Novel substituted pyrazine-carboxamide-imidazopyridine derivatives

Abstract

# imgabs0 # The invention relates to compounds of formula I, processes for their preparation, 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, Xa, Xb, Xc, Xd, A, R1 and R6 have the meanings given in the specification.

Description

Technical Field

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

[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 often leads to neurological or psychiatric disorders. Therefore, the regulation of the glutamatergic system is considered an attractive therapeutic direction.

[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 effects by coupling to G proteins and activating second messenger systems.

[0004] mGluR subtypes are divided into three groups (distinguished by sequence homology, pharmacology, and 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 ExpTher, 2001, 299:12-20), where they regulate glutamatergic as well as GABAergic transmission. Activation of Group III receptors, including mGluR4, reduces neurotransmitter release due to the activation of Gαi / o, resulting in decreased adenylate cyclase activity.

[0005] The mGluR4 receptor is mainly located at the presynaptic terminals of nerve endings. The expression of mGluR4 has been confirmed in multiple brain regions, with high expression in brain regions such as the basal ganglia and cerebellum. 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 motor control (including Parkinson's disease), impulse control, learning and memory, anxiety, pain, cerebellar function, epilepsy, and the regulation of 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 it has been reported that mGluR4 is also expressed in peripheral tissues such as the islets of Langerhans, but not limited thereto, antagonists of mGluR4 function are also considered to have therapeutic effects in diseases including but not limited to metabolic diseases, gastrointestinal diseases, and cancers (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 it has been reported that mGluR4 is also expressed in the vagal afferents and in the central satiety pathways and brain circuits, antagonists of mGluR4 function are also considered to potentially have therapeutic effects in diseases 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 these compounds seems to be too low to be suitable as drugs, especially since acidic arylsulfonamides may additionally undergo efflux at the blood-brain barrier, which limits their brain exposure upon CNS administration. Detailed Description of the Invention

[0010] The present invention provides novel substituted pyrazine-carboxamide derivatives of formula I

[0011]

[0012] wherein

[0013] A represents C1-C6 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl-C1-C2 alkyl-, C1-C3 alkyl-O-C1-C3 alkyl-, 4-6 membered heterocycloalkyl-, 4-6 membered heterocycloalkyl-C1-C3 alkyl-, with the latter groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, fluoro;

[0014] Xa represents N or C-R 2 ;

[0015] Xb represents N or C-R 3 ;

[0016] Xc represents N or C-R 4 ;

[0017] Xd represents C-R 5 ;

[0018] with the proviso that one of Xa, Xb and Xc represents N;

[0019] R 1 represents C1-C7 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C7 cycloalkyl, 4-6 membered heterocycloalkyl, C3-C7 cycloalkyl-C1-C3 alkyl-, 4-6 membered heterocycloalkylmethyl-, C5-C6 heterocycloalkyl ethyl-, with the latter groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C7 cycloalkoxy, hydroxy, fluoro;

[0020] R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, halogen, cyano, C1-C4 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C6 cycloalkyl, 4-6 membered C4-C6 heterocycloalkyl-, C1-C4 alkoxy-, C3-C6 cycloalkoxy-, with the latter six groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, fluoro;

[0021] R 6 represents halogen, C1-C3 alkyl optionally substituted by 2-3 fluorine atoms;

[0022] or a physiologically acceptable salt thereof.

[0023] In another embodiment, the present invention provides compounds of formulae Ia, Ib and Ic

[0024]

[0025] wherein

[0026] A represents C1-C6 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl-C1-C2 alkyl-, C1-C3 alkyl-O-C1-C3 alkyl-, 4-6 membered heterocycloalkyl-, 4-6 membered heterocycloalkyl-C1-C3 alkyl-, the latter groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, fluorine;

[0027] R 1 represents C1-C7 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C7 cycloalkyl, 4-6 membered heterocycloalkyl, C3-C7 cycloalkyl-C1-C3 alkyl-, 4-6 membered heterocycloalkylmethyl-, C5-C6 heterocycloalkyl ethyl-, the latter groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C7 cycloalkoxy, hydroxy, fluorine;

[0028] R 2 , R 3 , R 4 and R 5 each independently represent hydrogen, halogen, cyano, C1-C4 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C6 cycloalkyl, 4-6 membered C4-C6 heterocycloalkyl-, C1-C4 alkoxy-, C3-C6 cycloalkoxy-, the latter six groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, fluorine;

[0029] R 6 represents halogen, C1-C3 alkyl optionally substituted by 2-3 fluorine atoms;

[0030] or a physiologically acceptable salt thereof.

[0031] In another embodiment, in general formula I according to any one of the foregoing embodiments,

[0032] A represents C1-C3 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkylmethyl-, tetrahydrofuranyl-, tetrahydropyranyl-, 1,4-dioxanyl-, tetrahydrofuranylmethyl-, tetrahydropyranylmethyl-, 1,4-dioxanylmethyl-, C1-C2 alkyl-O-C1-C3 alkyl-, and the latter group is optionally substituted with 1-4 substituents selected from methyl, methoxy, hydroxy, and fluorine.

[0033] In a further embodiment, in the general formula I according to any one of the foregoing embodiments,

[0034] R 1 represents C1-C3 alkyl, C1-C2 alkyl-O-C1-C3 alkyl-, C3-C4 cycloalkyl, C4-C5 heterocycloalkyl, C3-C4 cycloalkyl-O-C1-C3 alkyl-, and the latter group is optionally substituted with 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, hydroxy, and fluorine.

[0035] In a further embodiment, in the general formula I according to any one of the foregoing embodiments,

[0036] R 2 、R 3 、R 4 and R 5 each independently represent hydrogen, fluorine, chlorine, bromine, cyano, methyl, cyclopropyl, methoxy, and the latter three groups are optionally substituted with 2-3 fluorine substituents.

[0037] In a further embodiment, in the general formula I according to any one of the foregoing embodiments,

[0038] R 6 represents C1-C3 alkyl optionally substituted with 2-3 fluorine atoms.

[0039] In another embodiment, in the general formula I according to any one of the foregoing embodiments,

[0040] A represents a group selected from the following:

[0041]

[0042] In another embodiment, in the general formula I according to any one of the foregoing embodiments,

[0043] R 1 represents a substituent selected from ethyl, -CH2-CHF2, and isopropyl.

[0044] In another embodiment, in the general formula I according to any one of the foregoing embodiments,

[0045] R2 represents hydrogen.

[0046] In another embodiment, in general formula I according to any one of the foregoing embodiments,

[0047] R 3 represents hydrogen, methyl and trifluoromethyl.

[0048] In another embodiment, in general formula I according to any one of the foregoing embodiments,

[0049] R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, methyl and trifluoromethyl.

[0050] In another embodiment, in general formula I according to any one of the foregoing embodiments,

[0051] R 5 represents hydrogen, methyl and methoxy.

[0052] In another embodiment, in general formula I according to any one of the foregoing embodiments,

[0053] R 6 represents methyl, trifluoromethyl and -CF2H.

[0054] The compounds of the present invention are potent negative modulators of mGluR4, which inhibit the function of mGluR4, thereby blocking glutamate-induced reduction of intracellular cAMP.

[0055] Accordingly, the present invention provides compounds for the treatment of mGluR4-mediated disorders.

[0056] The present invention also provides a method for treating an mGluR4-mediated disorder in a human individual, which comprises administering to the individual a compound of the present invention or a composition of the compound or a pharmaceutically acceptable salt thereof.

[0057] In one aspect, the present invention relates to a method for treating a disorder in which reducing mGluR4 activity can alleviate the severity of the disorder, which is carried out by administering a compound that inhibits the function of mGluR4, such as a compound that inhibits glutamate-induced reduction of intracellular cAMP described herein. Compounds as mGluR4 function antagonists are described herein, which have an IC for mGluR4 inhibition 50 measurement of 50 nanomoles or less.

[0058] On the other hand, the compounds described herein as mGluR4 function antagonists can be used to inhibit the function of mGluR4, such as mGluR4-mediated glutamate-induced reduction of intracellular cAMP. In some embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced reduction of intracellular cAMP in vitro (e.g., in cultured cells). In other embodiments, the compounds described herein can be used to inhibit mGluR4-mediated glutamate-induced reduction of intracellular cAMP in vivo.

[0059] Definitions

[0060] 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.

[0061] The terms "negative modulator", "antagonist", and "inhibitor" are used interchangeably and refer to an agent that reduces or inhibits biological activity, such as reducing receptor activity, and includes negative allosteric modulators (NAMs). The mGluR4 receptors described herein include homomultimeric and heteromultimeric 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.

[0062] For the subject methods of inhibition or treatment, 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, produces the desired clinical or functional result. Without being bound by theory, an effective amount of an mGluR4 antagonist for the methods of the invention includes an amount of the mGluR4 antagonist that effectively reduces one or more in vitro or in vivo functions of the mGluR4 receptor. Exemplary functions include, but are not limited to, altered intracellular cAMP, or synaptic neurotransmitter release, or altered neuronal activity or modulation of impulse behavior. Compounds that antagonize mGluR4 function include compounds that antagonize the in vitro or in vivo functional activity of mGluR4. When a particular functional activity is readily observable only in an in vitro assay, the ability of a compound to inhibit mGluR4 function in that in vitro assay can be used as a reasonable representation of the activity of the compound. In certain embodiments, an effective amount is an amount sufficient to inhibit mGluR4-mediated cellular function.

