neurotransmitter release due to their activation of Gαi / o, resulting in attenuated adenylate cyclase activity.

[0005] The mGluR4 receptor is mainly located in the presynaptic terminals of nerve endings. The expression of mGluR4 has been confirmed in multiple brain regions, with high expression in the basal ganglia, cerebellum, and other brain regions. Due to the expression of mGluR4 in relevant brain circuits and its role in regulating neurotransmitter release, mGluR4 modulators are considered to have an impact on the regulation of motor control (including Parkinson's Disease), impulse control, learning and memory, cognition, anxiety, pain, cerebellar function, epilepsy, and the excitatory / inhibitory 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 Physiol Res, 2012, 61:619-628), but not limited to these effects.

[0006] Since mGluR4 has also been reported to be expressed in peripheral tissues such as (but not limited to) islets of Langerhans, antagonists of mGluR4 function are also considered to have therapeutic effects in conditions including but not limited to metabolic disorders, gastrointestinal 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).

[0007] Since mGluR4 has also been reported to be expressed in vagal afferents and within the central satiety pathways and brain circuits, antagonists of mGluR4 function are also considered to have therapeutic effects in conditions 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).

[0008] WO21028512 describes arylsulfonamides as mGluR4 NAMs. However, the activity of those compounds appears to be too low to be useful as drugs, especially since acidic arylsulfonamides may also be prone to efflux at the blood-brain barrier, thus limiting their brain exposure for CNS applications. Detailed Description

[0009] The present invention provides novel substituted pyrazine-carboxamide derivatives which are unexpectedly potent mGluR4 negative modulators, i.e., compounds of formula I (Embodiment 1) wherein A represents 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-, 4-6 membered heterocycloalkyl-, 4-6 membered heterocycloalkyl-C 1 -C 3 alkyl-, the latter groups optionally being substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, fluoro; R 1 represents 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-, 4-6 membered heterocycloalkylmethyl-, C 5 -C 6 heterocycloalkylethyl-, the latter groups optionally being substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7substituted with 1 to 4 substituents of cycloalkyloxy, hydroxy, and fluorine; R 2 、R 3 、R 4 and R 5 each independently represents 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- to 6-membered C 4 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy-, C 3 -C 6 cycloalkyloxy-, the latter six groups optionally substituted with 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, and fluorine; provided that at least one of the groups R 2 、R 3 、R 4 and R 5 is not hydrogen; R 6 represents halogen optionally substituted with 2 to 3 fluorine atoms, C 1 -C 3 alkyl; or a physiologically acceptable salt thereof.

[0010] In another embodiment, in the general formula I according to any one of the foregoing embodiments, A represents C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 5 cycloalkylmethyl-, tetrahydrofuranyl-, tetrahydropyranyl-, 1,4-dioxanyl, tetrahydrofuranylmethyl-, tetrahydropyranylpyranylmethyl-, 1,4-dioxanylmethyl-, C 1 -C 2 alkyl-O-C 1 -C 2 alkyl-, the latter group optionally substituted with 1 to 4 substituents selected from methyl, methoxy, hydroxy, and fluorine.

[0011] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 1 represents 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-, with the latter group optionally being substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 4 cycloalkoxy, hydroxy, fluorine.

[0012] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 2 、R 3 、R 4 and R 5 each independently represent hydrogen, fluorine, chlorine, bromine, cyano, methyl, cyclopropyl, methoxy, with the latter three groups optionally being substituted by 2 to 3 fluorine substituents, provided that at least one of the groups R 2 、R 3 、R 4 and R 5 is not hydrogen.

[0013] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 6 represents C 1 -C 3 alkyl optionally substituted by 2 to 3 fluorine atoms.

[0014] In another embodiment, in the general formula I according to any one of the foregoing embodiments, A represents a group selected from the group consisting of:

[0015] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 1 represents a substituent selected from the group consisting of:

[0016] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 2 represents hydrogen.

[0017] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 3 represents hydrogen, fluorine, bromine and trifluoromethyl.

[0018] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, CF 3 O- and CHF 2 O-.

[0019] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 5 represents hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl and methoxy.

[0020] In another embodiment, in the general formula I according to any one of the foregoing embodiments, R 6 represents methyl, trifluoromethyl and -CF 2 H.

[0021] The compounds of the present invention are potent mGluR4 negative regulators that inhibit the function of mGluR4, thereby blocking glutamate-induced reduction of intracellular cAMP.

[0022] Accordingly, the present invention provides a compound for treating mGluR4-mediated disorders.

[0023] The present invention further provides a method for treating mGluR4-mediated disorders in a human subject, the method comprising administering to the subject a compound of the present invention or a composition of the compound or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, the present invention relates to a method of treating a condition in which reducing mGluR4 activity reduces the severity of the condition by administering a compound that inhibits mGluR4 function, such as a compound as described herein that inhibits glutamate-induced intracellular cAMP reduction. Described herein are compounds that are antagonists of mGluR4 function, which have an IC 50 of 100 nanomolar concentration, preferably 50 nM or less.

[0025] In another aspect, the compounds described herein that are antagonists of mGluR4 function can be used to inhibit the function of mGluR4, such as mGluR4-mediated glutamate-induced intracellular cAMP reduction. In some embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction in vitro (e.g., in cells in culture). In other embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction in vivo.

[0026] Definitions Terms not specifically defined herein should be given the meaning that would be ascribed to them by one of ordinary skill in the art in light of the present disclosure and the context.

[0027] The terms "negative modulator", "antagonist", and "inhibitor" are used interchangeably to refer to a reagent that reduces or inhibits biological activity (e.g., reduces the activity of a receptor) and includes negative allosteric modulators (NAMs). The mGluR4 receptor as described herein includes homomeric and heteromeric structures (e.g., homomeric mGluR4 and heteromeric mGluR4-mGluR2). Inhibitors of mGluR4 function include inhibitors having any combination of the structural and / or functional properties disclosed herein.

[0028] With respect to the inhibitory or therapeutic methods of the present invention, an "effective amount" of an (mGluR4) antagonist refers to the amount of the antagonist in a formulation that, when administered as part of a desired dosage regimen, elicits a desired clinical or functional outcome. Without being bound by theory, the effective amount of an mGluR4 antagonist for the methods of the present invention includes the amount of the mGluR4 antagonist that can effectively reduce one or more in vitro or in vivo functions of the mGluR4 receptor. Exemplary functions include, but are not limited to, altering intracellular cAMP or synaptic neurotransmitter release, or altering neuronal activity or modulating 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 the compound to inhibit mGluR4 function in that in vitro assay serves as a reasonable representation of the activity of the compound. In certain embodiments, the effective amount is an amount sufficient to inhibit mGluR4-mediated cellular function.

[0029] The mGluR4 antagonists for the methods of the present invention can be characterized according to their activity or lack of activity towards one or more receptors. When referring to other receptors, inhibition of the functions of such other receptors is similarly defined. For example, inhibition of a receptor or the activity of a receptor refers to an antagonist inhibiting one or more functional activities of another receptor. Such functions include, for example, signal transduction across cell membranes and / or changes in the intracellular concentration of intracellular substances (such as cAMP mediated by a specific receptor) and subsequent functions (such as neurotransmitter release).

[0030] The terms "compound" and "reagent" are used interchangeably to refer to the negative modulators of the present invention.

[0031] In the groups or moieties defined below, the number of carbon atoms is usually specified before the group. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms. Generally, for a group containing two or more sub-groups, the last-mentioned sub-group is the group attachment point. For example, the substituent "aryl-C1-3 alkyl-" refers to an aryl group attached to the C1-3 alkyl- group, and the latter is attached to the core or the group to which the substituent is attached.

[0032] In cases where the compounds of the present invention are depicted in chemical names and chemical formulas, if there are any inconsistencies, the chemical formula shall prevail.

[0033] An asterisk can be used in a sub-formula to indicate a bond attached to the core molecule as defined.

[0034] Stereochemistry / Solvate / Hydrate The compounds described herein may be chiral (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the invention containing an asymmetrically substituted carbon atom may be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, e.g., by resolution of a racemic mixture or by stereoselective synthesis.

[0035] Resolution of a racemic mixture of a compound may be carried out by any of a number of methods known in the art. One exemplary method involves fractional recrystallization using a "chiral resolving agent", which is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids (e.g., β-camphorsulfonic acid). Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., the S- and R-forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane.

[0036] Resolution of a racemic mixture may also be carried out by column elution with an optically active resolving agent (e.g., dinitrobenzoyl phenylglycine). Suitable elution solvent compositions may be determined by one of ordinary skill in the art. Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

[0037] Unless otherwise specifically indicated, throughout this specification and the appended claims, a given chemical formula or name shall cover its tautomers and all stereoisomers, optical isomers, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers) and their racemates, as well as mixtures of the individual enantiomers in different ratios, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers are present.

[0038] Compounds of the invention may also include all isotopes of atoms present in the intermediates or final compounds. For example, compounds of the invention may be radiolabeled with radioactive isotopes such as tritium ( 3 H) or carbon-14 ( 14 C). All isotopic variants, whether radioactive or not, are intended to be covered within the scope of the invention.

[0039] Salt The phrase "pharmaceutically acceptable" as used herein refers to those compounds, substances, compositions, and / or dosage forms that are suitable for use within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0040] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the invention in which the parent compound is reacted with an acid or a base to form a salt.

[0041] Examples of acids which form pharmaceutically acceptable salts with parent compounds 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, and tartaric acid. Also included are salts of amino acids such as arginine, and salts of 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).

[0042] The neutral form of the compounds of the invention is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but otherwise the salt is equivalent to the parent form of the compound for the purposes of the invention.

[0043] Halogen The term halogen generally denotes fluorine, chlorine, bromine, and iodine.

[0044] Alkyl The term "C 1 -n-alkyl" (where n is an integer from 2 to n) alone or in combination with another group denotes a non-cyclic saturated branched or straight-chain hydrocarbon radical having from 1 to n C atoms. For example, the term C 1 -C 5 alkyl encompasses the groups H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3C-CH 2 -CH(CH 3 )-、H 3 C-CH(CH 3 )-CH 2 -、H 3 C-C(CH 3 ) 2 -、H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -、H 3 C-CH 2 -CH 2 -CH(CH 3 )-、H 3 C-CH 2 -CH(CH 3 )-CH 2 -、H 3 C-CH(CH 3 )-CH 2 -CH 2 -、H 3 C-CH 2 -C(CH 3 ) 2 -、H 3 C-C(CH 3 ) 2 -CH 2 -、H 3 C-CH(CH 3 )-CH(CH 3 )- and H 3 C-CH 2 -CH(CH 2 CH 3 )-.

[0045] Cycloalkyl The term "C 3 -n-cycloalkyl" (where n is an integer from 4 to n) alone or in combination with another group represents a cyclic saturated non-branched hydrocarbon group having 3 to n C atoms. For example, the term C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0046] Heterocycloalkyl The term "heterocycloalkyl" refers to a saturated or unsaturated monocyclic or polycyclic system, including an aromatic ring system 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 where the heteroatoms are not part of the aromatic ring.

[0047] Many of the terms given above may be used repeatedly to define chemical formulas or groups and, in each case, independently have one of the meanings given above.

[0048] According to the present invention, the compounds of general formula (I) are obtained by methods known per se, for example by the following methods: (a) Preparation of the compounds of general formula (I), where A and R 1 to R 6 are defined as described in embodiment 1, and may optionally be protected at any amino, hydroxy, carboxy or thiol group by conventional protecting groups, such as those described in T.W. Greene, P.G.M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and protecting groups cleavable by methods known from the literature, are described in the examples or may be carried out according to a combination of reaction steps in process 1, for example according to the following formula.

[0049] Process 1 where Q represents a leaving group or a group convertible in situ into a leaving group, such as a halogen atom, hydroxy, C 1-4 alkoxy, alkoxycarbonyloxy, 4-pentafluorophenoxy, nitrophenoxy, trichloromethyl or acyloxy, or together with a carbonyl group represents a basic carboxylate group, and R11 represents a protecting group known from the literature for a carboxylic acid ester functional group, such as tert-butyl, methyl, ethyl, allyl or benzyl, and R12 represents a protecting group known from the literature for an amino functional group, such as tert-butoxycarbonyl, benzyloxycarbonyl or trifluoroacetyl, and R13 represents a leaving group for an alkylation reaction, such as an iodine or bromine atom or a toluenesulfonate or methanesulfonate group, and R14 represents a leaving group for a nucleophilic aromatic substitution reaction, such as a fluorine or chlorine atom.

[0050] The reaction step i (substitution) shown in process 1 can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: In a solvent such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution or sulfolane, optionally in the presence of an inorganic or organic base such as potassium carbonate, sodium hydride, triethylamine or Hünig's base, at a temperature between -20 °C and 200 °C, but preferably at a temperature between -10 °C and 100 °C, the compound of formula II is mixed with the compound of formula XIII.

[0051] Reaction step ix (substitution followed by nitro reduction) shown in Scheme 1 can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: Substitute the substrate IX with the amine XII as described above, and then carry out nitro reduction as described below: The nitro reduction to generate an amino group can be carried out in an aqueous solvent, such as in water, isopropanol / water, tetrahydrofuran / water or 1,4-dioxane / water, or in a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid and in the presence of a reducing metal such as zinc, iron, magnesium or calcium, or in the presence of a reducing agent such as triphenylphosphine or lithium aluminum hydride, at a temperature between -40 °C and 100 °C, preferably at a temperature between -10 °C and 50 °C. Alternatively, it can be carried out in the presence of a catalyst such as palladium / charcoal, Raney nickel or platinum, in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally in the presence of an added acid such as hydrochloric acid, at a temperature between -20 °C and 50 °C, but preferably at 0 °C to ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar, using hydrogen to achieve reduction.

[0052] Reaction steps ii and iv (acylation) can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: By acylating the amine (III or IV) with an optionally activated carboxylic acid (XI): In a solvent such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution or sulfolane, optionally in the presence of an inorganic or organic base such as potassium carbonate, sodium hydride, triethylamine or Hünig's base, at a temperature between -20 °C and 200 °C, but preferably at a temperature between -10 °C and 100 °C, conveniently carry out acylation with the corresponding halide or acid anhydride.

[0053] However, it is also possible, optionally in the presence of an acid activator or a dehydrating agent, such as in the presence of ethyl-1-ethoxy-1,2-dihydroquinoline-1-carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, propane phosphonic cyclic anhydride, N,N'-dicyclohexylcarbodiimide, 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 / 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'-sulfonyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of an auxiliary base such as sodium hydroxide solution, cesium, potassium or sodium carbonate or bicarbonate, or an amine base such as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine, at a temperature between -20 °C and 200 °C, but preferably at a temperature between -10 °C and 160 °C, with a free acid for acylation.

[0054] Other amide coupling methods are described, for example, in P.D. Bailey, I.D. Collier, K.M. Morgan, "Comprehensive Functional Group Interconversions", Volume 5, pages 257ff., Pergamon 1995, or Houben-Weyl, Supplement, Volume 22, published by Thieme, 2003 and the literature cited therein.