[0063] The mGluR4 antagonists used in the methods of the present invention can be characterized according to their activity or lack of activity against one or more receptors. When referring to other receptors, inhibition of the function of such other receptors is similarly defined. For example, inhibition of the activity of a receptor or receptors means that the antagonist inhibits 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, for example, neurotransmitter release.

[0064] The terms "compound" and "agent" are used interchangeably and refer to the negative modulators of the present invention.

[0065] In the groups, radicals or moieties defined below, the number of carbon atoms is often indicated in front of the group, for example, C1-6 alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Generally, for a group containing two or more sub-groups, the last named sub-group is the radical attachment point, for example, the substituent "aryl-C1-3 alkyl-" means an aryl bound to a C1-3 alkyl group, the C1-3 alkyl group being bound to the group to which the core or substituent is attached.

[0066] In the case where the compounds of the present invention are described in the form of chemical names and as chemical formulas, if there is any inconsistency, the chemical formula shall prevail.

[0067] An asterisk can be used in a sub-formula to indicate the bond connecting to the defined core molecule.

[0068] Stereochemistry / Solvate / Hydrate

[0069] The compounds described herein can be chiral (e.g., having one or more stereogenic centers). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended to be encompassed. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.

[0070] The racemic mixture of the resolving compound can be carried out by any of a variety of methods known in the art. Exemplary methods include using "chiral resolving agent" to carry out fractional recrystallization, and chiral resolving agent is an optically active salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid, in the form of D and L. Other resolving agents suitable for fractional crystallization methods include α-methylbenzylamine (for example, S- and R- forms, or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine and 1,2-diaminocyclohexane.

[0071] The separation of the racemic mixture can also be carried out by eluting on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by those skilled in the art. Compounds of the present invention also include tautomeric forms, such as keto-enol tautomers.

[0072] Unless otherwise indicated, throughout the specification and appended claims, a given chemical formula or name shall encompass tautomers and all stereoisomers, optical isomers, and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers) and racemates thereof, as well as mixtures of individual enantiomers in varying proportions, mixtures of diastereomers, or mixtures in which any of the foregoing forms of such isomers and enantiomers are present.

[0073] The compounds of the present invention may also include all isotopes of atoms that occur in the intermediates or final compounds. For example, the compounds of the present invention may be treated with radioactive isotopes, such as, for example, tritium ( 3 H) or carbon-14 ( 14 C) radiolabeled. All isotopic variations, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0074] Salt

[0075] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are suitable within the scope of sound medical judgment without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0076] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound forms salts with acids or bases.

[0077] 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 or tartaric acid. Also included are salts of amino acids such as arginine salts, 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).

[0078] The compounds of the invention in neutral form are preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties such as solubility in polar solvents, but for the purposes of the invention, the salt is equivalent to the parent form of the compound.

[0079] Halogen

[0080] The term halogen generally denotes fluorine, chlorine, bromine and iodine.

[0081] Alkyl

[0082] The term “C 1-n alkyl” (where n is an integer from 2 to n), alone or in combination with another radical, denotes an acyclic, saturated, branched or straight-chain hydrocarbon radical having from 1 to n C atoms. For example, the term C1-C5 alkyl includes the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0083] Cycloalkyl

[0084] The term “C 3-n cycloalkyl” (where n is an integer from 4 to n), alone or in combination with another radical, denotes a cyclic, saturated, unbranched hydrocarbon radical having from 3 to n C atoms. For example, the term C 3-7Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0085] Heterocycloalkyl:

[0086] The term "heterocycloalkyl" means 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, where the heteroatoms are not part of the aromatic ring.

[0087] Many of the terms given above can be reused in the definitions of formulas or groups, and in each case independently have one of the meanings given above.

[0088] According to the present invention, the compounds of general formula (I) are obtained by methods known per se, for example by the following methods:

[0089] (a) The preparation of the compounds of general formula (I) is described in the examples or can be carried out, for example, according to Scheme 1 below

[0090]

[0091] where A, Xa, Xb, Xc, Xd, and R 1 to R 6 are defined as described in Embodiment 1,

[0092] and they can optionally be protected at any amino, hydroxyl, carboxyl, or thiol group with common protecting groups, such as those described in "Protective Groups in Organic Synthesis" by T.W. Greene, P.G.M. Wuts, Wiley, 1991 and 1999, and the protecting groups can be cleaved by methods known in the literature.

[0093] Scheme 1

[0094]

[0095]

[0096] where

[0097] Q represents a leaving group or a group that can be converted in situ into a leaving group, such as a halogen atom, hydroxyl group, C 1-4 alkoxy, alkoxycarbonyloxy, 4-pentafluorophenoxy, nitrophenoxy, trichloromethyl, or acyloxy, or together with a carbonyl group represents an alkali metal carboxylate group, and

[0098] R11 represents a protecting group for a carboxylate functional group known in the literature, such as, for example, tert-butyl, methyl, ethyl, allyl or benzyl, and

[0099] R12 represents a protecting group for an amino functional group known in the literature, such as, for example, tert-butoxycarbonyl, benzyloxycarbonyl or trifluoroacetyl, and

[0100] R13 represents a leaving group for an alkylation reaction, such as, for example, an iodine or bromine atom or a tosylate group or a mesylate group, and

[0101] R14 represents a leaving group for a nucleophilic aromatic substitution reaction, such as, for example, a fluorine or chlorine atom.

[0102]

[0103] The reaction step i (substitution) shown in Route 1 can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0104] In a solvent such as dichloromethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base such as potassium carbonate, sodium hydride, triethylamine or Hünig’s base, at a temperature of -20 - 200 °C, but preferably at a temperature of -10 - 100 °C, the compound of general formula II is mixed with the compound of general formula XIII.

[0105]

[0106] The reaction step ix (substitution, followed by nitro reduction) shown in Route 1 can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0107] Substitute the substrate IX with the amine XII as described above, followed by nitro reduction as described below:

[0108] The reduction of nitro to amino can be achieved in an aqueous solvent (such as in water, isopropanol / water, tetrahydrofuran / water or dioxane / water), or in a solvent such as diethyl ether, tetrahydrofuran, 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 of -40 - 100 °C, preferably at a temperature of -10 - 50 °C. Alternatively, the reduction can be carried out in the presence of a catalyst such as palladium / carbon, Raney nickel or platinum, in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally adding an acid such as hydrochloric acid, at a temperature of -20 - 50 °C, but preferably at a temperature of 0 °C to ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar, with hydrogen.

[0109]

[0110] Reaction steps ii and iv (acylation) can be carried out in the manner described in the examples or according to the conditions known in the literature, for example as follows:

[0111] By acylating the amine (III or IV) with an optionally activated carboxylic acid (XI):

[0112] The acylation is conveniently carried out in a solvent such as dichloromethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran, 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 Hunig's base, at a temperature of -20 - 200 °C, but preferably at a temperature of -10 °C - 100 °C, with the corresponding halide or acid anhydride.

[0113] However, acylation can also be carried out, optionally in the presence of an acid activator or dehydrating agent, such as 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 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 adding an auxiliary base such as sodium hydroxide solution, a carbonate or bicarbonate of cesium, potassium or sodium, or an amine base such as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine, at a temperature of -20 to 200 °C, but more preferably at a temperature of -10 to 160 °C with a free acid.

[0114] Other methods of amide coupling are described, for example, in “Comprehensive Functional Group Interconversions” by P.D. Bailey, I.D. Collier, K.M. Morgan, Volume 5, pages 257 et seq., Pergamon 1995, or Houben-Weyl Supplementary Volume 22, published by Thieme, 2003, and the literature cited therein.

[0115]

[0116] Reaction step viii (acylation followed by deprotection) can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0117] Acylate the amine-carrying substrate VIII with reagent XI as described above, and then cleave the protecting group as described below:

[0118] Any protecting group used may optionally subsequently be cleaved, for example by hydrolysis in an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or 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, for example in the presence of iodotrimethylsilane, at a temperature of from 0 to 100 °C, preferably at a temperature of from 10 to 50 °C.

[0119] However, benzyl, methoxybenzyl or benzyloxycarbonyl are cleaved by hydrogenolysis, for example, in the presence of a catalyst such as palladium / carbon, in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at a temperature of from 0 to 50 °C, but preferably at ambient temperature, and with hydrogen at a hydrogen pressure of from 1 to 7 bar, but preferably from 1 to 5 bar.

[0120] However, the protecting groups can also be cleaved by the methods described in “Protective Groups in Organic Synthesis” by T.W. Greene, P.G.M. Wuts, Wiley, 1991 and 1999.

[0121]

[0122] 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:

[0123] Acylate the amine-bearing substrate V with reagent VI or VII as described above, followed by cyclization as described below:

[0124] The cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, acetic acid, benzene, chlorobenzene, toluene, xylene, ethylene glycol, ethylene glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide or tetralin, dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, for example at a temperature of from 0 to 250 °C, but preferably at a temperature of from 20 to 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 ethoxide or potassium tert-butoxide or in the presence of a metal salt such as lithium bromide, aluminum bromide, zinc bromide or aluminum-donated montmorillonite clay. However, the cyclization can also be carried out without a solvent and / or a condensing agent.

[0125]

[0126] Reaction step vi (acylation, followed by deprotection and cyclization) can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0127] Acylate the amine-carrying substrate VI with reagent X as described above, then cleave the protecting group as described above, and then carry out cyclization as described above.

[0128]

[0129] Reaction step x (acylation, followed by deprotection) shown in Route 1 can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0130] Acylate substrate VI with carboxylic acid or carboxylic acid derivative X as described above, and then carry out deprotection as described above.

[0131]

[0132] Reaction step xi (acylation, followed by cyclization) shown in Route 1 can be carried out in the manner described in the examples or according to conditions known in the literature, for example as follows:

[0133] Acylate substrate XIV with carboxylic acid or carboxylic acid derivative XI as described above, and then carry out cyclization as described above.

[0134] The terms "mGluR4", "mGluR4 protein" and "mGluR4 receptor" are used interchangeably throughout the application. Unless otherwise specified, the term mGluR4 includes homomeric structures (such as homomeric mGluR4) and heteromeric structures (such as heteromeric mGluR4-mGluR2).

[0135] Biological assay

[0136] The biological activity of the compound is determined by the following method:

[0137] A. In vitro test of mGluR4 potency

[0138] The in vitro activity of the compounds according to the invention can be studied as follows:

[0139] HEK293 cells overexpressing 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 dispensed into the wells of a assay plate from a stirred spinner flask. 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 uL of HBSS / HEPES buffer (10 uL of buffer remained in the wells after washing), 5 uL / 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 assay plate. Thereafter, 5 uL / well of L-glutamate (final concentration: 10 uM), forskolin (final concentration: 1 uM) and 1 mM IBMX (final concentration: 0.5 mM) dissolved in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) was added to the assay plate (final DMSO concentration: 1%). Several wells of the assay plate were used for positive and negative controls or for the cAMP standard curve. The assay plate was incubated at room temperature for 30 minutes. Then 5 ul / well of the anti-cAMP antibody d2 solution and 5 ul / well of the cAMP-Europium Cryptate dilution were added to all wells of the plate, and the plate was incubated at room temperature for another 60 minutes in the dark. TM Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) were measured on an EnVision

[0140] The cAMP standards were prepared by diluting the 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 ul / well of HBSS / Hepes buffer in the wells of the assay plate plus 5 ul / well of 4% DMSO in HBSS / Hepes containing 0.2% BSA (final DMSO concentration: 1% - the same as the wells containing the compound). The final cAMP concentrations in the assay plate were: 0, 0.17, 0.69, 2.78, 11.1, 44.5, 178 and 712 nM (two wells / cAMP concentration).

[0141] Each assay microtiter plate also has wells with a mediator control instead of a compound as a control for the L-glutamate-induced signal (negative control; 100% CTL; 10 uM L-glutamate + 1 uM forskolin + 0.5 mM IBMX + 1% DMSO), and wells with a mediator control without L-glutamate as a control for non-specific changes in the signal (positive control; 0% CTL; 0 uM L-glutamate + 1 uM forskolin + 0.5 mM IBMX + 1% DMSO).

[0142] Data analysis was performed by calculating the ratio of the emission at 665 nm to the emission at 615 nm (Em665 / Em615 ratio). Thereafter, using the positive and negative controls, the signal of the compound was normalized by the following formula:

[0143] PoC = 100 x ((signal sample - positive control) / (negative control - positive control))

[0144] B. Evaluation of metabolic stability in human liver microsomes (human MST)

[0145] The metabolic stability of the compounds according to the invention can be studied as follows:

[0146] The metabolic degradation of the test compound was determined using pooled human liver microsomes at 37°C. The final incubation volume of 100 μL at each time point contained TRIS buffer (0.1 M) at pH 7.6 at room temperature, MgCl2 (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM. After a short pre-incubation at 37°C, the reaction was initiated by adding reduced β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and the reaction was terminated at different time points by transferring an aliquot to the solvent. After centrifugation (10,000 g, 5 min), the amount of the parent compound in the aliquot of the supernatant was determined by LC-MS / MS. The half-life (t 1 / 2 ) was determined from the slope of the semi-logarithmic plot of the concentration-time curve.

[0147] C. Evaluation of efflux in Madin-Darby canine kidney (MDCK) cells transfected with the human MDR1 gene

[0148] The apparent permeability coefficient (PE) of the compound across the MDCK-MDR1 cell monolayer was measured (at pH 7.4, 37 °C) in the apical-to-basolateral (AB) and basolateral-to-apical (BA) transport directions. AB permeability (PEAB) represents the absorption of the drug from the blood into the brain, and BA permeability (PEBA) represents the efflux of the drug from the brain back into the blood via passive permeability and active transport mechanisms mediated by efflux and uptake transporters (primarily overexpressed human MDR1 P-gp) expressed on MDCK-MDR1 cells. The compound was assigned to a permeability / absorption class by comparing the AB permeability with that of a reference compound with known in vitro permeability and oral absorption rate in humans. Similar or identical permeabilities in both transport directions indicate passive permeation, and vectorial permeability indicates additional active transport mechanisms. A higher PEBA than PEAB indicates active efflux mediated by MDR1 P-gp. Active transport is concentration-dependent and saturable.

[0149] 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). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x 7H2O, 0.41 mM NaH2PO4 x H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare the transport solution (0.1 - 300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) was applied to the apical or basolateral donor side to measure A-B or B-A permeability (3 replicate filters). The receiving side contained the same buffer as the donor side. Samples were collected from the donor side at the start and end of the experiment and from the receiving side at different time intervals up to 2 hours for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiving side volume was replaced with fresh receiving side solution.

[0150] D. Evaluation of the efficacy on impulsive behavior tested in the five-choice serial reaction time task (5-CSRTT) in rats

[0151] The assessment of the efficacy on motor impulsive behavior can be studied as follows:

[0152] 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 five positions on the arced wall of a nose-poke 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 into a reward receptacle on the other side of the chamber. Infrared beams in each choice hole and the reward receptacle allowed precise detection of the rats' performance during task-related operations. Motor impulsive behavior was defined as a response (premature response) occurring at any nose-poke hole before the onset of the light cue.

[0153] After achieving stable performance, a new analytical method was applied, which revealed that the number of premature responses made by individual animals over several months had trait-like (long-term) stability. Generally, this analysis enabled reliable classification of animals into high-impulse and low-impulse groups based on a longitudinal assessment of the number of premature responses made by the animals during training.

[0154] The experiment was conducted in a crossover design such that all subjects received both the vehicle and the compound on different dates, with an administration interval of approximately 2 weeks each time. Among the subjects, the order of vehicle and compound administration was random, while a third group received atomoxetine on both experimental days as a technical control.

[0155] As a standardized numerical threshold for impulsivity level, animals with >40 and <40 premature responses in the vehicle (in 200 initiated trials) were labeled as high-impulse and low-impulse, respectively. Importantly, this numerical-threshold-based labeling overlapped 80% with the longitudinal analysis of the training data (as described above). The high convergence of these two stratification methods enabled us to reliably compare the compound effects between stably high-impulse and stably low-impulse rats in the 5-CSRTT.

[0156] Biological data

[0157] Table 1: In vitro potency of the structurally closest compounds disclosed in WO2019 / 138017 (as determined in Assay A)

[0158]

[0159] The compounds of the present invention are structurally different from the compound closest in structure in the prior art (i.e., Intermediate 213 in WO 2019 / 138017) in that the hetero monocyclic ring bound as a formamide is a substituted pyrazine (6-membered heteroaryl) rather than a pyrazole moiety (5-membered heteroaryl). Although the compounds disclosed in WO2019 / 138017 are immunomodulators (IL-17 modulators), the compounds of the present invention are unexpectedly highly potent negative modulators of mGluR4 (see Table 2). Testing the compound closest in structure disclosed in WO2019 / 138017 in Assay A, it was found that it does not have therapeutically relevant activity as an mGluR4 modulator (Table 1). Unexpectedly, the compounds of the present invention are >100-fold more potent in Assay A. (Compare the data in Table 1 and Table 2).

[0160] Table 2: In vitro potency of the compounds of the present invention as determined in Assay A

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] Therapeutic use / Method of use

[0171] The present invention relates to compounds for the treatment and / or prevention of diseases, disorders and conditions in which inhibition of mGluR4 activity has a therapeutic benefit, including but not limited to the treatment of psychiatric and neurological disorders 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 such as bulimia nervosa, attention deficit hyperactivity disorder, bipolar disorder, stress-related disorders such as post-traumatic stress disorder, tic disorders such as Tourette syndrome, and other movement disorders such as restless legs syndrome. According to another aspect of the present invention, the compounds of the present invention are useful for treating mGluR4-related pathophysiological disorders, cognition, motivated behavior / reward, mood and stress, and aggressive behavior. Additionally, there is a therapeutic benefit in cancer and related conditions associated with maladaptive tumorigenesis such as osteosarcoma.