[0055] Reaction step viii (acylation followed by deprotection) can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: Acylate the amine-bearing substrate VIII with reagent XI as described above, and then cleave the protecting group as described below: Any protecting group used may optionally be cleaved subsequently, for example by hydrolysis in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or 1,4-dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage in the presence of, for example, iodotrimethylsilane at a temperature between 0 °C and 100 °C, preferably at a temperature between 10 °C and 50 °C.

[0056] However, benzyl, methoxybenzyl or benzyloxycarbonyl are cleaved by hydrogenolysis with hydrogen, for example, in the presence of a catalyst such as palladium / charcoal in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally in the presence of an added acid such as hydrochloric acid, at a temperature between 0 °C and 50 °C, but preferably at ambient temperature and at a hydrogen pressure of 1 to 7 bar, but preferably at a hydrogen pressure of 1 to 5 bar.

[0057] However, the protecting groups can also be cleaved by the methods described by T.W. Greene, P.G.M. Wuts in “Protective Groups in Organic Synthesis”, Wiley, 1991 and 1999.

[0058] Reaction steps iii and v (acylation, followed by cyclization) can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: Acylation of the amine-bearing substrate VI or VII with the free carboxylic acid V as described above, followed by cyclization as described below: Cyclization is conveniently carried out in a solvent or solvent mixture (such as ethanol, isopropanol, acetic acid, benzene, chlorobenzene, toluene, xylene, ethylene glycol, glycol monomethyl ether, diglyme, sulfolane, dimethylformamide or tetralin, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride), for example at a temperature between 0 °C and 250 °C, but preferably between 20 °C and 100 °C, optionally in the presence of a condensing agent such as phosphorus oxychloride, 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 also in the presence of a base such as potassium methoxide or potassium tert-butoxide or in the presence of a metal salt such as lithium bromide, aluminum bromide, zinc bromide or aluminum-doped montmorillonite clay. However, cyclization can also be carried out without a solvent and / or without a condensing agent.

[0059] Reaction steps vi and vii (acylation, followed by deprotection and cyclization) can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: The amine-bearing substrate VI is acylated with reagent X as described above, followed by cleavage of the protecting group as described above and then cyclization as described above.

[0060] Reaction step x (acylation, followed by deprotection) shown in Scheme 1 can be carried out in the manner described in the examples or according to conditions known from the literature, for example as follows: The substrate VI is acylated with carboxylic acid or carboxylic acid derivative X as described above, followed by deprotection as described above.

[0061] 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 from the literature, for example as follows: The substrate XIV is acylated with carboxylic acid or carboxylic acid derivative XI as described above, followed by cyclization as described above.

[0062] Throughout the application, the terms "mGluR4", "mGluR4 protein" and "mGluR4 receptor" are used interchangeably. Unless otherwise specified, the term mGluR4 includes homomeric structures (such as homomeric mGluR4) and heteromeric structures (such as heteromeric mGluR4-mGluR2).

[0063] Biological assay The biological activity of the compounds was determined by the following methods: A. In vitro test of mGluR4 potency

[0064] The in vitro activity of the compounds according to the invention can be studied as follows:

[0065] HEK293 cells overexpressing the human metabotropic glutamate receptor 4 were thawed at 37 °C and immediately diluted with cell culture medium. After centrifugation, the cell pellet was resuspended in the medium and then distributed from a stirred spinner flask into the wells of a measurement plate. The plate was incubated at room temperature for one hour and then at 37 °C / 5% CO2 for 24 hours. After washing the cells in the plate three times with 80 μL of HBSS / HEPES buffer (10 μL of buffer remained in the wells after washing), 5 μL / well of the 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 measurement plate. Thereafter, 5 μL / well of L-glutamate (final concentration: 10 μM), forskolin (final concentration: 1 μM), and 1 mM IBMX (final concentration: 0.5 mM) (final DMSO concentration: 1%) dissolved in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) was added to the measurement plate. Several wells of the measurement plate were used for positive and negative controls or for the cAMP standard curve. The measurement plate was incubated at room temperature for 30 minutes. Next, 5 μL / well of the anti-cAMP-antibody-d2 solution and 5 μL / well of the cAMP-europium cryptate dilution were added to all wells of the plate, and the plate was incubated for an additional 60 minutes at room temperature in the dark. TM Emission at 615 nm and 665 nm (excitation wavelength: 320 nm) was measured on an EnVision

[0066] The cAMP standards were prepared by diluting a cAMP stock solution with HBSS / HEPES buffer: 5 μL / well of the cAMP dilution (in HBSS / HEPES buffer containing 1 mM IBMX and 0.2% BSA - final concentration: 0.5 mM IBMX and 0.1% BSA) was added to 10 μL / well of HBSS / HEPES buffer plus 5 μL / well of HBSS / HEPES containing 0.2% BSA with 4% DMSO (final DMSO concentration: 1%, the same as the wells containing the compound) located in the wells of the measurement plate. The final cAMP concentrations in the measurement plate were: 0, 0.17, 0.69, 2.78, 11.1, 44.5, 178, and 712 nM (two wells / cAMP concentration).

[0067] Each microtiter plate for measurement also contains wells with vehicle control instead of compound as a control for the L - glutamate - induced signal (negative control; 100% CTL; 10 μM L - glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO), and wells with vehicle control without L - glutamate as a control for non - specific changes in the signal (positive control; 0% CTL; 0 μM L - glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO).

[0068] Data analysis is performed by calculating the ratio of the emission at 665 nm to the emission at 615 nm (Em665 / Em615 ratio). Subsequently, the signal of the compound is normalized using the positive and negative controls by the following formula: PoC = 100×((signal sample - positive control) / (negative control - positive control))

[0069] B. Evaluation of metabolic stability in human liver microsomes (human MST)

[0070] The metabolic stability of the compounds of the present invention can be studied as follows: The metabolic degradation of the test compound is analyzed using pooled human liver microsomes at 37°C. The final incubation volume of 100 μL at each time point contains TRIS buffer pH 7.6 (0.1 M) at room temperature, MgCl 2 (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM. After a short pre - incubation period at 37°C, the reaction is initiated by adding reduced form of β - nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and the reaction is terminated by transferring aliquots to the solvent at different time points. After centrifugation (10,000 g, 5 min), aliquots of the supernatant are analyzed by LC - MS / MS for the amount of the parent compound. The half - life (t 1 / 2 ) is determined by the slope of the semi - log curve of the concentration - time curve.

[0071] C. Evaluation of efflux in Madin - Darby canine kidney (MDCK) cells transfected with the human MDR1 gene

[0072] The apparent permeability coefficient (PE) of a compound across the MDCK-MDR1 cell monolayer was measured in the top-to-bottom (AB) and bottom-to-top (BA) transport directions (pH 7.4, 37 °C). The AB permeability (PEAB) represents the drug absorption rate from blood to brain and the BA permeability (PEBA) represents the drug efflux rate from brain back to blood via passive diffusion and active transport mechanisms mediated by efflux and uptake transporters expressed on MDCK-MDR1 cells, predominantly by overexpressed human MDR1 P-gp. The permeability / absorption class of a compound was assigned by comparing the AB permeability of the compound with that of a reference compound with known in vitro permeability and oral absorption in humans. Similar or identical permeabilities in both transport directions indicate passive diffusion, and vectorial permeability indicates additional active transport mechanisms. A higher PEBA than PEAB indicates involvement of active efflux mediated by MDR1 P-gp. Active transport is concentration-dependent and saturable.

[0073] MDCK-MDR1 cells (1 - 2×10e5 cells / 1 cm2 area) were seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 7 days. Subsequently, MDR1 expression was enhanced by culturing the cells with 5 mM sodium butyrate in complete medium for 2 days. The compound was dissolved in a suitable solvent (such as DMSO, 1 - 20 mM stock solution). Using HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO 4 , 1.8 mM CaCl 2 , 4.17 mM NaHCO 3 , 1.19 mM Na 2 HPO 4 ×7H 2 O, 0.41 mM NaH 2 PO 4 ×H 2Dilute the stock solution in O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4 to prepare the delivery solution (0.1 - 300 μM compound, final DMSO ≤ 0.5%). Apply the delivery solution (TL) to the top or bottom outer donor side for measuring A - B or B - A permeability respectively (3 filter replicates). The receiver side contains the same buffer as the donor side. Collect samples from the donor at the start and end of the experiment and from the receiver side at various time intervals up to 2 hours for concentration measurement by HPLC - MS / MS or scintillation counting. Replace the receiver volume with fresh receiver solution after sampling.

[0074] D. Efficacy assessment of impulsive behavior tested in the five - choice serial reaction time task (5 - CSRTT) in rats

[0075] The efficacy assessment of locomotor impulsive behavior can be studied as follows: The 5 - CSRTT task training was conducted according to a standard protocol (Isherwood et al., Neuropharmacology 2017, 123:249 - 260). Briefly, rats were trained to nose - poke at the location of a light cue presented at one of 5 positions on the curved wall of an operant chamber (Med Associates Inc, St. Albans, Vermont). If a nose - poke occurred at the illuminated position during or within 1 s after the stimulus presentation, a sugar pellet was delivered to a reward receptacle located in the chamber. Infrared beams in each choice hole and the reward receptacle allowed precise detection of the rats during this task - related operation. Locomotor impulsive behavior was defined as any response of nose - poking the hole that occurred before the onset of the light cue (premature response).

[0076] After achieving stable performance, a new analytical method was applied, which revealed the trait (long - term) stability of the number of premature responses made by individual animals over several months. Generally, this analysis made it possible to stably classify animals into high - impulsive and low - impulsive groups based on the longitudinal assessment of the number of premature responses of animals during training.

[0077] The experiments were conducted in a crossover manner such that all experimental subjects received both vehicle and compound on separate days, with an interval of approximately 2 weeks between each administration. The order of vehicle and compound administration was randomized within the experimental subjects, and a third group received atomoxetine on both experimental days as a technical control.

[0078] As a standardized numerical limit of the impulse level, animals in the vehicle with >40 and <40 premature responses (in 200 initial trials) were labeled as high impulse and low impulse, respectively. Importantly, the labeling based on the numerical limit overlapped >80% with the longitudinal analysis of the training data (described above). The high convergence of these two stratification methods enabled a stable comparison of the compound effects in stably high-impulse rats and stably low-impulse rats in the 5-CSRTT.

[0079] Biological data Table 1: In vitro potency of the structurally closest compounds disclosed in WO2019 / 138017 (as determined in Assay A)

[0080] The compounds of the present invention are structurally different from the structurally closest compounds in the art (i.e., Examples 8, 12, 125, and Intermediate 250 in WO 2019 / 138017) in that the hetero monocyclic ring bonded as a formamide is a pyrazine (6-membered heteroaryl) group instead of a pyrazole or isoxazole moiety (5-membered heteroaryl). Although the structurally closest compounds disclosed in WO2019 / 138017 are immunomodulators (IL-17 modulators) as disclosed therein, the compounds of the present invention are unexpectedly highly potent negative mGluR4 modulators (see Table 2). The structurally closest compounds disclosed in WO2019 / 138017 were tested in Assay A and found to have no therapeutically relevant activity as mGluR4 modulators (Table 1). Unexpectedly, the compounds of the present invention have a potency >100-fold in Assay A. (Compare the data in Table 1 and Table 2).

[0081] Table 2: In vitro potency of the compounds of the present invention as determined in Assay A

[0082] Use in a method of treatment / use The present invention relates to compounds that can be used for the treatment and / or prevention of diseases, disorders, and conditions, where inhibition of mGluR4 activity is therapeutically beneficial, said therapeutic benefits including but not limited to the treatment of psychiatric and neurological conditions associated with impulse control deficits or maladaptive impulses. Such impulse control deficits are seen in addictions, including substance use disorders; personality disorders, such as borderline personality disorder, antisocial personality disorder, conduct disorder, eating disorders (e.g., bulimia nervosa), attention deficit hyperactivity disorder, bipolar disorder, stress-related conditions (e.g., post-traumatic stress disorder), tic disorders (such as Tourette's syndrome), other movement disorders (e.g., restless legs syndrome). According to another aspect of the present invention, the compounds of the invention can be used for the treatment of mGluR4-related pathophysiological disorders, cognition, locomotor behavior / reward, mood and stress, aggression. Additionally, there is a therapeutic benefit in cancer and related conditions associated with maladaptive tumorigenesis, such as osteosarcoma. According to another aspect of the present invention, the compounds of the invention can be used to treat metabolic disorders through mGluR4-related regulation of the satiety pathway and / or signaling to treat conditions including but not limited to obesity.

[0083] In view of the pharmacological effects of the compounds of the present invention, they are suitable for the treatment and / or prevention of diseases or conditions selected from the list consisting of: (1) Conditions associated with impulse control disorders, such as pathological gambling, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, compulsive shopping disorder, internet addiction, sexual compulsivity, sexual disorders, sexual dysfunction, psychosexual disorders, eating disorders (e.g., bulimia nervosa, binge eating disorder, anorexia nervosa, other specified feeding or eating disorders), obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi syndrome, binge eating, appetite / taste conditions, bipolar disorder, post-traumatic stress disorder; (2) Substance abuse / dependence / seeking or addiction and relapse prevention (including but not limited to drugs, such as cocaine; opioids, such as morphine, barbiturates, benzodiazepines, amphetamines, nicotine / tobacco, and other psychostimulants), alcoholism and alcohol-related conditions, drug abuse or addiction or relapse, narcotic tolerance or withdrawal from narcotics; (3) Disorders of the central nervous system, such as anxiety disorders (e.g., generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, adjustment disorder with anxiety, separation anxiety disorder, specific phobia, agoraphobia, other specified anxiety disorder, unspecified anxiety disorder), depression (e.g., major depressive disorder, persistent depressive disorder, bipolar disorder, other specified depressive disorder, unspecified depressive disorder), schizophrenia, schizoaffective disorder, delusional disorder, schizotypal personality disorder, autism spectrum disorder, attention deficit hyperactivity disorder, Tourette's syndrome, other tic disorders, movement disorders (e.g., Parkinson's disease, Huntington's disease, dystonia, tremors, other movement disorders), cognitive disorders (e.g., Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementia, other specified dementia, unspecified dementia), sleep disorders (e.g., insomnia, hypersomnia, narcolepsy, sleep apnea, other sleep disorders), epilepsy, migraine, neuropathic pain, fibromyalgia, chronic fatigue syndrome, and other central nervous system disorders; (3) Psychiatric and neurological conditions such as attention deficit hyperactivity disorder, conduct disorder, attention problems and related disorders, sleep disorders, anxiety disorders (e.g., generalized anxiety), panic disorder, phobias, post-traumatic stress disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Gilles de la Tourette's syndrome, restless legs syndrome, dementia, movement disorders, severe mental retardation, neurodegenerative disorders including disease classification entities (e.g., disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-pontine-nigral degeneration, mood disorders, bipolar disorder, mania, depression, manic depression, borderline personality disorder, antisocial personality disorder, aggression (e.g., impulsive aggression), suicidal tendencies, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neuropathy / disorder, depressive neuropathy / disorder, anxiety neuropathy, psychotic depression, neurological diseases (e.g., cerebral edema and angioedema), cerebral dementia (such as Parkinson's disease, Alzheimer's disease, senile dementia); multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, epileptic seizures, stroke, myasthenia gravis, brain and meninges infections such as encephalomyelitis, meningitis, HIV, and schizophrenia, delusional disorder, autism, affective disorder, and tic disorders including but not limited to Tourette's syndrome and other movement disorders, epilepsy, chronic pain; (4) Cognitive dysfunction in psychiatric or neurological conditions, cognitive impairment associated with schizophrenia, Alzheimer's disease, and other neurological and psychiatric conditions; (5) Personality disorders such as 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 unspecified personality disorders; (6) Sleep disorders such as narcolepsy, jet lag, sleep apnea, insomnia, parasomnia, circadian and diurnal rhythm disorders, sleep disorders associated with psychiatric and neurological conditions; (7) Non-neuronal conditions including metabolic conditions such as diabetes, insulin resistance, metabolic syndrome, overweight, obesity, and for weight loss, aesthetic weight loss, prevention of recurrence during or after obesity treatment, weight maintenance, vomiting, conditions associated with cardiovascular system disorders, and conditions associated with maladaptive blood pressure control such as hypertension or hypotension; (8) Cancers and related conditions associated with maladaptive tumorigenesis such as osteosarcoma, breast cancer, ependymoma, bladder cancer, colorectal cancer.

[0084] The applicable daily dose of the compounds of the present invention can vary within the range of 0.1 to 2000 mg.

[0085] 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. In any case, the dosage and manner of administration of the drug substance are such that a pharmaceutically effective amount suitable for the patient's condition can be delivered.

[0086] 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, dragees, solutions, syrups, elixirs, cachets, injectables, inhalants, and powders. The content of the pharmaceutically active compound can vary within the range of 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-%, of the overall composition.

[0087] Suitable tablets can be obtained 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.

[0088] Combination therapy The compounds according to the present invention can be combined with other treatment options known in the art for treating any complications, the treatment of which is the focus of the present invention.

[0089] Among such active pharmaceutical ingredients or treatment options that are considered suitable for combination with the compounds and the treatment according to the present invention are antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptic drugs, antiparkinson drugs, sleep agents, cognitive enhancers, stimulants, drugs for attention deficit hyperactivity disorder, extra-psychoactive drugs, anti-inflammatory drugs, analgesic drugs, chemotherapeutic drugs, and combinations with treatment options for metabolic disorders, liver diseases, and kidney diseases.

[0090] Experimental section List of abbreviations: %Sol Percentage of solvent μL Microliter ACN Acetonitrile AcOH Acetic acid aq. Aqueous Boc tert-Butyloxycarbonyl Boc 2 O Di-tert-butyl dicarbonate chir. Chiral CIP 2-Chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate conc. Concentrated day d diode array DA diode array detector DAD dichloromethane DCM N,N-dimethylformamide DMF evaporative light scattering detector ELSD ethyl acetate EtOAc ethanol ETOH gram g hour h half-concentration half-conc. high performance liquid chromatography HPLC in vacuo i.vac. isopropyl alcohol IPA molarity M methanol MeOH methanol MEOH milligram mg minute min milliliter ml milliliter mL mass spectrometer MS normal N N-bromo-succinimide NBS N-methylmorpholine NMM N-methylpyrrolidone NMP petroleum ether PE 1-propane phosphonic anhydride PPA preparative prep. pounds per square inch PSI quantitative quant. retardation front Rf retention time RT saturated sat. supercritical carbon dioxide scCO2 supercritical fluid chromatography SFC O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate TBTU triethylamine TEA temperature Temp. tert-butyl tert. trifluoroacetic acid TFA tetrahydrofuran THF weight wt Chloro-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)-phenyl)]-palladium(II) X-Phos G1

[0091] Method: HPLC-MS Method: Method A Method B Method C

[0092] Chiral SFC Analysis Method: Method 1: Method 2: Method 3: Method 4: Method 5: Method 6: Method 7: Method 8: Method 9: Method 10: Method 11: Method 12: Method 13: Method 14: Method 15: Method 16: Method 17: Method 18: Method 19: Method 20: Method 21: Method 22: Method 23: Method 24: Method 25: Method 26: Method 27: Method 28: Method 29: Method 30: Method 31: Method 32: Method 33: Method 34: Method 35: Method 36: Method 37: Method 38: Method 39: Method 40: Method 41: Method 42: Method 43 Method 44: Method 45: Method 46: Method 47: Method 48: Method 49: Method 50: Method 51: Method 52: Method 53: Method 54: Method 55: Method 56: Method 57: Method 58: Method 59: Method 60: Method 61: Method 62: Method 63: Method 64: Method 65: Method 63: Method 64: Method 65: Method 66: Method 67: Method 68: Method 69: Method 70: Method 71 Method 72 Method 73 Method 74 Method 75 Method 76 Method 77 Method 78 Method 79 Method 80 Method 81 Method 82 Method 83 Method 84 Method 85 Method 86 Method 87 Method 88

[0093] NMR method: The NMR spectra were recorded on a Bruker AVANCE III HD 400 MHz instrument using TopSpin 3.2 pl6 software. Chemical shifts were given in parts per million (ppm) downfield from an internal reference (such as trimethylsilane and / or water and / or solvent (e.g., d6-DMSO)) expressed in δ units. The selected data were reported in the following manner: chemical shift (multiplicity, coupling constant (J), number of hydrogens). Abbreviations were as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad peak).