[0172] In view of their pharmacological actions, the compounds of the present invention are suitable for the treatment and / or prevention of diseases or disorders selected from the following:

[0173] (1) Disorders associated with dysfunctions of impulse control, such as pathological gambling, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, compulsive shopping, internet addiction, sexual compulsivity, sexual disorders, sexual dysfunction, psychosexual disorder, eating disorders, such as bulimia nervosa, binge eating disorder, anorexia nervosa, other specified feeding or eating disorder, obesity, overweight, cachexia, appetite / taste disorder, vomiting, nausea, Prader-Willi syndrome, hyperphagia, appetite / taste disorder, bipolar disorder, post-traumatic stress disorder;

[0174] (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 disorders, drug abuse or addiction or relapse, tolerance to anesthetics or withdrawal from anesthetics;

[0175] (3) Psychiatric and neurological disorders, such as attention deficit hyperactivity disorder, conduct disorder, attention problems and related disorders, sleep disorders, anxiety disorders such as generalized anxiety disorder, panic disorder, phobias, post-traumatic stress disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Tourette syndrome, restless legs syndrome, dementia, movement disorders, severe mental retardation, neurodegenerative disease disorders, including taxonomic entities such as the disinhibition-dementia-Parkinsonism-amyotrophy complex, pallido-pontine-nigral degeneration, mood disorders, bipolar disorder, mania, depression, manic-depressive disorder, borderline personality disorder, antisocial personality disorder, aggressive behavior such as impulsive aggressive behavior, suicide, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neurosis / disorder, depressive neurosis / disorder, anxiety neurosis, dysthymic disorder, neurological diseases, such as cerebral edema and angioedema, cerebral dementia such as Parkinson's disease and Alzheimer's disease, senile dementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, seizures, stroke, myasthenia gravis, brain and meninges infections such as encephalomyelitis, meningitis, HIV, and schizophrenia, delusional disorder, autism, mood disorders, and tic disorders, including but not limited to Tourette syndrome and other movement disorders, epilepsy (dpilepsia), chronic pain;

[0176] (4) Cognitive dysfunction in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease, and other neurological and psychiatric disorders;

[0177] (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;

[0178] (6) Sleep disorders, such as narcolepsy, jet lag syndrome, sleep apnea, insomnia, parasomnias, biological and circadian rhythm disorders, sleep disturbances associated with psychiatric and neurological disorders;

[0179] (7) Non-neuronal disorders, including metabolic disorders such as diabetes, insulin resistance, metabolic syndrome, overweight, obesity, and for weight loss, cosmetic weight loss, prevention of recurrence during or after obesity treatment, weight maintenance, vomiting, disorders related to cardiovascular system dysfunction and disorders related to maladaptive blood pressure control such as hypertension or hypotension;

[0180] (8) Cancer and related disorders associated with maladaptive tumorigenesis, such as osteosarcoma, breast cancer, ependymoma, bladder cancer, colorectal cancer.

[0181] The applicable daily dose of the compounds of the invention can vary between 0.1 and 2000 mg.

[0182] 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 pharmaceutical substance should be administered in a dose and manner that permits delivery of a pharmaceutically effective amount appropriate to the patient's condition.

[0183] Pharmaceutical compositions

[0184] Suitable compositions for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injections, inhalants and powders. The content of the pharmaceutically active compound can vary in the range of 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% of the total composition.

[0185] Suitable tablets can be obtained, for example, by mixing the compounds of the invention with known excipients (such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants) and compressing the resulting mixture into tablets.

[0186] Combination therapies

[0187] The compounds according to the invention can be used in combination with other treatment regimens known in the art for treating any indication that is the focus of treatment of the invention.

[0188] Among such active pharmaceutical ingredients or treatment regimens that are considered suitable for combination with the compounds and treatments according to the invention are antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptics, antiparkinsonian agents, sleep aids, cognitive enhancers, stimulants, drugs for attention deficit hyperactivity disorder, additional psychoactive drugs, anti-inflammatory agents, analgesics, chemotherapeutic agents, and combinations with treatment regimens for metabolic disorders, liver diseases and kidney diseases.

[0189] Experimental section

[0190] List of Abbreviations:

[0191] % Sol Percentage of solvent

[0192] μL Microliter

[0193] ACN Acetonitrile

[0194] AcOH Acetic acid

[0195] aq. Aqueous

[0196] Boc tert-Butyloxycarbonyl

[0197] Boc2O Di-tert-butyl dicarbonate

[0198] chir. chiral

[0199] CIP 2-Chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate

[0200] conc. concentrated

[0201] d dextro-

[0202] DA Diode array

[0203] DAD Diode array detector

[0204] DCM Dichloromethane

[0205] DMF N,N-Dimethylformamide

[0206] ELSD Evaporative light scattering detector

[0207] EtOAc Ethyl acetate

[0208] ETOH Ethanol

[0209] g gram

[0210] h hour

[0211] half-conc. semi-concentrated

[0212] HPLC High performance liquid chromatography

[0213] i.vac. in vacuo

[0214] IPA Isopropyl alcohol

[0215] M mole

[0216] MeOH Methanol

[0217] MEOH Methanol

[0218] mg milligram

[0219] min minute

[0220] ml milliliter

[0221] mL milliliter

[0222] MS Mass spectrometer

[0223] N normal

[0224] NBS N-Bromosuccinimide

[0225] NMM N-Methylmorpholine

[0226] NMP N-Methylpyrrolidone

[0227] PE Petroleum ether

[0228] PPA 1-Propane phosphonic acid cyclic anhydride

[0229] prep. Preparative

[0230] PSI Pounds per square inch

[0231] quant. Quantitative

[0232] Rf Retarding front

[0233] RT Retention time

[0234] sat. Saturated

[0235] scCO2 Supercritical carbon dioxide

[0236] SFC Supercritical fluid chromatography

[0237] TBTU O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate

[0238] TEA Triethylamine

[0239] Temp. Temperature

[0240] tert. Tertiary

[0241] TFA Trifluoroacetic acid

[0242] THF Tetrahydrofuran

[0243] wt Weight

[0244] X-Phos G1 Chloro-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)-phenyl)]palladium(II)

[0245] Method:

[0246] HPLC-MS Method:

[0247] Method 1

[0248] Method 2

[0249] Method Name: Z003_S05 Equipment Description: Agilent 1200 with DA and MS detectors Column: XBridge C18_3.0x 30mm_2.5μm Column Manufacturer: Waters Description:

[0250]

[0251] Method 3

[0252] Method Name: Z011_S03 Equipment Description: Agilent 1200 with DA and MS detectors Column: XBridge C18_3.0x 30mm_2.5μm Column Manufacturer: Waters Description:

[0253]

[0254] Method 4

[0255] Method Name: Z018_S04 Equipment Description: Agilent 1200 with DA and MS detectors Column: Sunfire C18_3.0x 30mm_2.5μm Column Manufacturer: Waters Description:

[0256]

[0257] Chiral SFC Analysis Method: I_C2_10_MEOH_NH3_002

[0258]

[0259] I_C2_20_MEOH_NH3_002

[0260]

[0261] I_C4_10_MEOH_NH3_002

[0262]

[0263] I_C4_15_MEOH_NH3_002

[0264]

[0265]

[0266] I_C4_20_MEOH_NH3_001

[0267]

[0268] I_IA_15_ETOH_NH3_001

[0269]

[0270] I_IG_10_MEOH_NH3_002

[0271]

[0272] I_IG_15_IPA_NH3_001

[0273]

[0274] I_IG_15_MEOH_NH3_001

[0275]

[0276]

[0277] I_IG_25_IPA_NH3_001

[0278]

[0279] I_IG_25_MeOH_NH3_001

[0280]

[0281] I_SA_10_IPA_NH3_001

[0282]

[0283] I_SA_10_MEOH_NH3_001

[0284]

[0285] I_SA_15_MEOH_NH3_001

[0286]

[0287]

[0288] I_SB_10_IPA_NH3_001

[0289]

[0290] I_SB_20_MEOH_NH3_001

[0291]

[0292] I_SC_05_IPA_NH3_001

[0293]

[0294] I_SC_10_IPA_NH3_001

[0295]

[0296] I_SC_10_MEOH_NH3_001

[0297]

[0298]

[0299] I_SC_15_IPA_NH3_001

[0300]

[0301] I_SC_20_IPA_NH3_001

[0302]

[0303] I_SC_20_MEOH_NH3_001

[0304]

[0305] I_SC_25_MEOH_NH3_001

[0306]

[0307] NMR Method: 1H NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2pl6 software. Chemical shifts are given in parts per million (ppm) relative to internal trimethylsilane and are reported downfield as δ values. The selected data are reported in the following format: chemical shift (splitting pattern, coupling constant (J), number of hydrogens). The abbreviations used are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).

[0308] MS (ESI + ):(M+H) + 170

[0309] HPLC: RT = 0.23 min, method F Example

[0310] Example 1:

[0311]

[0312] Step 1:

[0313] 5-Bromo-2-chloro-4-methyl-3-nitropyridine (2.0 g, 7.9 mmol) was mixed with isopropylamine (10 mL, 117 mmol) and stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo. The residue was washed with water, filtered, washed with water and dried in vacuo.