[0094] Examples: Example 1: Step 1: 1,4-Difluoro-2-nitro-benzene (1 g, 6.3 mmol) was mixed with 2N ethyl-amine solution in THF (15 mL, 30 mmol) and stirred at ambient temperature for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with water and filtered, washed with water and dried at ambient temperature. Yield: 1.13 g (6.1 mmol; 98%) Int-1a MS (ESI + ): (M+H) + 185; HPLC: RT = 1.05 min, method: Z018_S04 Step 2: Int-1a (100 mg, 0.54 mmol) was mixed with 50 mg of Raney nickel in 10 mL of THF and hydrogenated at 50 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. Yield: 80 mg (0.52 mmol; 96%) Int-1b MS (ESI + ): (M+H) + 155; HPLC: RT = 0.55 min, method: Z018_S04 Step 3: (2S)-2-Amino-2-cyclopropyl-ethyl acetate hydrochloride (2.9 g, 18 mmol) was mixed with 5-methyl-pyrazine-2-carboxylic acid (3.0 g, 22 mmol) and TEA (10 mL, 72 mmol) in 100 mL of THF at 0 °C, and CIP (5.2 g, 19 mmol) was added. After stirring at 0 °C for 30 min, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with Na 2 CO 3Washed with aqueous solution (0.5 N) and extracted with DCM, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in 40 mL of MeOH, mixed with aqueous NaOH solution (4 N, 6.0 mL, 24 mmol) and stirred at ambient temperature for 1 h. Subsequently, the mixture was acidified by adding AcOH, filtered, and the filtrate was purified by preparative HPLC (gradient (H 2 O + 0.15% TFA) / ACN: 9:1 -> 7:3, C-18 Sunfire, 50 °C). The eluate fractions containing the product were combined and lyophilized. Yield: 3.0 g (13 mmol; 73%) Int-1c MS (ESI + ): (M + H) + 236; HPLC: RT = 0.73 min, method: Z018_S04 Step 4: At 0 °C, PPA (50%, 280 μL, 0.48 mmol) was added to a mixture of Int-1b (80 mg, 0.52 mmol) and Int-1c (100 mg, 0.43 mmol) in 5 mL of DCM with NMM (160 μL, 1.5 mmol). The cooling was removed and the mixture was stirred for 45 min. 100 μL of water was added and the mixture was stirred at ambient temperature for 30 min. Subsequently, 5 mL of AcOH was added and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (gradient (H 2 O + 0.15% TFA) / ACN: 88:12 -> 68:32, C-18 Sunfire, 50 °C). The eluate fractions containing the product were combined and lyophilized. The residue was dissolved in MeOH and passed through a cartridge equipped with an ion exchange resin (Agilent PL-HCO3 MP SPE) and concentrated in vacuo. Yield: 110 mg (0.31 mmol; 73%) Example 1 Similar to Example 1, the following products were obtained: Similar to Example 1, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 19, 19-1, 19-2, 19-3 Similar to Example 1, the following products were obtained: Similar to Example 1, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 48, 48-1, 48-2, 48-3 Similar to Example 1, the following compounds were obtained. Similar to Example 1, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 70, 70-1, 70-2, 70-3 Similar to Example 1, the following compounds were obtained Similar to Example 1, the following compounds were obtained. The product is a mixture of four stereoisomers. Two stereoisomers were obtained by chiral SFC separation: Example 84, 84-1 Similar to Example 1, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 91, 91-1, 91-2, 91-3 Similar to Example 1, the following compounds were obtained: Similar to Example 1, the following compounds were obtained. The product was a mixture of four stereoisomers separated by chiral SFC: Example 97, 97-1, 97-2, 97-3 Similar to Example 1, the following compounds were obtained. Example 4: Step 1: A mixture of 1,4-difluoro-2-nitro-benzene (100 g; 0.63 mol) and 2,2-difluoroethylamine (266 mL; 3.8 mol) in 800 mL of ACN with K 2 CO 3 (400 g; 1.3 mol) was stirred at 80 °C for 2 days. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was used without further purification. Rf: 0.4 (PE / EtOAc 85:15) Yield: 105 g (0.48 mol; 76%) Int-4a MS (ESI + ): (M+H) + 221; HPLC: RT = 1.00 min, method: Z018_S04 Step 2: A mixture of Int-4a (50 g, 0.23 mol) with 10 g of Raney nickel in 500 mL of MeOH was hydrogenated at 50 psi (hydrogen) at ambient temperature for 4 h. Subsequently, the mixture was filtered, washed with EtOAc and concentrated in vacuo. The residue was used without further purification. Rf: 0.4 (PE / EtOAc 85:15) Yield: 45 g (0.22 mol; 98%) Int-4b MS (ESI + ): (M+H) + 191; HPLC: RT = 0.71 min, method: Z018_S04 Step 3: At 0 °C, PPA (50 wt% solution in EtOAc, 609 g, 0.96 mol) was added to a mixture of Int-4b (91 g, 0.48 mol) and (S)-Boc-amino-cyclopropyl-acetic acid (103 g, 0.48 mol) in 300 mL of pyridine. The mixture was stirred at ambient temperature for 16 h. 600 mL of water was added and the mixture was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was used without further purification. Yield: 125 g (0.32 mol; 67%) of Int-4c MS (ESI + ): (M+H) + 388; HPLC: RT = 1.02 min, method: Z011_S03 Step 4: Int-4c (100 g, 0.26 mol) was stirred in 300 mL of acetic acid at 40 °C for 2 days. Subsequently, the mixture was concentrated, 600 mL of water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with an aqueous solution of NaHCO 3 , dried over Na 2 SO 4 , filtered, and the filtrate was concentrated. The residue was purified by column chromatography (100 to 200 mesh silica gel, PE / EtOAc 7:3), the eluates containing the product were combined and all solvents were removed in vacuo. The residue was dissolved in ether and the solvent was evaporated. Yield: 70 g (0.19 mol; 73%) of Int-4d MS (ESI + ): (M+H) + 370; HPLC: RT = 1.17 min, method: Z003_S05 Step 5: To 50 mL of dioxane containing Int-4d (80 g, 0.22 mol) was added dioxane containing HCl (4 M, 100 mL) and the mixture was stirred at ambient temperature for 4 h. Subsequently, the mixture was filtered, and the solid was washed with ether and dried. Yield: 67 g (0.22 mol; quantitative) of Int-4e MS (ESI + ): (M+H) + 270; HPLC: RT = 0.83 min, method: Z011_S03 Step 6: To 70 mL of EtOAc containing 5-(difluoromethyl)-pyrazine-carboxylic acid (4.4 g, 25 mmol) was added Int-4e (7.0 g, 23 mmol) and 12.7 mL of TEA (92 mmol). At 0 °C, a PPA solution (50 wt% solution in EtOAc, 17.7 mL, 30 mmol) was added over a period of 4 min to avoid heating above 5 °C. After an additional 15 min, cooling was removed and the mixture was stirred at ambient temperature for 1.5 h. 70 mL of EtOAc was added, followed by addition of NH 3 aqueous solution to adjust the pH to basic and the organic phase was collected. The organic phase was washed with semi-concentrated NaCl (aqueous solution), dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H 2 O + 0.1% NH 3 ):ACN 61:39 -> 41:59). The fractions containing the product were combined and concentrated in vacuo. The suspension was filtered, the solid was washed with water and dried at 50 °C. Yield: 5.8 g (13.7 mmol; 60%) Similar to Example 4, the following products were obtained: Similar to Example 4, the following compounds were obtained as a mixture of four stereoisomers separated by chiral SFC: Example 40, 40-1, 40-2, 53 Similar to Example 4, the following compounds were obtained. Similar to Example 4, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 58, 58-1, 58-2, 89 Similar to Example 4, the following compounds were obtained: Similar to Example 4, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 71, 71-1, 71-2, 71-3 Among the four stereoisomers, two stereoisomers were separated after separation by chiral SFC: Example 76, 76-1 Similar to Example 4, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 78, 78-1, 78-2, 78-3 Similar to Example 4, the following compounds were obtained. Example 14: Step 1: Sodium (0.95 g, 41.2 mmol) was placed in 80 mL of EtOH and the mixture was cooled to no more than 35 °C and stirred for 45 min. 20 mL of EtOH containing N1-methyl-4-(trifluoromethyl)-benzene-1,2-diamine (2.50 g, 12.9 mmol) and diethyl ethoxyacetate (4.15 mL, 23.2 mmol) was added and the mixture was heated to reflux for 20 h. Subsequently, 200 mL of saturated NH 4 Cl aqueous solution was added, the mixture was concentrated in vacuo, the residue was diluted with 250 mL of water and extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H2 O + 0.15% NH 3 ): ACN:56:44 -> 36:64) Purification. The eluate fractions containing the product were combined and lyophilized. The solid was dissolved in DCM and concentrated in vacuo. Yield: 1.78 g (5.89 mmol; 46%) Int-14a MS (ESI + ): (M + H) + 303; HPLC: RT = 1.05 min, method: Z011_S03 Step 2: A mixture of Int-14a (12.8 g, 42.3 mmol) and hydrochloric acid in dioxane (4N; 128 mL, 512 mmol) was stirred and heated to reflux for 1.5 h. Heating was removed and the mixture was poured into a mixture of 800 mL of water and 500 mL of saturated NaHCO 3 aqueous solution. The mixture was stirred for 5 min and filtered. The solid was washed with water and dried in vacuo. The residue was dissolved in n-butyl acetate and concentrated in vacuo. Yield: 9.33 g (40.1 mmol; 95%) Int-14b MS (ESI + ): (M + H) + 229; HPLC: RT = 0.88 min, method: Z011_S03 Step 3: A mixture containing Int-14b (23.2 g, 99.6 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (13.3 g, 105 mmol) and Cs 2 CO 3 (42.2 g, 130 mmol) in 370 mL of DCM was stirred while heating and refluxing for 1.25 h. Subsequently, heating was removed, MgSO 4 was added, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and diisopropyl ether and concentrated in vacuo. The solid formed was filtered and collected. The filtrate was further concentrated in vacuo and the residue was purified by column chromatography (silica gel; eluent gradient: petroleum ether:EtOAc:80:20 -> 45:55). The eluate fractions containing the product were combined and concentrated in vacuo. The residue was combined with the solid collected. Yield: 31.6 g (95.4 mmol; 96%) Int-14c MS (ESI + ): (M + H) + 332; HPLC: RT = 1.07 min, method: Z018_S04 Chiral SFC retention time 4.27 min (Method: I_SA_10_IPA_NH3_003) Step 4: In an argon atmosphere and in an additionally dried glassware, 150 mL of THF containing 1,4-dioxane (17.18 mL, 211.25 mmol) was cooled to -35 °C, and n-hexyllithium (2.45 N hexane solution; 76.98 mL, 188.52 mmol) was added while maintaining the temperature below -30 °C. Subsequently, the cooling was removed and the mixture was allowed to warm to 20 °C. The mixture was immediately cooled to 0 °C and stirred at this temperature for 30 min. Subsequently, the mixture was cooled to -65 °C, and a mixture of Int-14c (50 g, 150.89 mmol) in 500 mL of THF was added to the additionally dried glassware under argon at -75 °C in such a manner that the temperature of the mixture was below -70 °C. Subsequently, the mixture was stirred at -70 °C for 20 min. Subsequently, the mixture was poured into 650 mL of saturated NH 4 Cl aqueous solution, tert-butyl methyl ether (650 ml) was added, and the mixture was warmed to room temperature with stirring. The aqueous layer was extracted with tert-butyl methyl ether, and the combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo. EtOAc (70 ml) was added to the residue. The mixture was filtered and washed with EtOAc, and the solid was collected. The resulting product contained only one stereoisomer. Yield: 38.5 g (92 mmol; 61%) Int-14d Chiral SFC retention time 5.38 min (Method: I_IH_15_IPA_NH3_003) Step 5: At 10 °C, hydrogen chloride in dioxane (4 N, 18.3 mL, 73.0 mmol) was added to 347 mL of MeOH containing Int-14d (15.4 g, approximately 90%, 33.2 mmol). After 5 min, the cooling was removed and the mixture was stirred at ambient temperature for 22 h. Subsequently, the aqueous solution was concentrated, NH 3 solution was added to adjust the pH to 7.5, and the mixture was concentrated in vacuo. The residue was adjusted to pH 8 by adding concentrated NH 3 aqueous solution, 300 mL of water was added, and the mixture was extracted with DCM. The aqueous layer was adjusted to pH 10 by adding Na 2 CO 2 solution (aqueous solution, 2 N) and extracted with EtOAc. The organic layers were washed with water, combined, dried over MgSO 4 and concentrated in vacuo. Yield: 12.4 g (content approximately 75%; 29.8 mmol; 90%) Int-14e MS (ESI + ): (M + H) + 314; HPLC: RT = 0.87 min, method: Z011_S03 Chiral SFC retention time 3.51 min (method: I_IG_20_IPA_NH3_003) Step 6: Add Boc 2 O (8.3 g, 38.0 mmol) to Int-14e (12.4 g, ~75%, 29.8 mmol) in 250 mL of DCM containing TEA (8.8 mL, 63.3 mmol), and stir the mixture at ambient temperature for 15.5 h. Wash the organic layer with water, dry with MgSO 4 and concentrate in vacuo. Subsequently, purify it by chromatography (silica gel, eluent gradient: petroleum ether: EtOAc 75:25 -> 45:55). Combine the eluates containing the product and concentrate in vacuo. Yield: 9.82 g (23.7 mmol; 75%) Int-14f MS (ESI + ): (M + H) + 414 Chiral SFC retention time 4.64 min (method: I_IG_10_IPA_NH3_003) Step 7: Mix 300 mL of THF containing Int-14f (8.8 g, 21.3 mmol) with palladium / charcoal (10%, 1.3 g), and hydrogenate the mixture at 60 psi in a hydrogen atmosphere for 22 h. Subsequently, add palladium / charcoal (10%, 1 g) again, continue hydrogenation for 5 h, then add palladium / charcoal (10%, 0.5 g) and continue hydrogenation for 3 h. Let the mixture stand overnight, then filter it and concentrate in vacuo. Obtain the product in the form of a mixture of stereoisomers, which can be used further without separation. Only the major isomer is depicted in the synthetic scheme. Yield: 8.76 g (21.1 mmol; 99%) Int-14g MS (ESI + ): (M + H) + 416; HPLC: RT = 1.04 min, method: Z011_S03 Stereoisomer 1: Chiral SFC retention time 2.69 min (method: I_IG_10_IPA_NH3_003) Stereoisomer 2: Chiral SFC retention time 3.33 min (method: I_IG_10_IPA_NH3_003) Step 8: At 5 °C, TFA (14.3 mL, 186 mmol) was added to 65 mL of DCM containing Int-14g (7.7 g, 18.7 mmol). The cooling was removed and the mixture was stirred at ambient temperature for 3.8 h. 150 g of ice was added and the mixture was adjusted to pH ~10 by adding concentrated NH 3 aqueous solution. The aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO 4 and concentrated in vacuo. Yield: 5.92 g (18.7 mmol; quantitative) of Int-14h Chiral SFC retention time 2.57 min (Method: I_SA_10_MEOH_NH3_003) Step 9: To a mixture of NMM (5.1 mL, 46.8 mmol) and Int-14h (5.9 g, 18.7 mmol) in 59 mL of EtOAc was added 5-methylpyrazine-2-carboxylic acid (3.2 g, 22.6 mmol) and the mixture was stirred and cooled to 0 °C. Subsequently, PPA (50% solution in EtOAc; 14.5 mL, 24.3 mmol) was added dropwise while maintaining the temperature below 10 °C. After 5 min, the cooling was removed and the mixture was stirred at ambient temperature for 75 min. Water was added and the mixture was adjusted to pH 9 by adding NMM. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with semi-concentrated brine, charcoal was added, stirred and dried over MgSO 4 After filtration, the mixture was concentrated in vacuo, the residue was dissolved in EtOAc and purified by chromatography (silica gel, eluent: EtOAc:EtOH 97:3). The eluates containing the product were combined and concentrated in vacuo. The product was obtained as a mixture of two stereoisomers, which was purified by chiral SFC. Yield: 4.05 g (9.30 mmol) of Example 14 and 0.71 g (1.63 mmol) of Example 14-1 Examples 18 and 54: Step 1: At 0 °C, PPA (50% solution in EtOAc; 330 μL, 0.56 mmol) was added to a mixture of 1,2-diamino-4-bromo-3-methyl-benzene (110 mg, 0.55 mmol), Int-1c (120 mg, 0.51 mmol) and NMM (190 μL, 1.7 mmol) in 5 mL of DCM. After stirring for 45 min at 0 °C, 200 μL of water was added and the mixture was stirred for 30 min at ambient temperature. Subsequently, 5 mL of acetic acid was added and the mixture was stirred for 16 h at ambient temperature. The mixture was concentrated in vacuo and purified by preparative HPLC (at 50 °C, C-18 Sunfire, eluent gradient (water + 0.15% TFA): ACN 83:17 -> 63:37). The eluates containing the product were combined, made basic with aqueous NH 3 and concentrated in vacuo. The aqueous phase was extracted with DCM, and the combined organic layers were dried over MgSO 4 and concentrated in vacuo. Yield: 200 mg (0.50 mol; 98%) of Int-18a MS (ESI + ): (M + H) + 400; HPLC: RT = 0.79 min, method: Z018_S04 Step 2: Int-18a (200 mg, 0.5 mmol) was stirred with 1-bromo-2-methoxy-ethane (50 μL, 0.53 mmol) and Cs 2 CO 3 (300 mg, 0.92 mmol) in 3 mL of DMF for 16 h at ambient temperature. Subsequently, it was stirred for 30 min at 50 °C, then Cs 2 CO 3 (300 mg, 0.92 mmol) and 1-bromo-2-methoxy-ethane (50 μL, 0.53 mmol) were added and the mixture was stirred for 20 h at ambient temperature. DCM and water were added, and the aqueous phase was extracted with DCM. The combined organic layers were dried over MgSO 4 and concentrated in vacuo. The residue was purified by preparative HPLC (at 50 °C, C-18 X-Bridge, eluent gradient (water + 0.15% NH 3 ) : ACN 54:46 -> 34:66). The eluates containing the product were combined and lyophilized. Yield: 170 mg (0.37 mol; 74%) of Example 54 Step 3: At 100 °C, Example 54 (155 mg, 0.34 mmol) was stirred with Zn(CN) 2 (80 mg, 0.68 mmol) and X-Phos G1 (15 mg, 0.02 mmol) in 750 μL of NMP under argon for 30 min. Subsequently, water was added and the mixture was sonicated. 10 mL of a 1:1 mixture of ACN / THF was added, the mixture was filtered, and the filtrate was purified by preparative HPLC (at 50 °C, C-18 X-Bridge, eluent gradient (water + 0.15% NH 3 )): ACN 65:35 -> 45:55). The elution fractions containing the product were combined and lyophilized. The residue was further purified by chiral SFC. Yield: 90 mg (0.27 mmol; 66%) Example 18 Example 20: Step 1: Cerium(IV)-ammonium nitrate (3.62 g, 6.6 mmol) was added to a solution of Int-60b (1.30 g, 4.4 mmol) in 30 mL of ACN and 10 mL of water and the mixture was stirred at ambient temperature for 3 h. Subsequently, the mixture was concentrated in vacuo, the residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was dissolved in 3 mL of THF and 10 mL of TEA, Boc 2 O (3.48 g, 6.4 mmol) was added, and the mixture was stirred at ambient temperature for 3 h. Subsequently, the mixture was concentrated in vacuo. Yield: 0.80 g (2.8 mmol; 63%) Int-20a MS (ESI + ): (M+H) + 290 Step 2: LiOH (0.10 g, 4.2 mmol) was added to a solution of Int-20a (0.80 g, 2.8 mmol) in 10 mL of MeOH and 3 mL of water and the mixture was stirred at ambient temperature for 3 h. Subsequently, the mixture was concentrated in vacuo and purified by preparative HPLC. Yield: 0.60 g (2.3 mmol, 82%) of Int-20b as a mixture of stereoisomers MS (ESI + ): (M+H) + 262 Step 3: At 0 °C, PPA (50% solution in EtOAc; 1.3 mL, 2.2 mmol) was added to a mixture of int-4b (280 mg, 1.4 mmol), int-20b (380 mg, 1.4 mmol) and NMM (0.95 mL, 8.7 mmol) in 3 mL of DCM. After stirring for 2 h at 0 °C, the mixture was concentrated in vacuo. Subsequently, 2.1 g of acetic acid was added and the mixture was stirred at 50 °C for 8 days. The mixture was concentrated in vacuo. The mixture contained four stereoisomers, which were separated into two pairs of enantiomers by preparative HPLC (C-18 Sunfire, 10 μm, eluent gradient (water + 0.15% TFA): ACN 64:36 -> 44:56). The eluates containing the product were combined and lyophilized. Only one pair of enantiomers (Int-20c) was used in Step 4, which is depicted in the reaction scheme. Stereoisomer pair 1: Int-20c in the form of a mixture of enantiomers: Yield: 119 mg (0.29 mmol; 20%). MS (ESI + ): (M+H) + 416; HPLC: RT = 0.98 min, method: Z018_S04 Stereoisomer pair 2 in the form of a mixture of enantiomers: Yield: 104 mg (0.25 mmol; 17%) MS (ESI + ): (M+H) + 416; HPLC: RT = 0.97 min, method: Z018_S04 Step 4: Int-20c (119 mg, 0.29 mmol) was stirred in dioxane containing HCl (4N; 3.0 mL, 12 mmol) at ambient temperature for 2 h. The mixture was concentrated in vacuo. Yield: 111 mg (0.29 mmol; quantitative) of Int-20d in the form of a mixture of enantiomers MS (ESI + ): (M+H) + 316 Step 5: Stir a mixture of Int-20d (111 mg, 0.29 mmol), 5-methyl-pyrazine-2-carboxylic acid (39 mg, 0.29 mmol) and NMM (189 μL, 1.7 mmol) in 3.5 mL of DCM at 0 °C, add PPA (50% solution in EtOAc; 0.3 mL, 0.5 mmol), and stir the mixture at 0 °C for 1 h. Concentrate the mixture in vacuo, dissolve it in ACN, filter and purify the filtrate by preparative HPLC (C-18 X-Bridge, 10 μm, eluent gradient (water + 0.15% NH 3 ): ACN 71:29 -> 51:49). Combine the eluted fractions containing the product and lyophilize. Subsequently, perform chiral SFC to obtain the desired enantiomers (Example 20 and 20-1). Yield: 28 mg (64 μmol; 45%) Example 20 Example 23 and Example 77: Step 1: Mix 1-fluoro-2-nitro-4-(trifluoromethoxy)-benzene (50 g, 0.22 mol) with 2-methoxy-ethylamine (33.4 g, 0.44 mol) in 250 mL of THF, add TEA (31 mL, 0.22 mol) and stir the mixture at 50 °C for 2 h. Subsequently, add EtOAc and water, wash the organic layer with brine and concentrate. Yield: 62 g (0.22 mol; quantitative) Int-23a MS (ESI + ): (M+H) + 281; HPLC: RT = 1.07 min, method: Z011_S03 Step 2: A solution of Int-23a (62 g, 0.22 mol) containing 7.5 g of Raney nickel in 600 mL of THF is hydrogenated with 50 psi of hydrogen at ambient temperature for 16 h. Filter the mixture and concentrate the filtrate in vacuo. Use the residue without further purification. Yield: 55.8 g (0.22 mol; quantitative) Int-23b MS (ESI + ): (M+H) + 251; HPLC: RT = 0.96 min, method: Z011_S03 Step 3: At 0 °C, PPA (50% solution in EtOAc, 14.4 mL, 24 mmol) was added to a mixture of 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid (3.0 g, 12.2 mmol) and NMM (8.1 mL, 73 mmol) in Int-23b (3.7 g, 15 mmol) in 60 mL of DCM, and the mixture was then stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo, EtOAc and water were added and the organic layer was washed with aqueous NaHCO 3 aqueous solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative HPLC. Yield: 5.1 g (11 mmol; 87%) of Int-23c MS (ESI + ): (M+H) + 478; HPLC: RT = 1.05 min, method: Z011_S03 Step 4: Int-23c (5.1 g, 11 mmol) was stirred with dioxane containing HCl (4 N, 20 mL, 80 mmol) at ambient temperature for 2 h. Subsequently, the mixture was concentrated in vacuo. The residue was used without further purification. Yield: 4.5 g (11 mmol; quantitative) of Int-23d MS (ESI + ): (M+H) + 378; HPLC: RT = 0.90 min, method: Z011_S03 Step 5: Int-23d (2.3 g, 5.6 mmol) was added to a mixture of 5-(difluoromethyl)-pyrazine-2-carboxylic acid (0.97 g, 5.6 mmol), TBTU (1.96 g, 6.1 mmol) and TEA (3.9 mL, 28 mmol) in 20 mL of DMF, and the mixture was stirred at ambient temperature for 3 h. Water was then added and the mixture was purified by preparative HPLC. Yield: 1.4 g (2.6 mmol; 47%) of Int-23e MS (ESI + ): (M+H) + 534; HPLC: RT = 1.02 min, method: Z011_S03 Step 6: Int-23e (1.4 g, 2.6 mmol) was mixed with 10 mL of acetic acid and stirred at 95 °C for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in THF and water. The mixture was made basic with aqueous NH 3 and purified by preparative HPLC. The mixture of four stereoisomers was separated by chiral SFC. The biological potency is described in Examples 23 and 77. Yield: 107 mg (0.21 mmol; 35%). The following compounds were obtained in Example 23: Example 23, 77, 23-1, 23-2 Similar to Example 23, the following products were obtained: Similar to Example 23, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 56, 56-1, 56-2, 75 Similar to Example 23, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 62, 62-1, 62-2, 62-3 Similar to Example 23, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 82, 82-1, 82-2, 82-3 Similar to Example 23, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: 87, 87-1, 87-2, 87-3 Similar to Example 23, the following compounds were obtained. The product is a mixture of four stereoisomers separated by chiral SFC: Example 90, 90-1, 90-2, 102 Similar to Example 23, the following compounds were obtained. Similar to Example 23, the following compounds were obtained. The product was a mixture of four stereoisomers separated by chiral SFC: Example 103, 103-1, 103-2, 103-3 Similar to Example 23, the following compounds were obtained. The product was a mixture of four stereoisomers separated into two pairs of enantiomers by RP-HPLC (SF, TFA, narrow, ACN / H2O): Example 113, 113-1. For Example 113, the absolute stereochemistry was only assigned randomly Similar to Example 23, the following compounds were obtained Example 33: Step 1: A mixture of 1-fluoro-3-methyl-2-nitro-benzene (5.0 g, 32 mmol) and NH 3 aqueous solution (32%, 15 mL, 248 mmol) in 30 mL of ACN was stirred in an autoclave for 4 days. Subsequently, water was added and the mixture was concentrated in vacuo. The solid formed was filtered off, washed with water and dried. The product was used without further purification. Yield: 4.0 g (26 mmol; 81%) Int-33a MS (ESI + ): (M+H) + 153; HPLC: RT = 0.87 min, method: Z018_S04 Step 2: 40 mL of ACN containing Int-33a (4.0 g, 26 mmol) was mixed with NBS (4.7 g, 26 mmol) and the mixture was stirred at ambient temperature for 30 min. Water was added and the mixture was concentrated in vacuo. The solid formed was filtered off, washed with water and dried. The product was used without further purification. Yield: 6.0 g (26 mmol; quantitative) Int-33b MS (ESI + ): (M+H) +231 / 233(Br); HPLC: RT = 1.01 min, method: Z018_S04 Step 3: Hydrogenate a mixture of Int-33b (6.0 g, 26 mmol) containing Raney nickel (600 mg) in 60 mL of THF at ambient temperature and 50 psi hydrogen pressure. Filter the mixture and concentrate the filtrate in vacuo. The residue is used without further purification. Yield: 5.2 g (25.6 mmol; 98%) Int-33c MS (ESI + ): (M + H) + 201 / 203(Br); HPLC: RT = 0.79 min, method: Z018_S04 Step 4: Stir a mixture of Int-33c (3.0 g, 14.9 mmol) containing Zn(CN) 2 (2.5 g, 21.3 mmol) and XPhos-G1 (500 mg, 0.68 mmol) in 10 mL of NMP at 100 °C for 1 h. After cooling, pour the mixture into 150 mL of water, add 10 mL of DCM, stir vigorously and filter. Separate the aqueous phase and extract with DCM. The combined organic layers are dried over MgSO 4 and concentrated in vacuo. Wash the solid in the filtrate with MeOH, combine the extracts with the residue in the extract and concentrate in vacuo. Purify the residue by preparative HPLC (X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ) : ACN 95:5 -> 75:25). Combine the elution fractions containing the product and concentrate in vacuo. Yield: 1.74 g (11.8 mmol; 79%) Int-33d MS (ESI + ): (M + H) + 148; HPLC: RT = 0.55 min, method: Z011_S03 Step 5: Stir a mixture of Int-33d (500 mg, 3.4 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (750 mg, 3.5 mmol) in 6.0 mL of pyridine at 0 °C and add PPA (50% solution in EtOAc, 3.0 mL, 5.1 mmol). After 15 minutes at 0 °C, stir the mixture at ambient temperature for 30 min. Add water and DCM, extract the aqueous phase with DCM, and dry the combined organic layers over MgSO 4Dry and concentrate in vacuo. The residue was dissolved in dioxane and lyophilized. The residue was dissolved in 10 mL of AcOH and stirred at ambient temperature for 4 days. Purify the mixture by preparative HPLC (at 50 °C, Sunfire C-18, eluent gradient (H 2 O + 0.15% TFA): ACN 80:20 -> 60:40). Combine the eluates containing the product and lyophilize. Yield: 1.3 g (3.0 mmol, 88%) Int-33e MS (ESI + ): (M + H) + 327; HPLC: RT = 0.83 min, method: Z018_S04 Step 6: Stir Int-33e (1.3 g, 3 mmol) in dioxane (4N, 10 mL, 40 mmol) containing HCl at ambient temperature for 1 h. Concentrate the mixture in vacuo and use the residue without further purification. Yield: 900 mg (3 mmol, quantitative) Int-33f. MS (ESI + ): (M + H) + 227; HPLC: RT = 0.66 min, method: Z018_S04 Step 7: Add TBTU (260 mg, 0.81 mmol) to a mixture of Int-33f (225 mg, 0.75 mmol) in 3 mL of DMF containing 5-(difluoromethyl)-pyrazine-2-carboxylic acid (160 mg, 0.92 mmol) and TEA (550 μL, 4.0 mmol), and stir the mixture at ambient temperature for 15 min. Add water and purify the mixture by preparative HPLC (at 50 °C, X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ): ACN 73:27 -> 53:47). Combine the eluates containing the product and lyophilize. Yield: 220 mg (0.58 mmol, 77%) Int-33g MS (ESI + ): (M + H) + 383; HPLC: RT = 0.85 min, method: Z018_S04 Step 8: At ambient temperature, combine Int-33f (100 mg, 0.26 mmol) with ethyl 4-methylbenzenesulfonate (55 mg, 0.28 mmol) and Cs2 CO 3 (200 mg, 0.61 mmol) was stirred in 2 mL of DMF for 40 h. Subsequently, ethyl 4-methylbenzenesulfonate (50 mg, 0.25 mmol) was added and the mixture was stirred at ambient temperature for 24 h. Subsequently, THF was added to the mixture and the resulting mixture was filtered, and the filtrate was purified by preparative HPLC (at 50 °C, X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ): ACN 6:4 -> 4:6). The eluate fractions containing the product were combined and concentrated in vacuo. The residue was further purified by chiral SFC. Yield: 52 mg (0.10 mmol, 42%) Example 33 Similar to Example 33, the following products were obtained: Example 44: Step 1: A mixture of 1-fluoro-3-methyl-2-nitrobenzene (2.0 g, 13.3 mmol) and difluoroethylamine (4.0 g, 49 mmol) in 10 mL of ACN was stirred in a microwave oven at 140 °C for 35 h. Subsequently, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and DCM, the aqueous phase was extracted with DCM, the organic layers were combined, dried over MgSO 4 and concentrated in vacuo. Yield: 2.8 g (approx. 90%; 12 mmol; 90%) Int-44a MS (ESI + ): (M + H) + 217; HPLC: RT = 1.03 min, method: Z018_S04 Step 2: 30 mL of ACN containing Int-44a (2.8 g, 12 mmol) was mixed with NBS (2.1 g, 12 mmol) and the mixture was stirred at ambient temperature for 30 min. Water was added and the mixture was purified by preparative HPLC (at 50 °C, X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ): ACN 5:5 -> 3:7). The eluate fractions containing the product were combined and concentrated in vacuo, sonicated to form a solid and filtered. The solid was washed with water and dried in vacuo. Yield: 2.7 g (9.2 mmol; 78%) Int-44b MS (ESI+ ): (M+H) + 295 / 297 (Br); HPLC: RT = 1.12 min, method: Z018_S04 Step 3: Hydrogenate a mixture of Int-44b (750 mg, 2.5 mmol) and Raney nickel (100 mg) in 20 mL of THF at ambient temperature under a hydrogen pressure of 50 psi. Subsequently, filter the mixture and purify the filtrate by preparative HPLC (at 50 °C, X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ): ACN 62:38 -> 42:58). Combine the eluted fractions containing the product and lyophilize. Yield: 540 mg (2.0 mmol; 80%) of Int-44c MS (ESI + ): (M+H) + 265 / 267 (Br); HPLC: RT = 0.97 min, method: Z018_S04 Step 4: Stir a mixture of Int-44c (150 mg, 0.57 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (125 mg, 0.58 mmol) in 4.0 mL of pyridine at 0 °C and add PPA (50% solution in EtOAc, 600 μL, 1.0 mmol). After 1 h at 0 °C, add water and filter off the precipitate, wash with water and dissolve in 5 mL of AcOH. Stir the mixture at ambient temperature for 40 h. Subsequently, stir the mixture at 60 °C for 48 h. Concentrate the residue in vacuo, dissolve in THF / MeOH, set to basic conditions with TEA and purify by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.1% NH 3 ): ACN 46:54 -> 26:74). Combine the eluted fractions containing the product and lyophilize. Yield: 141 mg (0.32 mmol, 56%) of Int-44d MS (ESI + ): (M+H) + 444 / 446 (Br); HPLC: RT = 1.16 min, method: Z011_S03 Step 5: At ambient temperature, Int-44d (141 mg, 0.32 mmol) was stirred in dioxane containing HCl (4N, 0.95 mL, 3.8 mmol) for 16 h. The mixture was concentrated in vacuo, and the residue was dissolved in ACN and concentrated again in vacuo. Yield: 128 mg (0.31 mmol, 97%) of Int-44e MS(ESI + ):(M+H) + 344 / 346(Br); HPLC: RT = 0.98 min, method: Z011_S03 Step 6: To a mixture of Int-44e (125 mg, 0.30 mmol) in 3.5 mL of DMF containing 5-methyl-pyrazine-2-carboxylic acid (46 mg, 0.33 mmol) and TEA (187 μL, 1.3 mmol), TBTU (101 mg, 0.32 mmol) was added, and the mixture was stirred at ambient temperature for 1 h. The mixture was poured into water at 0 °C, stirred for 10 min, the solid formed was filtered and washed with water, dissolved in dioxane and lyophilized. Yield: 137 mg (0.28 mmol, 94%) of Int-44f MS(ESI + ):(M+H) + 464 / 466(Br); HPLC: RT = 1.08 min, method: Z011_S03 Step 7: A mixture of Int-44f (125 mg, 0.27 mmol) containing Zn(CN) 2 (65 mg, 0.55 mmol) and XPhos-G1 (20 mg, 27 μmol) in 750 μL of NMP was stirred under argon at 100 °C for 1 h. After cooling, 1 drop of water was added, followed by 2 mL of ACN and THF each. The mixture was filtered and purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.15% NH 3 )): ACN 65:35 -> 45:55). The eluate fractions containing the product were combined and lyophilized. The residue was purified by chiral SCF. Yield: 66 mg (0.16 mmol, 64%) of Example 44 Example 57: Step 1: Ethylamine (2 M in THF; 33.6 mL; 67 mmol) was slowly added to a mixture of 1,4,5-trifluoro-2-nitro-benzene (7 mL; 61 mmol) and TEA (21 mL; 153 mmol) in 200 mL of DCM, and the mixture was stirred at ambient temperature for 22 h. Ethylamine (2 M in THF; 7 mL; 14 mmol) was added and the mixture was stirred at ambient temperature for 6 h. The mixture was washed with water, and the organic layer was dried over Na 2 SO 4 dried, filtered and concentrated in vacuo. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel; eluent gradient petroleum ether:EtOAc = 90:10 -> 80:20). The eluate fractions containing the product were combined and concentrated in vacuo. Rf: 0.43 (PE / EtOAc 9:1) Yield: 5.7 g (28 mmol; 46%) Int-57a MS (ESI + ): (M+H) + 203; R f : 0.43 (PE / EtOAc 9:1) Step 2: A mixture of Int-57a (1.0 g, 4.9 mmol) containing 100 mg of 10% palladium on charcoal in 20 mL of THF was hydrogenated at 50 psi (hydrogen) at ambient temperature for 15 h. Subsequently, the mixture was filtered and concentrated in vacuo. Yield: 820 mg (approx. 90% content; 4.8 mmol; 96%) Int-57b MS (ESI + ): (M+H) + 173; HPLC: RT = 0.65 min, method: Z018_S04 Step 3: At 0 °C, PPA (50 wt% solution in EtOAc, 1.4 mL, 2.3 mmol) was added to a mixture of Int-57b (approx. 90%, 330 mg, 1.7 mmol) and (2S)-2-Boc-amino-3-hydroxy-3-methylbutyric acid (450 mg, 1.9 mmol) in 5 mL of DCM containing NMM (800 μL, 7.3 mmol). The mixture was then stirred at 0 °C for 5 h. Water was added and the mixture was concentrated in vacuo. By preparative HPLC (XBridge C18, 50 °C, eluent gradient: (H 2 O + 0.15% NH 3): Purify the residue with ACN 59:41->39:61). Combine the elution fractions containing the product and lyophilize. Yield: 550 mg (1.4 mmol; 81%) Int-57c MS (ESI + ): (M+H) + 388; HPLC: RT = 1.05 min, method: Z018_S04 Step 4: Stir Int-57c (540 mg, 1.4 mmol) in 10 mL of AcOH at 70 °C for 30 h. Subsequently, purify the mixture by preparative HPLC (Sunfire C18, 50 °C, eluent gradient: (H 2 O + 0.15% TFA): ACN 72:28->52:48). Combine the elution fractions containing the product and lyophilize. Yield: 510 mg (1.1 mol; 76%) Int-57d MS (ESI + ): (M+H) + 370; HPLC: RT = 0.90 min, method: Z018_S04 Step 5: Stir Int-57d (510 mg, 1.1 mmol) in a solution of dioxane containing HCl (4 N, 5 mL, 20 mmol) at ambient temperature for 30 min. Subsequently, concentrate the mixture in vacuo, dissolve the residue in MeOH, pass it through an ion exchange cartridge (Agilent PL-HCO3 MP SPE) and concentrate in vacuo. Purify the residue by preparative HPLC (X-Bridge C18, 50 °C, eluent gradient: (H 2 O + 0.15% NH 3 ): ACN 79:21->59:41). Combine the elution fractions containing the product and lyophilize. Yield: 190 mg (0.71 mmol; 67%) Int-57e MS (ESI + ): (M+H) + 270; HPLC: RT = 0.84 min, method: Z011_S03 Step 6: To 4 mL of DMF containing 5-(difluoromethyl)-pyrazine-carboxylic acid (65 mg, 0.37 mmol), Int-57e (80 mg, 0.3 mmol) and TEA (250 μL, 1.8 mmol) were added. TBTU (100 mg, 0.31 mmol) was added and the mixture was stirred for 20 min at ambient temperature. Water was added and the mixture was purified by preparative HPLC (XBridge C18, 50 °C, eluent gradient: (H 2 O + 0.1% NH 3 ):ACN 58:42 -> 38:62). The eluate fractions containing the product were combined and lyophilized. Yield: 78 mg (0.18 mmol; 62%) Example 57 Example 60: Step 1: A mixture of 4-methoxy-aniline (10 g, 81 mmol), glyoxylic acid ethyl ester in polymeric form (47% solution in toluene, 17 mL, 81 mmol), and MgSO 4 (24 g, 203 mmol) in 125 mL of DCM was stirred at 40 °C for 3 h. The mixture was filtered and the filtrate was evaporated at 25 °C. The residue was used without further purification. Yield: 20.8 g (approx. 