[0314] Yield: 2.17 g (7.9 mmol; quantitative) Int-1a

[0315] MS (ESI +): (M+H) + 274 / 276 (Br); HPLC: RT = 1.22 min, method: Z018_S04

[0316] Step 2:

[0317] Mix Int-1a (1.0 g, 3.6 mmol) with 150 mg of Raney nickel in 20 mL of THF and hydrogenate at 50 psi and ambient temperature for 19 h. Filter the mixture and concentrate the filtrate in vacuo. Yield: 870 mg (3.6 mmol; 98%) of Int-1b

[0318] MS (ESI + ):(M+H) + 244 / 246 (Br); HPLC: RT = 0.94 min, method: Z011_S03

[0319] Step 3:

[0320] Under argon, stir Int-1b (245 mg, 1.00 mmol) with Zn(CN)2 (200 mg, 1.70 mmol) and X-Phos G1 (70 mg, 0.10 mmol) in 2.0 mL of NMP at 110 °C for 16 h. Then, add ACN, filter the mixture, and purify the filtrate by preparative HPLC (C-18 X-Bridge, 50 °C, eluent gradient (water + 0.15% NH3):ACN 79:21->59:41). Combine the fractions containing the product and lyophilize. Yield: 160 mg (0.84 mmol; 84%) of Int-1c

[0321] MS (ESI + ):(M+H) + 191; HPLC: RT = 0.61 min, method: Z018_S04

[0322] Step 4:

[0323] Cool 2-N-Boc-amino-3-methoxy-3-methylbutyric acid (186 mg, 0.75 mmol) and Int-1c (130 mg, 0.68 mmol) in 1.5 mL of pyridine to 0 °C and add PPA (50% in EtOAc, 1.05 mL, 1.71 mmol) with stirring. After stirring at ambient temperature for 2 h, concentrate the mixture in vacuo. Dissolve the residue in 1:1 water and EtOAc and extract with EtOAc. Wash the combined organic layers with saturated NaHCO3 (aq.), dry over Na2SO4, and concentrate in vacuo. Treat the residue with ether, filter, and dry in vacuo.

[0324] Yield: 260 mg (0.62 mmol; 91%) Int-1d

[0325] MS (ESI + ): (M+H) + 420; HPLC: RT = 1.04 min, method: Z011_S03

[0326] Step 5:

[0327] Mix Int-1d (270 mg, 0.64 mmol) with 5 mL of 4M HCl dioxane solution, and stir the mixture at ambient temperature for 2 h. Then, concentrate the mixture in vacuo.

[0328] Yield: 229 mg (0.64 mmol; quantitative) Int-1 e . HPLC: RT = 0.86 min, method: Z011_S03

[0329] Step 6:

[0330] At ambient temperature, add Int-1e (203 mg, 0.57 mmol) to a mixture of 5-(difluoromethyl)pyrazine-2-carboxylic acid (109 mg, 0.63 mmol), TBTU (201 mg, 0.63 mmol) and TEA (0.40 mL, 2.85 mmol) in 3.0 mL of DMF, and stir the mixture for 3 h. Add 100 μl of water, and purify the mixture by basic preparative HPLC. Combine the fractions containing the product and lyophilize.

[0331] Yield: 170 mg (0.36 mmol; 63%) Int-1f

[0332] MS (ESI + ): (M+H) + 476; HPLC: RT = 1.01 min, method: Z011_S03

[0333] Step 7:

[0334] Stir Int-1f (70 mg, 0.15 mmol) in 4.0 mL of AcOH at 97 °C for 8 d. Then, concentrate the mixture in vacuo, dissolve in THF / water, adjust to basic pH by adding NH3(aq.), and purify by basic preparative HPLC. Combine the fractions containing the product and lyophilize. Then separate the mixture by chiral SFC.

[0335] Yield: 34 mg (0.074 mmol; 49%) Example 1

[0336]

[0337] Similar to Example 1, the following products were obtained:

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] Example 5:

[0372]

[0373] Step 1:

[0374] In an autoclave, a mixture of 2-chloro-4-hydroxy-3-nitropyridine (2.00 g; 11.5 mmol) and isopropylamine (3.6 mL, 41.9 mmol) in 20 mL of n-butanol was stirred at 110 °C for 18 h. The mixture was concentrated in vacuo, dissolved in MeOH, and acidified with AcOH. The mixture was filtered. The filtrate was purified by column chromatography (C18 Sunfire, 50 °C, eluent gradient: (H2O + 0.1% TFA):ACN 95:5->75:25). The fractions containing the product were combined and lyophilized. The lyophilizate was combined with the filtered solid and dried in vacuo. Yield: 1.59 g (8.06 mmol; 70%) Int-5a. MS (ESI + ): (M+H) + 198; HPLC: RT = 0.61 min, method: Z018_S04

[0375] Step 2:

[0376] A mixture of Int-5a (1.59 g, 8.06 mmol) and POCl3 (2 mL, 21 mmol) in 20 mL of ACN was stirred at 80 °C for 30 min. Then, the mixture was concentrated in vacuo, and the residue was dissolved in DCM and water. The mixture was basified with 2N Na2CO3(aq.) and the aqueous phase was extracted with DCM. The combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue was used without further purification. Yield: 1.74 g (8.07 mmol; quantitative) Int-5b

[0377] MS(ESI + ):(M+H) + 216 / 218(Cl); HPLC: RT = 1.13 min, method: Z018_S04

[0378] Step 3:

[0379] A mixture of Int-5b (1.74 g, 8.07 mmol) and sodium methoxide (5.4 N in MeOH, 2.25 mL, 12.2 mmol) in 15 mL of MeOH and 15 mL of THF was stirred at ambient temperature for 3 d. Then the mixture was concentrated in vacuo, and the residue was treated with water and filtered. The solid was washed with ACN and dried in vacuo. Yield: 1.62 g (7.67 mmol; 95%) Int-5c

[0380] MS(ESI + ):(M+H) + 212; HPLC: RT = 0.84 min, method: Z018_S04

[0381] Step 4:

[0382] A mixture of Int-5c (1.62 g, 7.67 mmol) and NBS (1.40 g, 7.87 mmol) in 30 mL of ACN was stirred at ambient temperature for 6 h and then at 45 °C for 20 min. Then the mixture was concentrated in vacuo, and the residue was dissolved in 0.5N Na2CO3 and DCM. The aqueous phase was extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Yield: 2.23 g (7.67 mmol; quantitative) Int-5d. MS(ESI + ):(M+H) + 290 / 292(Br); HPLC: RT = 1.18 min, method: Z018_S04

[0383] Step 5:

[0384] Int-5d (400 mg, 1.38 mmol) was mixed with Raney nickel (100 mg) in 20 mL of THF and hydrogenated under 50 psi hydrogen pressure for 20 h. The mixture was then filtered and concentrated in vacuo.

[0385] Yield: 350 mg (1.35 mmol; 98%) of Int-5e. MS (ESI + ): (M+H) + 260 / 262 (Br); HPLC: RT = 0.65 min, method: Z018_S04

[0386] Step 6:

[0387] At 0 °C, PPA (50 wt% in AcOH, 1.5 mL, 2.45 mmol) was added to Int-5e (350 mg, 1.35 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (300 mg, 1.39 mmol) in 5 mL of pyridine, and the mixture was stirred at 0 °C for 1 h. Water and ACN were added, and the mixture was purified by column chromatography (XBridge C18, 50 °C, eluent gradient: (H2O + 0.1% NH3):ACN 55:45->35:65). The fractions containing the product were combined and lyophilized.

[0388] Yield: 440 mg (0.96 mmol; 72%) of Int-5f

[0389] MS (ESI + ): (M+H) + 457 / 459 (Br); HPLC: RT = 0.92 min, method: Z018_S04

[0390] Step 7:

[0391] Int-5f (440 mg, 0.96 mmol) in HCl dioxane solution (4 M, 4 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo, and the residue was dissolved in 1N Na2CO3 (aq.) and DCM. The aqueous phase was extracted with DCM, the organic layers were combined, dried over MgSO4, and concentrated in vacuo.

[0392] Yield: 310 mg (0.87 mmol; 90%) of Int-5g

[0393] MS (ESI + ): (M+H) + 357 / 359 (Br); HPLC: RT = 0.66 min, method: Z018_S04

[0394] Step 8:

[0395] Stir Int-5g (310 mg, 0.26 mmol) and ZnBr2 (400 mg, 1.78 mmol) in 5 mL of n-butyl acetate at 100 °C for 3 h, and then stir at ambient temperature for 16 h. Then, concentrate the mixture in vacuo, dissolve the residue in ACN, acidify by adding AcOH, add some water and filter. Purify the filtrate by column chromatography (Sunfire C-18, 50 °C, eluent gradient: (H2O + 0.15% TFA):ACN 80:20 -> 60:40). Combine the fractions containing the product and lyophilize.