80% content; 81 mol; quantitative) Int-60a MS (ESI + ): (M + H) + 208; HPLC: RT = 0.90 min, method: Z011_S03 Step 2: 150 mL of dioxane (without stabilizer) containing Int-60a (21 g 80% content, 81 mmol) was degassed and kept under nitrogen. Copper(II) chloride (0.54 g, 4 mmol) and tert-butyl hydroperoxide (5.5 M in decane; 17.5 mL, 96 mmol) were added and the mixture was stirred at 50 °C for 16 h. The mixture was concentrated in vacuo and purified by continuous column chromatography (silica gel, PE / EtOAc gradient 9:1 -> 4:1, then 7:3, then 4:1, and each time the eluate fractions containing the product were combined and concentrated before the next purification). Yield: 6.4 g (22 mmol; 27%) of Int-60b in the form of a mixture of stereoisomers MS (ESI +):(M+H) + 296; HPLC: RT = 0.90 min, method: Z011_S03 Step 3 At ambient temperature, Int-60b (300 mg, 1.02 mmol) was stirred with cerium(IV) ammonium nitrate (835 mg, 1.6 mmol) in a solution of 10 mL ACN containing 3 mL of water for 3 h. Subsequently, the mixture was filtered and concentrated in vacuo. Yield: 300 mg (purity: ca. 33%; 0.53 mmol; 52%) of Int-60c as a mixture of stereoisomers MS (ESI + ):(M+H) + 190; TLC: Rf = 0.5 (eluent: DCM:MeOH 95:5) Step 4: To a mixture of Int-60c (3.0 g, 16 mmol) in 15 mL of THF containing TEA (8.0 g; 79 mmol) was added Boc-anhydride (5.2 g; 24 mmol), and the mixture was stirred at ambient temperature for 18 h, then concentrated in vacuo and purified by silica gel column chromatography (eluent gradient: hexane:EtOAc 100:0 -> 60:40). Yield: 1.0 g (purity: ca. 65%; 2.2 mmol; 9%) of Int-60d as a mixture of stereoisomers MS (ESI + ):(M+H) + 234; TLC: Rf = 0.5 (eluent: hexane:EtOAc 7:3) Step 5: LiOH (100 mg; 4.2 mmol) was added to a solution of Int-60d (0.8 g, 2.8 mmol) in 10 mL of MeOH containing 3 mL of water, the mixture was stirred at ambient temperature for 3 h, concentrated in vacuo and purified by preparative HPLC. Yield: 0.5 g (1.9 mmol; 68%) of Int-60e as a mixture of stereoisomers MS (ESI + ):(M+H) + 262; TLC: Rf = 0.5 (eluent: DCM:MeOH 95:5) Step 6: To 100 mL of DCM containing 1-fluoro-2-nitro-4-trifluoromethyl-benzene (2.2 mL; 15.7 mmol) was added ethylamine (2 M in THF; 15.7 mL, 31.4 mmol), and the mixture was stirred at ambient temperature for 20 h. 100 mL of DCM was added and the mixture was extracted with 100 mL of water. The organic layer was collected, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Yield: 3.30 g (14.1 mmol; 90%) Int-60f MS (ESI + ): (M+H) + 235; HPLC: RT = 1.10 min, method: Z017_S04 Step 7: Int-60f (200 mg, 0.85 mmol) was mixed with palladium / carbon (10%, 50 mg) in 20 mL of MeOH and hydrogenated at 50 psi hydrogen pressure for 3.5 h. The mixture was then filtered and concentrated in vacuo. Yield: 170 mg (0.83 mol; 97%) Int-60g MS (ESI + ): (M+H) + 205; HPLC: RT = 0.86 min, method: Z018_S04 Step 8: 5 mL of DCM containing Int-60e (210 mg, 0.80 mmol), Int-60g (170 mg, 0.83 mmol) and 350 μL of NMM was stirred at ambient temperature and PPA (50% solution in EtOAc; 600 μL, 1.0 mmol) was added. After stirring at ambient temperature for 16 h, water was added and the mixture was stirred at ambient temperature for 20 min. Subsequently, 5 mL of AcOH was added and the mixture was stirred at 50 °C for 3 h, stirred at ambient temperature for 16 h and stirred at 80 °C for 2 h. The mixture contained four stereoisomers, which were separated into two pairs of enantiomers by preparative HPLC (at 50 °C, C-18 Sunfire, eluent gradient (water + 0.15% TFA): ACN 58:42->38:62). The eluates containing the product were combined and lyophilized. Only one pair of enantiomers (Int-60h) was used in Step 9, which is depicted in the reaction scheme. Stereoisomer pair 1: Yield: 70 mg (0.13 mmol; 16%) Int-60h as a mixture of enantiomers MS (ESI + ): (M+H)+ 430; HPLC: RT = 1.03 min, Method: Z018_S04 Stereoisomer pair 2: Yield: 120 mg as a mixture of enantiomers MS(ESI + ): (M + H) + 430; HPLC: RT = 1.04 min, Method: Z018_S04 Step 9: At ambient temperature, Int-60h (70 mg, 0.13 mmol) was stirred in 4 mL of hydrochloric acid (4 M in dioxane) for 1 h. The mixture was concentrated in vacuo. Yield: 52 mg (0.13 mmol; quantitative) of Int-60i in the form of a mixture of enantiomers MS(ESI + ): (M + H) + 330; HPLC: RT = 0.77 min, Method: Z018_S04 Step 10: At ambient temperature, a mixture of Int-60i (52 mg, 0.13 mmol), 5-methyl-pyrazine-2-carboxylic acid (22 mg, 0.16 mmol), TBTU (44 mg, 0.14 mmol) and TEA (100 μL, 0.72 mmol) in 4.0 mL of DMF was stirred for 15 min. Water was added and the mixture was purified by preparative HPLC (at 50 °C, C-18 X-Bridge, eluent gradient (water + 0.15% NH 3 ): ACN 61:39 -> 41:59). The eluate fractions containing the product were combined and lyophilized. Subsequently, chiral SFC was performed to obtain the desired enantiomer. Yield: 15 mg (0.033 mol; 36%) of Example 60 Example 63: Step 1: Methylamine (2 N in THF; 36 mL, 72 mmol) was slowly added with stirring to a mixture of 3-fluoro-1-trifluoromethyl-4-nitro-benzene (10.1 g, 48 mmol) and K 2 CO 3 (10.0 g, 72 mmol) in 60 mL of DMF, thereby slowly maintaining the mixture below 35 °C. Subsequently, the mixture was stirred at ambient temperature for 1 h. The mixture was poured into saturated NaHCO 3An aqueous solution was cooled to 0 °C, filtered and the solid was washed with water. The solid was dried under vacuum and used without further purification. Yield: 10.4 g (47 mmol; 98%) Int-63a MS (ESI + ): M + 220; HPLC: RT = 1.03 min, method: Z011_S03 Step 2: At ambient temperature and 60 psi hydrogen pressure, 300 mL of MeOH containing Int-63a (19.9 g, 90.4 mmol) and 2.0 g of 10% Pd / C were hydrogenated for 1 h. The mixture was filtered, and the filtrate was dried over MgSO 4 and concentrated in vacuo. Yield: 15.7 g (82.7 mmol; 91%) Int-63b MS (ESI + ): (M+H) + 191; HPLC: RT = 0.78 min, method: Z018_S04 Step 3: A mixture of Int-63b (15.7 g, 82.7 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (21.9 g, 102 mmol) in 150 mL of pyridine was stirred at -10 °C and PPA (50% solution in EtOAc, 83 mL, 141 mmol) was slowly added to keep the temperature below 0 °C. After 2 h at 0 °C, 50 mL of pyridine was added and the mixture was stirred at ambient temperature for 18 h. The mixture was poured into 3.5 L of water containing 20 mL of concentrated NH 3 aqueous solution and stirred vigorously. The solid formed was filtered, washed with water and dried under vacuum. The solid was dissolved in 125 mL of AcOH and stirred at ambient temperature for 17 h. 400 mL of dioxane was added and the mixture was lyophilized. The residue was dissolved in ACN and 2 L of water, the volatile organic solvents were removed in vacuo, the aqueous phase was adjusted to pH ca. 9 by adding concentrated NH 3 aqueous solution, the mixture was stirred vigorously and filtered. The solid was washed with 650 mL of water and dried under vacuum. Yield: 18.7 g (50.7 mmol, 65%) Int-63c MS (ESI + ): (M+H) + 370; HPLC: RT = 0.94 min, method: Z018_S04 Step 4: Under cooling conditions, at 10 °C, dioxane (65 mL) containing Int-63c (18.7 g, 50.6 mmol) was added to dioxane containing HCl (4 N, 130 mL, 520 mmol), and the temperature was slowly maintained below 15 °C. Subsequently, the mixture was stirred at ambient temperature for 2 h. 600 mL of ether was added and the mixture was stirred for 5 min. The solid formed was filtered and washed with ether. The solid was dissolved in 600 mL of water, the pH was adjusted to 8.5 by adding concentrated NH 3 aqueous solution, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with semi-concentrated brine, dried over MgSO 4 and concentrated in vacuo. The residue was used without further purification. Yield: 13.6 g (50.5 mmol, 99%) of Int-63d MS (ESI + ): (M+H) + 270; HPLC: RT = 0.90 min, method: Z011_S03 Step 5: A mixture of Int-63d (13.6 g, 50.5 mmol) and 5-methyl-pyrazine-2-carboxylic acid (8.6 g, 61 mmol) in 350 mL of EtOAc was stirred at 0 °C, and PPA (50% solution in EtOAc, 39 mL, 66 mmol) was added while keeping the mixture below 5 °C. After 45 min, at 0 - 10 °C, 200 mL of EtOAc and 500 mL of water were added, and the pH of the mixture was adjusted to approximately 8.5 by adding concentrated NH 3 aqueous solution. The organic phase was washed with brine and 1.5 g of charcoal was added. The mixture was dried over MgSO 4 and filtered, and the filter solid was washed with 250 mL of EtOAc. The filtrate was concentrated in vacuo, and the residue was treated with 100 mL of diisopropyl ether. The mixture was filtered and the solid was washed with 100 mL of diisopropyl ether. The solid was dried in vacuo. Yield: 18.5 g (47.6 mmol, 94%) of Example 63 Example 66: Step 1: 1,2-Diamino-4,5-difluoro-benzene (100 mg, 0.69 mmol) was mixed with Int-1c (120 mg, 0.51 mmol) and TEA (425 μL, 3.1 mmol) in 5.0 mL of DCM. PPA (50% solution in EtOAc, 600 μL, 1.0 mmol) was added at 0 °C, and the mixture was stirred for 1 h at 0 °C. Subsequently, 100 μL of water was added and the mixture was stirred for 1 h at ambient temperature. 5.0 mL of AcOH was added and the mixture was stirred for 16 h at ambient temperature. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (at 50 °C, Sunfire C-18, eluent gradient (H 2 O + 0.15% TFA): ACN 88:12 -> 68:32). The eluates containing the product were combined and lyophilized. The residue was dissolved in MeOH and passed through an ion-exchange cartridge (Agilent PL-HCO3 MP SPE) and concentrated in vacuo. Yield: 160 mg (0.47 mmol; 91%) of Int-66a MS (ESI + ): (M + H) + 344; HPLC: RT = 0.75 min, method: Z018_S04 Step 2: To a mixture of Int-66a (160 mg, 0.47 mmol) in 5 mL of ACN containing Cs 2 CO 3 (250 mg, 0.77 mmol), methyl methanesulfonate (40 μL, 0.47 mmol) was added. The mixture was stirred for 1 h at ambient temperature. Subsequently, the mixture was filtered and the filtrate was purified by preparative HPLC (at 50 °C, X-Bridge C-18, eluent gradient (H 2 O + 0.15% NH 3 ): ACN 68:32 -> 48:52). The eluates containing the product were combined and lyophilized. Yield: 140 mg (0.39 mmol; 84%) of Example 66 Similar to Example 66, the following products were obtained: Example 69: Step 1: At ambient temperature, a mixture of N-Boc-threonine (10 g, 46 mmol), benzyl bromide (5.2 mL, 43 mmol) and NaHCO 3 (9 g, 107 mmol) in 80 mL of DMF was stirred for 4 days. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 500 mL of water and extracted with tert-butyl methyl ether. The combined organic layers were dried over MgSO 4 and concentrated in vacuo. Yield: 11.8 g (38 mmol; 88%) Int-69a MS (ESI + ): (M+H) + 310; HPLC: RT = 0.98 min, method: Z011_S03 Step 2: At 50 °C, over a period of 220 min, 400 mL of ACN containing 2,2-difluoro-2-(fluorosulfonyl)-acetic acid was added to a mixture of Int-69a (11.8 g, 38 mmol) and CuI (3.6 g, 19 mmol) in 400 mL of ACN. The mixture was stirred for an additional 90 min at 50 °C, then 30 mL of TEA was added at ambient temperature and the mixture was concentrated in vacuo. The residue was dissolved in 40 mL of THF and 10 mL of concentrated NH 3 aqueous solution was added. Celite was added, the mixture was filtered and the solid was washed with THF. The filtrate was stored at ambient temperature for 18 h, filtered and 5 g of PL-thiol resin (Agilent, 2.2 mmol / g, 100A, 45 μm) was added, stirred and filtered. THF was added to a total volume of 75 mL and the mixture was purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.1% NH 3 ): ACN 52:48 -> 32:68). The eluate fractions containing the product were combined and lyophilized. Yield: 4.3 g (12 mmol; 31%) Int-69b MS (ESI + ): (M+H) + 360; HPLC: RT = 1.10 min, method: Z011_S03 Step 3: Under a hydrogen pressure of 60 psi, 100 mL of MeOH containing Int-69b (2.2 g, 5.4 mmol) and 300 mg of 10% Pd / C were hydrogenated at ambient temperature for 1.5 h. The mixture was filtered and the filtrate was dried over MgSO 4 and concentrated in vacuo. Yield: 1.6 g (5.3 mmol; 99%) Int-69c MS (ESI + ): (M+H) + 270 Step 4: Stir a mixture of Int-4b (885 mg, 4.2 mmol) and Int-69c (1.4 g, 4.6 mmol) in 10 mL of pyridine at -10 °C, and slowly add PPA (50% solution in EtOAc, 3.5 mL, 5.9 mmol) to keep the temperature below 0 °C. After 2.5 h at 0 °C, add 1 mL of water and concentrate the mixture in vacuo. The residue was purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.1% NH 3 ): ACN 55:45 -> 35:65). Combine the eluates containing the product and lyophilize. Yield: 1.6 g (3.6 mmol, 86%) Int-69d MS (ESI + ): (M+H) + 442; HPLC: RT = 1.07 min, method: Z011_S03 Step 5: Add dioxane containing HCl (4 N, 9 mL, 36 mmol) to 9 mL of dioxane containing Int-69d (800 mg, 1.8 mmol) at 0 °C and under cooling. Then, stir the mixture at ambient temperature for 2 h. Concentrate the mixture in vacuo, dissolve in DCM and concentrate in vacuo. Yield: 710 mg (1.7 mmol, 95%) Int-69e MS (ESI + ): (M+H) + 342; HPLC: RT = 0.92 min, method: Z011_S03 Step 6: Stir a mixture of Int-69e (350 mg, 0.76 mmol) and 5-methyl-pyrazine-2-carboxylic acid (126 mg, 0.91 mmol) in 6.5 mL of ACN containing TEA (371 μL, 2.7 mmol), add CIP (233 mg, 0.84 mmol), and stir the mixture at ambient temperature for 1 h. Pour the mixture into 250 mL of semi-concentrated NaCl (aqueous solution), and by adding concentrated NH 3The aqueous solution sets the mixture to a pH of about 9. The mixture is concentrated in vacuo, the solid is filtered, washed with water and dried in vacuo. The solid is dissolved in 5 mL of AcOH, stirred at 55 °C for 1 h and stirred at 65 °C for 15 h. The mixture is concentrated in vacuo, and the residue is dissolved in THF and MeOH and set to an alkaline pH by adding TEA. It is purified by preparative HPLC. The eluates containing the product are combined and lyophilized. Yield: 49 mg (0.11 mmol, 15%) Example 69 Similar to Example 69, the following products were obtained: Example 85: Step 1: 1,2-Diamino-4,5-difluoro-benzene (500 mg, 3.5 mmol) was mixed with N-Boc-O-methyl-L-threonine (890 mg, 3.8 mmol), and 50 mL of DCM containing NMM (2.3 mL, 21 mmol), PPA (50% solution in EtOAc, 4.1 mL, 6.9 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 1.8 h and at ambient temperature for 14.5 h. Subsequently, the mixture was washed with an aqueous solution of Na 2 CO 3 (0.5 N) and water, and the organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in MeOH / THF and purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.1% NH 3 ) : ACN 66:34 -> 46:54). The eluates containing the product were combined and lyophilized. Yield: 361 mg (1.0 mmol; 27%) Int-85a. MS (ESI + ): (M + H) + 358; HPLC: RT = 0.95 min, method: Z011_S03 Step 2: At 95 °C, Int-85a (360 mg, 1.0 mmol) was stirred in AcOH (3.0 mL, 51 mmol) for 1.25 h. The mixture was concentrated in vacuo, then dissolved in dioxane containing HCl solution (4 N, 3.0 mL, 12 mmol). After stirring for 45 min at ambient temperature, the mixture was concentrated in vacuo, dissolved in ACN and concentrated again in vacuo. Yield: 391 mg (content: about 90%, 1.0 mmol; quantitative) Int-85b MS(ESI + ):(M+H) + 242; HPLC: RT = 0.97 min, method: Z011_S03 Step 3: At ambient temperature, CIP (307 mg, 1.1 mmol) was added to a mixture of Int-85b (390 mg, 1.0 mmol) containing 2-methylpyrazine-5-carboxylic acid (145 mg, 1.1 mmol) and TEA (0.7 mL, 5.0 mmol) in 10 mL of ACN, and then stirred at ambient temperature for 30 min. The mixture was concentrated in vacuo, THF was added, and the mixture was purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H 2 O + 0.1% NH 3 ) : ACN 74:26 -> 54:46). Yield: 144 mg (0.38 mmol; 38%) Int-85c MS(ESI + ):(M+H) + 362; HPLC: RT = 0.87 min, method: Z011_S03 Step 4: Methyl methanesulfonate (35 μL, 0.42 mmol) was added to a mixture of Int-85c (125 mg, 0.35 mmol) containing Cs 2 CO 3 (237 mg, 0.73 mmol) in 6.5 mL of ACN. The mixture was stirred at ambient temperature for 3 h. Subsequently, the mixture was concentrated in vacuo, the residue was dissolved in DCM, washed with water, the organic layer was dried over MgSO 4 , mixed with dioxane and freeze-dried. The residue was dissolved in DCM and concentrated in vacuo. Yield: 131 mg (0.35 mmol; quantitative) Example 85 Example 14 Similar to Example 14 (see above), except for Step 7, the following compounds were obtained: Example 132 and Example 133: Step 7: A mixture of Int-132f (2.9 g, 6.75 mmol) and Wilkinson's catalyst (950 mg, 1.03 mmol) in ethanol (145 ml) was hydrogenated at 40 psi and 40 °C under a hydrogen atmosphere for 22 h. The mixture was filtered and concentrated in vacuo. The residue was dissolved in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H2O + 0.1% NH4OH): 58:42 -> 38:62 I). The product-containing eluates were combined and concentrated in vacuo. The product was isolated as a mixture of stereoisomers and used as such in the following step. Yield: 2.05 g (4.74 mmol; 70.4%) of Int-132g MS (ESI + ): (M+H) + 432; HPLC: RT = 1.03 min, method: Z011_S03 Chiral SFC retention time for stereoisomer 1: 0.66 min (method: I_AC_10_IPA_NH3_002) Chiral SFC retention time for stereoisomer 2: 0.86 min (method: I_AC_10_IPA_NH3_002) Step 8: The title compound was synthesized from Inter-132g as in Step 8 of Example 14 to give a mixture of stereoisomers, which was used as such in the next step. Yield: 1.18 g (3.56 mmol; 76.8%) of Int-132h MS (ESI + ): (M+H) + 332; HPLC: RT = 0.84 min, method: Z011_S03 Chiral SFC retention time for diastereomer 1: 1.23 min (method: I_IG_20_MEOH_NH3_002) Chiral SFC retention time for diastereomer 2: 1.56 min (method: I_IG_20_MEOH_NH3_002) Step 9: Synthesis was carried out by Int-132h similar to Step 9 of Example 14 to obtain Examples 132 and 133 in the form of a mixture of stereoisomers separated by chiral SFC. Yield: 1.18 g (3.56 mmol; 76.8%) of Examples 132 and 133 MS (ESI + ): (M+H) + 332; HPLC: RT = 0.84 min, method: Z011_S03 Similar to Example 14, the following compound was obtained. The product is a mixture of two stereoisomers. One stereoisomer was separated: Example 134 Similar to Example 14, the following compounds were obtained. The products are mixtures of two stereoisomers separated by chiral SFC: Examples 135, 135-1, 136, 136-1, 137, 137-1 Similar to Example 14, the following compounds were obtained. The products are mixtures of two stereoisomers separated by chiral SFC: Examples 136, 136-1 Similar to Example 14, the following compounds were obtained. The products are mixtures of two stereoisomers separated by chiral SFC: Examples 137, 137-1 Similar to Example 1, the following compounds were obtained: Similar to Example 23, the following compounds were obtained: (synthesis is described again) Example 139: Step 1 A mixture of N-ethyl-2-nitro-4-(trifluoromethyl)aniline (1.4 g, 5.97 mmol), methanol (50 ml) and 10% Pd / C (150 mg) was stirred for 5 hours at room temperature under a hydrogen atmosphere of 50 psi. Then the mixture was filtered, concentrated and purified by HPLC. Yield: 1.22 g (5.97 mmol; 99%) Int-139a HPLC: RT = 0.978 min, Method: Z011_S03 Step 2 Under ice-cooling, to a mixture of Int-139a (1.19 g, 5.87 mmol), 2-{[(tert-butoxy)carbonyl]amino}-2-(oxolan-3-yl)acetic acid (1.2 g, 4.89 mmol), N-methylmorpholine (3.23 ml, 29.35 mmol) and DCM (30 ml) was added PPA (50%) (5.76 ml, 9.78 mmol). The resulting mixture was stirred at room temperature for 2 h. Water was added and then the mixture was concentrated in vacuo. Water was added to the residue. The mixture was filtered, dissolved in THF / ACN and purified by chromatography. Yield: 1.3 g (3.01 mmol; 61.6%) Int-139b MS(ESI + ): (M+H) + 432, HPLC: RT = 1.057 min, Method: Z011_S03 Step 3 A mixture of Int-139b and hydrochloric acid (solution in 4M dioxane, 20 ml) was stirred at room temperature for 2 h. The mixture was concentrated and used without further purification. Yield: 1.1 g (2.99 mmol; 99%) Int-139c HPLC: RT = 0.786 min, Method: Z011_S03 Step 4 To a mixture of Int-139c (1.1 g, 299 mmol), 5-methylpyrazine-2-carboxylic acid (0.496 g, 3.589 mmol), triethylamine (2.084 ml, 14.954 mmol) and DMF (15 ml) was added TBTU (1.056 g, 3.20 mmol). The mixture was stirred at room temperature for 12 h. The mixture was diluted with THF and water, concentrated and purified by HPLC. Yield: 1.1 g (3.01 mmol; 81.5%) Int-139d MS(ESI + ): (M+H) + 451, HPLC: RT = 0.987 min, Method: Z011_S03 Step 5 A mixture of Int-130d (1.1 g, 2.437 mmol) and acetic acid (20 ml) was stirred at 90 °C for 4 h. The mixture was then concentrated and THF and MeOH were added. Triethylamine was added until the mixture showed an alkaline pH. The mixture was then purified by HPLC. The product was isolated as a mixture of four stereoisomers separated by chiral SFC. Yield: 0.9 g (3.01 mmol; 85.2%) MS (ESI + ): (M+H) + 433, HPLC: RT = 1.145 min, method: Z011_S03 Similar to Example 139, the following compounds were obtained. The product was a mixture of four stereoisomers separated by chiral SFC: Example 141, 141-1, 141-2, 142 Example 143 and Example 144 Step 1: PPA (50% solution in EtOAc, 9.72 mL, 15.88 mmol) was added to a mixture of N1-ethyl-4-fluorobenzene-1,2-diamine (1.36 g, 7.94 mmol), 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid (2.27 g, 8.34 mmol) and NMM (5.2 mL, 47.66 mmol) in 30 mL DCM at 0 °C, and the mixture was then stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo, EtOAc and water were added and the organic layer was washed with an aqueous NaHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative HPLC. The product was isolated as a mixture of stereoisomers. Yield: 2.6 g (6.81 mmol; 86%) Int-143a MS (ESI + ): (M+H) + 382; HPLC: RT = 0.8 min, method: Z011_S03 Step 2: A mixture of Int-143a (2.6 g, 5.45 mmol) and zinc bromide (2.59 g, 11.45 mmol) in 87 ml of butyl acetate was stirred at 110 °C for 22 h. The mixture was cooled and concentrated in vacuo. Ice-cooled water (50 ml) was added to the residue and stirred for several minutes. Concentrated aqueous ammonia solution (4 ml) was then added. The resulting solid was filtered and dried to give the product in the form of a mixture of stereoisomers. Yield: 2.05 g (5.45 mmol; 99%) of Int-143b MS (ESI + ): (M+H) + 264; HPLC: RT = 0.89 min and 0.92 min, method: Z003_S05 Step 3: PPA (50% solution in EtOAc, 4.21 mL, 7.08 mmol) was added to a mixture of Int-143b (2.05 g, 5.45 mmol) containing 5-methylpyrazine-2-carboxylic acid (2.27 g, 8.34 mmol) and TEA (3.02 mL, 21.79 mmol) in 20 mL of EtOAc at 0 °C and then stirred at ambient temperature for 2 h. The mixture was concentrated in vacuo, DCM and water were added and the organic layer was washed with aqueous NaHCO 3 solution, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H2O + 0.1% NH4OH): 73:27 -> 53:47 ACN). Yield: 1.87 g (4.88 mmol; 89%) The product was separated as a mixture of four stereoisomers by chiral SFC to give Example 143, 143-1, 143-2 and Example 144 Example 145 and 146 Step 1 A mixture of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (9.65 g, 45.22 mmol), 2,2-difluoroethylamine (4.93 ml, 67.84 mmol) and potassium carbonate (9.38 g, 67.84 mmol) in 110 ml of ACN was stirred at 60 °C for 36 h. The mixture was poured into 500 ml of water and then concentrated in vacuo. The mixture was filtered and the remaining solid was washed with 500 ml of water. The solid was dried. Yield: 11.98 g (44.34 mmol; 98%) Int-145a MS (ESI + ): (M+H) + 271; HPLC: RT = 1.1 min, method: Z018_S04 Step 2: In a Parr apparatus at 60 psi and 25 °C, a mixture of Int-145a (1.34 g, 4.95 mmol) and palladium / charcoal (10%) in 27 ml of THF was hydrogenated for 2 h. The mixture was then filtered. The filtrate was evaporated in vacuo. The residue was used in the next step without further purification. Yield: 1.19 g (44.34 mmol; 100%) Int-145b HPLC: RT = 0.94 min, method: Z011_S03 Step 3: Prepared from Int-145b and 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid analogously to step 1 of Example 143. Yield: 2.55 g (4.92 mmol; 99%) Int-145c MS (ESI + ): (M+H) + 468 Step 4: Prepared from Int-145c and zinc bromide analogously to step 2 of Example 143. Yield: 1.78 g (4.08 mmol; 83%) Int-145d MS (ESI + ): (M+H) + 350 HPLC: RT = 1.04 min and 1.02 min, method: Z011_S03 Step 5: Prepared from Int-145d and 5-methylpyrazine-2-carboxylic acid analogously to step 3 of Example 143. Yield: 0.83 g (1.76 mmol; 43%) The product was separated into a mixture of four stereoisomers by chiral SFC, yielding Examples 145, 145-1, 145-2, and 146. The following examples were prepared in a manner similar to Example 1 as a mixture of four stereoisomers separated by chiral SFC, yielding Examples 147, 147-1, 147-2, and 148. Example 149 Step 1: Over a 15-minute period, a 2.5 M solution of n-butyllithium in hexanes (1.91 g, 30 mmol) was added to a stirred solution of R-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5 g, 27 mmol) in THF (50 ml) at -78 °C, and the mixture was stirred at -78 °C for 1 h. Subsequently, 30 ml of THF containing dihydropyran-3-one (2.72 g, 27 mmol) was added dropwise, and the mixture was stirred at -25 °C for 30 min. The mixture was quenched by the addition of acetic acid (dissolved in THF), diluted with water (30 ml), and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography using silica gel (eluent; 30% EtOAc / petroleum ether). Yield: 5.5 g (19 mmol; 71%) Int-149a Step 2: At 0 °C, a 0.2 N hydrochloric acid solution (150 ml) was added dropwise slowly to a mixture of Int-149a (15 g, 53 mmol) in THF (50 ml), and the mixture was stirred at room temperature for 16 h. The pH of the reaction mixture was adjusted to 7.5 with sodium hydroxide solution and freeze-dried. The crude product was used without further purification. Yield: 9.5 g (19 mmol; 95%) Int-149b Step 3: At room temperature, triethylamine (6.42 g, 63 mmol) and di-tert-butyl dicarbonate (9.23 g, 42 mmol) were added to a mixture of Int-149b (8 g, 42 mmol) in THF (80 ml). The mixture was stirred at room temperature for 2 h. Subsequently, the mixture was diluted with water and extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with brine solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography using silica gel with 50% EtOAc / petroleum ether. Yield: 2.8 g (10 mmol; 23%) Int-149c Step 4: Lithium hydroxide monohydrate (1.51 g, 36 mmol) was added to a stirred solution of Int-149c (5.2 g, 18 mmol) in THF (50 ml) and water (10 ml). The mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated, diluted with water, and extracted with EtOAc (2 x 30 ml). The aqueous layer was acidified with citric acid (pH 6) and extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography using silica gel with 80% EtOAc / petroleum ether. Yield: 4.2 g (15 mmol; 85%) Int-149d. Step 5: A solution of 2M ethylamine in THF (71.45 ml, 142.9 mmol) was added dropwise to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (10 ml, 71.45 mmol) in DCM (300 ml). The mixture was stirred overnight. Subsequently, DCM (100 ml) was added and the mixture was extracted with water (250 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. Yield: 16.6 g (70.88 mmol; 99%) Int-149e MS (ESI + ): (M+H) + 235; HPLC: RT = 1.1 min, method: Z017_S04 Step 6: At room temperature, a mixture of Int-149e (1.4 g, 5.97 mmol) and 10% palladium on charcoal (150 mg) in methanol (50 ml) was hydrogenated at 50 psi. The mixture was filtered and the filtrate was concentrated in vacuo. Yield: 1.22 g (5.97 mmol; 99%) Int-149f HPLC: RT = 0.97 min, method: Z011_S03 Step 7: At 0 °C, PPA 50% (2.47 ml, 4.19 mmol) was added to a mixture of Int-149f (0.51 g, 2.51 mmol), Int-149d (0.6 g, 2.09 mmol) and N-methylmorpholine in DCM (20 ml). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated, EtOAc was added and the mixture was extracted with water. The organic layer was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography. Yield: 1.22 g (5.97 mmol; 99%) of Int-149g MS (ESI + ): (M+H) + 462; HPLC: RT = 1.06 min, method: Z011_S03 Step 8 A mixture of Int-149g (0.51 g, 1.11 mmol) and acetic acid (10 ml, 174.5 mmol) was stirred at 50 °C for 24 h and at 90 °C for 24 h. The mixture was concentrated in vacuo. THF and methanol were added to the residue and TEA was added until the mixture was basic. This mixture was purified by HPLC. Yield: 1.22 g (5.97 mmol; 99%) of Int-149h MS (ESI + ): (M+H) + 444; HPLC: RT = 1.13 min, method: Z011_S03 Step 9 A mixture of Int-149h (0.2 g, 45 mmol) and 4 M hydrochloric acid in dioxane (5 ml) was stirred at room temperature for 2 h. The mixture was concentrated and used without further purification. Yield: 1.22 g (5.97 mmol; 99%) of Int-149i HPLC: RT = 0.91 min, method: Z011_S03 Step 10 To a mixture of Int-149i (0.085 g, 0.22 mmol), 5-methylpyrazine-2-carboxylic acid (0.037 g, 0.27 mmol) and TEA (0.16 ml, 1.12 mmol) in 5 ml of DMF was added TBTU (0.079 g, 0.25 mmol). The mixture was stirred at room temperature for 2 h. Water and acetonitrile were added. The mixture was filtered and concentrated. The residue was purified by HPLC. Yield: 0.081 g (0.17 mmol; 78%) of Example 149 Similar to Example 149, the following examples were obtained. Example 154 Step 1 At a temperature below -65 °C, a solution of n-butyllithium (39.375 ml, 63 mmol, 1.6 N in hexane) was added dropwise to a mixture of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (11.948 ml, 60 mmol) in anhydrous THF (250 ml) cooled to -75 °C. The resulting mixture was stirred at this temperature for 1 h. Then, a mixture of oxolan-3-one (4.571 ml, 60 mmol) in anhydrous THF (80 ml) was added dropwise while maintaining the temperature below -55 °C. The mixture was stirred at this temperature for 1 h. Then, glacial acetic acid (3.61 ml, 63 mmol) dissolved in THF (30 ml) was added dropwise. The mixture was diluted with diethyl ether (500 ml) and extracted twice with sodium bicarbonate (2%, 250 ml each time). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Purification was achieved by silica gel column chromatography (eluent: cyclohexane / ethyl acetate). Yield: 6.35 g (23.5 mmol; 39%) of Int-154a and 2.48 g (9.17 mmol, 15.3%) of Int-154b Step 2 A mixture of Int-154a (2 g, 7.399 mmol), hydrochloric acid (0.2 N, 73.98 ml, 14.797 mmol) and THF (50 ml) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo, freeze-dried and used in the next step without further purification. Yield: 3.24 g (40% purity) of Int-154c Step 3 To a mixture of Int-154c (3.24 g, purity 40%, 7.3 mmol), THF (75 ml) and triethylamine (6.187 ml, 44.38 mmol) was added 5-methylpyrazine-2-carboxylic acid (2.146 g, 15.536 mmol), and the mixture was cooled in an ice bath. Subsequently, CIP (4.328 g, 15.536 mmol) was added. The mixture was stirred for 5 min under ice cooling and for 1 h at room temperature. The mixture was concentrated in vacuo. The residue was dissolved in methanol (20 ml), filtered and purified by HPLC (XBridge C18, water / NH 4 OH / CAN, flow rate 50 ml, T column = 600 °C). The eluates containing the product were combined and stirred for 2 h on a rotary evaporator (bath temperature 450 °C). After concentration in vacuo, the residue was lyophilized. Yield: 0.8 g (2.844 mmol, 38.4%) of Int-154d Step 4 To a mixture of 1-fluoro-4-methyl-2-nitrobenzene (15 g, 82.885 mmol), potassium carbonate (22.911 g, 165.769 mmol) and THF (150 ml) was added THF containing ethylamine solution (2 N, 82.885 ml, 165.769 mmol). The resulting mixture was stirred at room temperature for 16 h and filtered. The mixture was concentrated in vacuo, ether was added and the mixture was concentrated again in vacuo. Yield: 16.75 g (83.49 mmol, 100%) of Int-154e Step 5 A mixture of Int-154e, THF (30 ml) and Raney nickel (300 mg) was hydrogenated at 60 psi and room temperature for 7 h. After 1 h, an additional 300 mg of Raney nickel was added. The mixture was then filtered and concentrated in vacuo. Yield: 2.1 g (12.307 mmol, 98.8%) of Int-154f Step 6 To a cold mixture of Int-154f (180 mg, 1.055 mmol), Int-154d (370.8 mg, 1.055 mmol) and DMF (12 ml) was added diisopropylethylamine (0.735 ml, 4.219 mmol) and T3P (1.243 ml, 2.11 mmol). The mixture was stirred for 1 h under ice cooling. The mixture was then allowed to reach room temperature and stirred for 20 h. After addition of methanol, the mixture was filtered and purified by HPLC (XBridge C18, water / NH 4 OH / ACN, flow rate 50 ml, T column = 600 °C). The eluates containing the product were combined, concentrated in vacuo and lyophilized. Yield: 43 mg (0.099 mmol, 9.4%) Int-154 g Step 7 A mixture of Int-154 g (58 mg, 0.134 mmol) and glacial acetic acid (3 ml) was stirred at 85 °C for 3 h. Ethyl acetate (30 ml) and potassium carbonate solution were added at room temperature. The organic phase was separated and dried over sodium sulfate. Similar to Example 154, the following compounds were obtained Similar to Example 143, the following examples were obtained: The following examples were obtained similar to Example 143: Example 159, 159-1, 159-2, 160 The following examples were obtained similar to Example 143: Example 161, 161-1, 161-2, 162 The following examples were obtained similar to Example 143: Example 163, 163-1, 163-2, 164 Except for Step 8, the following compounds were obtained similar to Example 14. In Step 8, the product consisting of two stereoisomers was purified by crystallization to obtain a single stereoisomer. Example 14 Examples 165 and 166: Step 8: TFA (5.083 ml, 65.88 mmol) was added to 30 ml of DCM containing Int-165 g (2.5 g, 6.589 mmol) at 5 °C. The cooling was removed and the mixture was stirred at ambient temperature for 6.5 h. DCM (50 ml) was added to the mixture and then water (150 ml) was added. The organic phase was extracted twice with water (100 ml). By adding concentrated NH 3The aqueous solution adjusted the combined aqueous phase to a pH of approximately 10. The aqueous layer was extracted with ethyl acetate (250 ml). The combined organic layers were dried over MgSO 4 and concentrated in vacuo. Ethanol (11.75 ml) and water (0.62 ml) were added to the residue (1.67 g). The mixture was heated at 70 °C. Then 5-methylpyrazine-2-carboxylic acid (0.775 g, 5.612 mmol) was added. Ethanol (5.87 ml) and water (0.31 ml) were added to this mixture, and the mixture was heated at 70 °C for 1 hour. Thereafter, the mixture was slowly cooled to room temperature. Subsequently, the mixture was cooled to 20 °C within 1 minute. The mixture was filtered, washed with ethanol (3 ml) and dried with a dry gun at 50 °C. Yield: 1.81 g (4.33 mmol; 73%) of Int-165h in the salt form of 5-methylpyrazine-2-carboxylic acid Step 9: A mixture of Int-165h (0.55 g, 1.32 mmol) in the salt form of 5-methylpyrazine-2-carboxylic acid, NMM (0.581 mL, 5.27 mmol) in 5.5 ml of EtOAc and 5-methylpyrazine-2-carboxylic acid (90.9 mg, 0.66 mmol) was cooled to 0 °C with stirring. Subsequently, PPA (50% solution in EtOAc; 1.165 mL, 1.97 mmol) was added. After 10 min, the cooling was removed and the mixture was stirred at ambient temperature for 45 min. Ethyl acetate (20 ml) was added to the mixture, and then the mixture was extracted twice with sodium bicarbonate solution. The combined organic phases were dried over MgSO 4 and concentrated in vacuo. The residue was dissolved in THF / MeOH and purified by chromatography (XBridge C18, 10, (H2O + 0.1% NH4OH + 28 - 48% ACN)). The eluates containing the product were combined and concentrated in vacuo. The product in the form of a single stereoisomer was obtained. Yield: 0.461 mg (1.15 mmol; 87%) of Example 165. Similar to Example 165, the following compounds were obtained. Starting from Int-154b, Example 167 was prepared in a manner similar to Example 154.