[0396] Yield: 230 mg (0.51 mmol; 58%) Int-5h

[0397] MS (ESI + ): (M+H) + 339 / 341 (Br); HPLC: RT = 0.83 min, method: Z018_S04

[0398] Step 9:

[0399] Add TBTU (180 mg, 0.56 mmol) to a mixture of Int-5h (230 mg, 0.51 mmol), 5-methyl-pyrazine-carboxylic acid (100 mg, 0.72 mmol) and TEA (400 mg, 3.95 mmol) in 4 mL of DMF, and stir the mixture at ambient temperature for 15 min. Add water, and purify the mixture by column chromatography (XBridge C18, 50 °C, eluent gradient: (H2O + 0.15% NH3):ACN 46:54 -> 26:74). Combine the fractions containing the product and lyophilize.

[0400] Yield: 210 mg (0.46 mmol; 90%) Example 5

[0401]

[0402] Example 6:

[0403]

[0404] Step 1:

[0405] A mixture of 2-chloro-3-nitro-5-trifluoromethyl-pyridine (1.50 g; 6.62 mmol) and isopropylamine (2.0 mL, 23.5 mmol) in 10 mL of THF was stirred at ambient temperature for 10 min. The mixture was concentrated in vacuo, the residue was treated with water, filtered, the solid was washed with water and dried in vacuo. Yield: 1.55 g (6.22 mmol; 94%) Int-6a

[0406] MS(ESI + ): (M+H) + 250; HPLC: RT = 1.17 min, method: Z018_S04

[0407] Step 2:

[0408] Int-6a (1.55 g, 6.22 mmol) was mixed with Raney nickel (200 mg) in 30 mL of THF and hydrogenated at ambient temperature and 50 psi hydrogen pressure for 17 h. The mixture was then filtered and concentrated in vacuo. Yield: 1.32 g (6.02 mmol; 97%) Int-6b

[0409] MS(ESI + ): (M+H) + 220; HPLC: RT = 0.94 min, method: Z011_S03

[0410] Step 3:

[0411] At 0 °C, N-2-Boc-amino-3-cyclopropyl-propionic acid (20 g, 87 mmol) was mixed with HCl dioxane solution (4 N, 150 mL, 600 mmol), and the mixture was stirred at 0 °C for 15 min and at ambient temperature for 3 d. The mixture was concentrated in vacuo, the residue was dissolved in dioxane and concentrated in vacuo again. Yield: 14.4 g (87 mmol; quantitative) Int-6c

[0412] MS(ESI + ): (M+H) + 130

[0413] Step 4:

[0414] With stirring at ambient temperature, thionyl chloride (8.0 mL, 110 mmol) was added to Int-6c (14.4 g, 87 mmol) in 150 mL of MeOH, and the mixture was stirred for 5 h. The mixture was concentrated in vacuo, the residue was dissolved in dioxane, concentrated in vacuo, the residue was dissolved in ACN and concentrated in vacuo again. Yield: 15.6 g (87 mmol; quantitative) Int-6d

[0415] MS (ESI + ):(M + H) + 144

[0416] Step 5:

[0417] A mixture of Int-6d (7.00 g, 39.0 mmol) and 5-methyl-pyrazine-2-carboxylic acid (7.00 g, 50.7 mmol) in 400 mL of THF was stirred at 0 °C. TEA (15 mL, 108 mmol) was added, followed by CIP (11.5 g, 41.3 mmol). The mixture was stirred at 0 °C for 20 min. Water was added, and the mixture 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 MgSO4, and concentrated in vacuo.

[0418] Yield: 23 g (content: 45%; 39 mmol; quantitative) of Int-6e

[0419] MS (ESI + ):(M + H) + 264; HPLC: RT = 0.91 min, method: Z018_S04

[0420] Step 6:

[0421] Int-6e (23 g, content: 45%, 39 mmol) in 150 mL of MeOH was mixed with 1N NaOH(aq.) (40 mL, 40 mmol) and stirred at ambient temperature for 1 h. Then, 4N NaOH (10 mL, 40 mmol) was added, and the mixture was stirred at ambient temperature for 1.5 h. The mixture was concentrated in vacuo, the residue was dissolved in water, acidified to pH 1 with 4N HCl(aq.), and the aqueous phase was extracted with DCM. The combined organic layers were dried over MgSO4, concentrated in vacuo, and the residue was purified by preparative HPLC (C-18 Sunfire, 50 °C, eluent gradient (water + 0.15% TFA): ACN 83:17 -> 63:37). The fractions containing the product were combined, concentrated in vacuo, the aqueous phase was extracted with DCM, and the combined organic layers were dried over MgSO4 and concentrated in vacuo.

[0422] Yield: 7.07 g (28.4 mmol, 72%) of Int-6f

[0423] MS (ESI + ):(M + H) + 250; HPLC: RT = 0.80 min, method: Z018_S04

[0424] Step 7:

[0425] Stir Int-6b (100 mg, 0.46 mmol), Int-6f (100 mg, 0.40 mmol) and NMM (265 μL, 2.41 mmol) in 5 mL of DCM at 0 °C, and add PPA (50% in EtOAc; 470 μL, 0.80 mmol). After stirring for 1 h at 0 °C, remove the cooling and stir the mixture at ambient temperature for 16 h. Add water and 5 mL of AcOH, and stir the mixture at 90 °C for 45 min, then at 100 °C for 3 h, then at ambient temperature for 3 d, and then at 100 °C for 2 h. Dilute the mixture with MeOH, filter, and purify the filtrate by HPLC (C-18 Sunfire, 50 °C, eluent gradient (water + 0.15% TFA): ACN 45:55 -> 25:75). Combine the fractions containing the product and lyophilize. Dissolve the residue in MeOH, pass through an ion exchange column (Agilent PL-HCO3 MP SPE), and concentrate in vacuo. Purify the residue by chiral SFC.

[0426] Yield: 54 mg (0.12 mmol; 59%) Example 6

[0427]

[0428] Similar to Example 6, the following products were obtained:

[0429]

[0430]

[0431]

[0432]

[0433] Example 8:

[0434]

[0435] Step 1:

[0436] Under argon, acetylacetone (342 μL, 3.32 mmol) and copper(II) acetylacetonate (217 mg, 0.83 mmol) were added to a mixture of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (2.00 g, 8.30 mmol) and NH3(aq.) (30%; 5.45 mL, 41.5 mmol) in 12 mL of DMF, and the mixture was stirred at 90 °C for 18 h. 100 mL of EtOAc and 60 mL of water were added, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: DCM:MeOH 98:2), and the fractions containing the product were combined and concentrated in vacuo. Yield: 1.51 g (content: 98%; 8.30 mmol; quantitative) Int-8a. MS (ESI + ): (M+H) + 178; HPLC: RT = 0.69 min, method: Z011_S03

[0437] Step 2:

[0438] At 0 °C, NMM (894 μL, 8.05 mmol) and PPA (50 wt% in AcOH, 2.7 mL, 4.41 mmol) were added to Int-8a (453 mg, 2.56 mmol) and (2S)-2-Boc-amino-2-cyclopropylacetic acid (500 mg, 2.33 mmol) in 10 mL of DCM, and then the mixture was stirred at 0 °C for 4.5 h. DCM and NaHCO3(aq., 5%) were added, and the mixture was stirred vigorously. The organic layer was dried over Na2SO4, concentrated in vacuo, the residue was dissolved in diethyl ether, and concentrated in vacuo. Yield: 1.00 g (content: 96%; 2.56 mmol; quantitative) Int-8b. MS (ESI + ): (M+H) + 375; HPLC: RT = 0.97 min, method: Z011_S03

[0439] Step 3:

[0440] A mixture of Int-8b (900 mg, 2.41 mmol), ZnBr2(1.08 g, 4.81 mmol) and n-butyl acetate was stirred at 110 °C for 2.5 d. EtOAc and NaHCO3(aq., 5%) were added, and the mixture was stirred vigorously. The mixture was filtered, and the solid was dried at ambient temperature and used without further purification.

[0441] Yield: 1.20 g (content: 50%; 2.34 mmol; 97%) Int-8c

[0442] MS(ESI + ):(M+H) + 257; HPLC: RT = 0.64 min, method: Z011_S03

[0443] Step 4:

[0444] Int-8c (50%; 1.74 g, 3.40 mmol) and 2-methyl-pyrazine-5-carboxylic acid (100 mg, 0.40 mmol) in 30 mL of DCM were stirred at 0 °C, and NMM (1.50 mL, 14.4 mmol) and PPA (50% in EtOAc; 4.0 mL, 3.40 mmol) were added. After stirring at 0 °C for 1 h, the cooling was reduced over 16 h to reach ambient temperature. EtOAc and NaHCO3 (aq., 5%) were added, and the mixture was stirred vigorously. The mixture was filtered, and the solid was dried at ambient temperature.