Claims

1. A compound of formula I, wherein A represents 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-, 4-6 membered heteroalkyl-, 4-6 membered heteroalkyl-C 1 -C 3 alkyl-, wherein the following group is optionally substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, fluoro; R 1 represents 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 - 6 - membered heterocycloalkylmethyl -, C 5 -C 6 heterocycloalkyl ethyl -, wherein the latter group is optionally substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 7 cycloalkoxy, hydroxy, fluoro; R 2 、R 3 、R 4 and R 5 each independently represents 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- to 6-membered C 4 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy-, C 3 -C 6 cycloalkoxy-, wherein the latter six groups are optionally substituted by 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, and fluoro; Provided that the group R 2 , R 3 , R 4 and R 5 is at least one not being hydrogen; R 6 represents halogen, C 1 -C 3 alkyl optionally substituted by 2 to 3 fluorine atoms; or a physiologically acceptable salt thereof.

2. The compound according to claim 1, wherein A represents 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 2 alkyl-, wherein the latter group is optionally substituted by 1 to 4 substituents selected from methyl, methoxy, hydroxy, and fluorine.

3. The compound according to claim 1 or 2, wherein R 1 represents 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 -, where the latter group is optionally substituted with 1 to 4 substituents selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 4 cycloalkoxy, hydroxy, fluoro 4. The compound according to any one of the preceding claims, wherein R 2 、R 3 、R 4 and R 5 each independently represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, cyclopropyl, methoxy, where the latter three groups are optionally substituted by 2 to 3 fluorine substituents, provided that at least one of the groups R 2 、R 3 、R 4 and R 5 is not hydrogen.

5. The compound according to any one of the preceding claims, wherein R 6 represents an optionally C-substituted by 2 to 3 fluorine atoms 1 -C 3 alkyl group.

6. The compound according to any one of the preceding claims, wherein A represents a group selected from the group consisting of:

7. The compound according to any one of the preceding claims, wherein R 1 represents a substituent selected from the group consisting of:

8. The compound according to any one of the preceding claims, wherein R 2 represents hydrogen.

9. The compound according to any one of the preceding claims, wherein R 3 represents hydrogen, fluorine, bromine and trifluoromethyl.

10. The compound according to any one of the preceding claims, wherein R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, CF 3 O− and CHF 2 O−.

11. The compound according to any one of the preceding claims, wherein R 5 represents hydrogen, fluorine, chlorine, methyl, ethyl, cyclopropyl and methoxy.

12. The compound according to any one of the preceding claims, wherein R 6 represents methyl, trifluoromethyl and -CF 2 H.

13. The compound according to any one of the preceding claims, namely a compound selected from the group consisting of:

14. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 13.

15. The compound according to any one of claims 1 to 13 or the pharmaceutically acceptable salt according to claim 14, wherein the compound or pharmaceutically acceptable salt is used as a medicine.

16. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt according to claim 14.

17. The compound according to any one of claims 1 to 13 or the pharmaceutically acceptable salt according to claim 14, wherein the compound or pharmaceutically acceptable salt is used for the treatment and / or prevention of a disease or disorder, wherein inhibiting the activity of metabotropic glutamate receptor subtype 4 (mGluR4) has a therapeutic benefit.

18. The compound according to any one of claims 1 to 13 or the pharmaceutically acceptable salt according to claim 14 for use according to claim 17, wherein the disease or disorder is a psychiatric, neurological, neurodegenerative, non-neuronal or metabolic disease, cancer or related disorder.

19. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt according to claim 14 for use according to the use of claim 17 or 18, wherein the disease or disorder is selected from the group consisting of: psychiatric and neurological conditions associated with impulse control deficits or maladaptive impulses; substance use disorders; personality disorders such as borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders such as bulimia nervosa; attention deficit hyperactivity disorder; bipolar disorder; stress-related conditions such as post-traumatic stress disorder; tic disorders such as Tourette's syndrome; movement disorders such as restless legs syndrome; cognitive dysfunction in psychiatric or neurological conditions, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric conditions; overweight, obesity; cancer and related conditions associated with maladaptive tumorigenesis such as osteosarcoma.

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