[0445] Yield: 1.36 g (content: 94%; 3.40 mmol; quantitative) of Int-8d

[0446] MS(ESI + ):(M+H) + 377; HPLC: RT = 0.69 min, method: Z011_S03

[0447] Step 5:

[0448] To Int-8d (600 mg, 1.60 mmol) in 7.0 mL of DMF were added Cs2CO3 (779 mg, 2.39 mmol) and isopropyl methanesulfonate (100 μL, 3.19 mmol), and the mixture was stirred at 90 °C for 17 h. Then more isopropyl methanesulfonate (385 μL, 0.83 mmol) was added, and the mixture was stirred at 90 °C for 8 h. Then, EtOAc was added, and the mixture was filtered. The filtrate was concentrated in vacuo, the residue was dissolved in MeOH, filtered, and the filtrate was purified by preparative HPLC (C-18 X-Bridge, 60 °C, eluent (water + 0.15% NH3): ACN mixture). The fractions containing the product were combined and lyophilized.

[0449] Yield: 107 mg (0.26 mmol; 16%) of Example 8

[0450]

[0451] Example 11:

[0452]

[0453] Step 1:

[0454] Under stirring, 5-bromo-2-chloro-4-methyl-3-nitropyridine (20.0 g, 79.5 mmol) was added to isopropylamine (60 mL, 704 mmol) over 2 min, and the mixture was stirred at ambient temperature for 17 h. Then, the mixture was concentrated in vacuo, the residue was treated with water, filtered, the solid was washed with water, dissolved in ACN, and dried in vacuo at 45 °C. Yield: 21.2 g (77.3 mmol; 97%) of Int-11a. MS (ESI + ): (M+H) + 274 / 276 (Br); HPLC: RT = 1.22 min, method: Z018_S04

[0455] Step 2:

[0456] Int-11a (10.0 g, 36.5 mmol) was mixed with Raney nickel (200 mg) in 150 mL of THF and hydrogenated at ambient temperature and 50 psi hydrogen pressure for 18 h. Then the mixture was filtered, concentrated, and dried in vacuo. Yield: 9.00 g (content: 98%; 36.1 mmol; 99%) of Int-11b

[0457] MS (ESI + ) : (M+H) + 244 / 246 (Br); HPLC: RT = 0.94 min, method: Z011_S03

[0458] Step 3:

[0459] Under argon, tetrakis(triphenylphosphine)palladium(0) (6.40 g, 5.54 mmol) was added to a mixture of Int-11b (27.6 g, 111 mmol) and Zn(CN)2 (13.3 g, 113 mmol) in 100 mL of NMP, and the mixture was stirred at 115 °C for 45 min. Then 300 mL of DCM and 300 mL of water were added, and the mixture was stirred vigorously and filtered. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DCM, mixed with extrelut, concentrated in vacuo, and purified by silica gel column chromatography (eluent gradient: PE:EtOAc 85:15 -> 55:45). The quenched aqueous phase was extracted with EtOAc, and the combined organic layers were washed with NaCl(aq.), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent gradient: PE:EtOAc 85:15 -> 55:45). The fractions containing the product were combined separately and concentrated in vacuo, and the residues were combined. Yield: 13.6 g (71.5 mmol; 65%) of Int-11c

[0460] MS(ESI + ):(M+H) + 191; HPLC: RT = 0.81 min, method: Z011_S03

[0461] Step 4:

[0462] A mixture of Int-11c (13.6 g, 71.5 mmol), (S)-2-(Boc-amino)-3-cyclopropyl-propanoic acid, and NMM (38.5 mL, 350 mmol) in 1.0 L of DCM was cooled to -10 °C, and PPA (50% in EtOAc; 84.6 mL, 144 mmol) was added with stirring over 8 min. The cooling was reduced to ambient temperature over 16 h with stirring. 200 mL of NaHCO3(aq., 5%) was added, and the organic phase was washed with water. 250 mL of water was added, and the mixture was acidified to pH 4 with KHSO4(aq. 0.5 N) and stirred vigorously. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was treated with diisopropyl ether and dried in vacuo at 45 °C.

[0463] Yield: 20.6 g (51.4 mmol; 73%) of Int-11d

[0464] MS(ESI + ):(M+H) + 402; HPLC: RT = 1.06 min, method: Z011_S03

[0465] Step 5:

[0466] A mixture of Int-11d (20.2 g, 50.2 mmol) and K2CO3 (8.33 g, 60.3 mmol) in 300 mL of 2-propanol was stirred at 85 °C for 22 h and at 90 °C for 34 h. 200 mL of DCM was added, filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in DCM / MeOH, silica gel was added, and the mixture was concentrated in vacuo. The residue was used for purification via silica column chromatography (eluent DCM:EtOH 98:2). The fractions containing the product were combined and concentrated in vacuo. Yield: 16.0 g (41.7 mmol; 83%) of Int-11e

[0467] MS (ESI + ): (M+H) + 384; HPLC: RT = 1.16 min, method: Z011_S03

[0468] Step 6:

[0469] HCl in dioxane solution (4 N; 52.2 mL, 209 mmol) was slowly added to Int-11e (16.0 g, 41.7 mmol) in 250 mL of DCM. The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo.

[0470] Yield: 14.9 mg (41.7 mmol; quantitative) of Int-11f

[0471] MS (ESI + ) : (M+H) + 284; HPLC: RT = 0.95 min, method: Z011_S03

[0472] Step 7:

[0473] A mixture of Int-11f (300 mg, 0.84 mmol), 5-difluoromethyl-pyrazine-2-carboxylic acid (188 mg, 1.08 mmol) and pyridine (2.1 mL, 26 mmol) was stirred at 0 °C, PPA (50% in EtOAc; 0.7 mL, 1.2 mmol) was added, and the mixture was stirred at 0 °C for 30 min and at ambient temperature for 16 h. THF and water were added, and the mixture was purified by preparative HPLC (C-18X-Bridge 10 μm, eluent gradient (water + 0.1% NH3):ACN 52:48->42:58). The fractions containing the product were combined, concentrated in vacuo, the residue was dissolved in ACN and water and lyophilized.

[0474] Yield: 125 mg (284 μmol; 42%) Example 11

[0475]

[0476] Similar to Example 11, the following products were obtained:

[0477]

[0478]

[0479] Example 16:

[0480]

[0481] Step 1:

[0482] Under stirring at ambient temperature, NBS (20.2 g, 113 mmol) was added portionwise to 2-methyl-6-trifluoromethyl-pyridin-3-amine (20 g, 108 mmol) in 230 mL of ACN over 3 min. Stirring was continued for 2.5 h. The mixture was then concentrated in vacuo, and the residue was dissolved in DCM and washed with water. The organic phase was dried over MgSO4 and concentrated in vacuo. Yield: 27.2 g (107 mmol; 99%) Int-16a. MS (ESI + ): (M+H) + 255; HPLC: RT = 0.99 min, method: Z018_S04

[0483] Step 2:

[0484] In an autoclave, Int-16a (27.0 g, 106 mmol) was mixed with isopropylamine (91.4 mL, 1.06 mol), 169 mL of water, CuI (1.21 g, 6.35 mmol) and 1-pyridin-2-yl-ethanone oxime (1.19 g, 8.47 mmol). The mixture was stirred at 90 °C for 24 h. Then THF and water were added, and the mixture was concentrated in vacuo. The residue was extracted with EtOAc, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was mixed with DCM, THF and extrelut, and the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent gradient: PE:EtOAc 67:33->37:63). The fractions containing the product were combined and concentrated in vacuo. Yield: 10.1 g (43.3 mol; 41%) Int-16b

[0485] MS (ESI + ): (M+H) +234; HPLC: RT = 0.92 min, method: Z011_S03

[0486] Step 3:

[0487] Cool the mixture of Int-16b (10.1 g, 42 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (9.95 g, 46 mmol) in 100 mL of pyridine to -10 °C. With stirring, add PPA (50% in EtOAc, 37.1 mL, 63 mmol) over 8 min, and stir the mixture at -5 °C for 1 h. Pour the mixture into water at 0 °C, stir vigorously, adjust to pH 8 by adding NH3(aq., concentrated), and stir vigorously again. Filter the formed solid, wash with water, and dry in vacuo at 60 °C.

[0488] Yield: 17.0 g (39.6 mmol; 94%) of Int-16c. MS (ESI + ): (M+H) + 431; HPLC: RT = 1.06 min, method: Z011_S03

[0489] Step 4:

[0490] Stir Int-16c (17.0 g, 37.5 mmol) and ZnBr2 (18.6 g, 82.5 mmol) in n-butyl acetate at 115 °C for 21 h and then at 135 °C for 2 h. Pour the mixture into ice water and stir. Adjust the pH to 8.5 by adding NH3(aq., concentrated), add diatomaceous earth, stir and filter. Wash the solid with EtOAc. Wash the organic layer with NaCl(aq.), dry over MgSO4, and concentrate in vacuo. Dissolve the residue in EtOAc and purify by silica column chromatography (eluent gradient: EtOAc:(EtOH + 5% NH3(aq., concentrated)) 97:3 -> 80:20). Combine the fractions containing the product and concentrate in vacuo. Yield: 11.5 g (36.9 mmol; 98%) of Int-16d.

[0491] MS (ESI + ) : (M+H) + 313; HPLC: RT = 0.93 min, method: Z011_S03

[0492] Step 5:

[0493] Under nitrogen, to 5-methyl-pyrazine-2-carboxylic acid (188 mg, 1.08 mmol) and TEA (80 mL, 576 mmol) in 500 mL of EtOAc was added Int-16d (60.0 g, 192 mmol), and the mixture was cooled to -5 °C. With stirring and cooling, PPA (50% in EtOAc; 149 mL, 250 mmol) was added to keep the temperature below 0 °C. Then the cooling was removed, and the mixture was stirred at ambient temperature for 45 min. 1.0 L of water was added, and the mixture was stirred for 5 min. The organic phase was washed twice with 500 mL of NaCl solution (aq., semi-concentrated) and 5 mL of NH3 (aq., concentrated). 10 g of charcoal was added and stirred for 10 min, then filtered, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DCM and ether and concentrated again in vacuo, then dried in vacuo at ambient temperature. The residue was dissolved in 80 mL of diisopropyl ether, and then a total of 320 mL of n-heptane was added in portions with vigorous stirring. The solid was filtered, washed with 200 mL of n-heptane, and dried in vacuo at 55 °C. Then the solid was placed in 1.46 L of water and stirred at ambient temperature for 22 h, filtered off, washed with 1.5 L of water, and dried under nitrogen at 65 °C for 22 h.

[0494] Yield: 69.6 g (162 mmol; 84%) Example 16

[0495]

[0496] Similar to Example 16, the following products were obtained:

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504] Example 27:

[0505]

[0506] Step 1:

[0507] A mixture of 4,5-diamino-2-(trifluoromethyl)pyridine (605 mg, 3.42 mmol), (2S)-2-Boc-amino-2-cyclopropylacetic acid (700 mg, 3.26 mmol) and NMM (1.25 mL, 11 mmol) in 40 mL of DCM was cooled to -10 °C, and PPA (50% in EtOAc, 3.8 mL, 6.60 mmol) was added with stirring. After 1.25 h, the ice bath was removed, DCM and NaHCO3 (aq., 5%) were added, and the mixture was stirred vigorously at ambient temperature. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in diethyl ether and concentrated in vacuo.

[0508] Yield: 1.50 g (content: 75%; 3.01 mmol; 92%) Int-27a

[0509] MS (ESI + ): (M+H) + 375; HPLC: RT = 0.88 min, method: Z011_S03

[0510] Step 2:

[0511] A mixture of Int-27a (810 mg, 2.3 mmol) and ZnBr2 (974 mg, 4.33 mmol) in 15 mL of n-butyl acetate was stirred at 110 °C for 19 h. EtOAc and NaHCO3 (aq., 5%) were added, the mixture was stirred vigorously, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo.

[0512] Yield: 600 mg (2.3 mmol; quantitative) Int-27b

[0513] MS (ESI + ) : (M+H) + 257; HPLC: RT = 0.58 min, method: Z011_S03

[0514] Step 3:

[0515] Cool the mixture of Int-27b (221 mg, 0.86 mmol), 5-(difluoromethyl)-pyrazine-2-carboxylic acid (150 mg, 0.86 mmol) and NMM (379 μL, 2.72 mmol) in 10 mL of DCM to 0 °C and add PPA (50% in EtOAc, 1.0 mL, 1.74 mmol) with stirring. Remove the ice bath and continue stirring at ambient temperature for 17 h. Add DCM and NaHCO3 (aq., 5%) and stir the mixture vigorously at ambient temperature. Dry the organic layer over Na2SO4 and concentrate in vacuo.

[0516] Yield: 304 mg (0.74 mmol; 86%) of Int-27c

[0517] MS (ESI + ): (M+H) + 413; HPLC: RT = 0.72 min, method: Z011_S03

[0518] Step 4:

[0519] At 0 °C, add diisopropyl azodicarboxylate (40% in toluene, 543 μL, 1.11 mmol) to a mixture of Int-27c (304 mg, 0.74 mmol), triphenylphosphine (290 mg, 1.11 mmol) and isopropanol (284 μL, 3.69 mmol) in 5 mL of THF and stir at 0 °C for 3.5 h and at ambient temperature for 17 h. Then, add triphenylphosphine (100 mg, 0.38 mmol) and diisopropyl azodicarboxylate (40% in toluene, 543 μL, 0.41 mmol) at 0 °C and stir for 5.5 h to reach ambient temperature. Add water, stir vigorously and extract with EtOAc. Combine the organic layers, dry over Na2SO4 and concentrate in vacuo. Dissolve the residue in DCM and purify by silica gel column chromatography (eluent DCM:MeOH 98:2). Combine the fractions containing the product and concentrate in vacuo. Purify the residue further by chiral SFC.

[0520] Yield: 68 mg (0.15 mmol, 20%) of Example 27

[0521]

[0522] Similar to Example 27, the following products were obtained:

[0523]

[0524] Example 28:

[0525]

[0526] Step 1:

[0527] Cool a mixture of Int-11c (365 mg, 1.82 mmol), (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (471 mg, 2.19 mmol) and NMM (1.2 mL, 10.9 mmol) in 25 mL of DCM to -5 °C and add PPA (50% in EtOAc, 2.1 mL, 3.65 mmol) with stirring. After 10 min, remove the cooling and stir the mixture at ambient temperature for 3.5 d. Add water and concentrate the organic layer in vacuo. Dissolve the residue in THF and MeOH and purify by preparative HPLC (XBridge C-18 10 μm, eluent gradient (H2O + 0.1% NH3):ACN 61:39 -> 41:59). Combine the fractions containing the product and lyophilize. Yield: 518 mg (1.34 mmol, 73%) of Int-28a

[0528] MS (ESI + ) : (M+H) + 388; HPLC: RT = 1.00 min, method: Z011_S03

[0529] Step 2:

[0530] At ambient temperature, add a solution of HCl in dioxane (4 N, 6.6 mL, 26.6 mmol) to Int-28a (515 mg, 1.33 mmol) in 6.7 mL of dioxane containing 250 μL of MeOH over 2.25 h. Concentrate the mixture in vacuo, dissolve the residue in ACN and concentrate in vacuo. Yield: 520 mg (1.31 mmol, 99%) of Int-28b

[0531] MS (ESI + ) : (M+H) + 288; HPLC: RT = 0.79 min, method: Z011_S03

[0532] Step 3:

[0533] To a mixture of Int-28b (255 mg, 0.64 mmol) with 5-methyl-pyrazine-2-carboxylic acid (93 mg, 0.66 mmol) and TEA (403 μL, 2.89 mmol) in 10 mL of ACN, add CIP (188 mg, 0.68 mmol) and stir the mixture at ambient temperature for 25 min. Concentrate the mixture in vacuo, dissolve the residue in DCM, wash with water, dry over MgSO4 and concentrate in vacuo.

[0534] Yield: 189 mg (0.46 mmol, 72%) Int-28c

[0535] MS (ESI + ): (M+H) + 408; HPLC: RT = 0.90 min, method: Z011_S03

[0536] Step 4:

[0537] To Int-28c (185 mg, 0.45 mmol) in 3.0 mL of isopropanol was added K2CO3 (75 mg, 0.55 mmol), and the mixture was stirred at 85 °C for 39 h. Then, 5 mL of THF was added, the resulting mixture was filtered, and the filtrate was purified by preparative HPLC (X-Bridge C-18 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 61:39 -> 41:59). The fractions containing the product were combined and concentrated in vacuo. The residue was further purified by chiral SFC.

[0538] Yield: 72 mg (0.19 mmol, 42%) Example 28

[0539]

[0540]

[0541] Similar to Example 28, the following products were obtained:

[0542]

[0543]

[0544] Example 33:

[0545]

[0546] Step 1:

[0547] To 3-bromo-6-chloro-2-methyl-5-nitropyridine (0.60 g, 2.39 mmol) in 5 mL of DCM was added 0.56 g (9.54 mmol) of isopropylamine, and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo, water was added, the mixture was filtered, and the solid was dried.

[0548] Yield: 0.66 g (2.39 mmol; quantitative) Int-33a

[0549] MS (ESI + ): (M+H)+ 274

[0550] Step 2:

[0551] Int-33a (0.38 g, 1.39 mmol) was mixed with Raney nickel (70 mg) in 5 mL of methanol and hydrogenated at ambient temperature and 50 psi hydrogen pressure for 17 h. The mixture was then filtered, concentrated, and dried in vacuo.

[0552] Yield: 0.36 g (1.48 mmol; quantitative) of Int-33b

[0553] MS (ESI + ): (M+H) + 244 / 246 (Br); HPLC: RT = 1.02 min, method: Z011_S03

[0554] Step 3:

[0555] Under argon, to a mixture of Int-33b (0.36 g, 1.48 mmol) and Zn(CN)2 (0.29 g, 2.43 mmol) in 10 mL of NMP was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.10 g, 0.135 mmol), and the mixture was stirred at 110 °C for 18 h. Water was then added, the mixture was vigorously stirred and filtered. The solid was dried at ambient temperature. Yield: 0.17 g (0.87 mmol; 59%) of Int-33c

[0556] MS (ESI + ): (M+H) + 191; HPLC: RT = 0.88 min, method: Z011_S03

[0557] Step 4:

[0558] Int-33c (165 mg, 0.87 mmol), Int-6f (216 mg, 0.87 mmol) and NMM (158 mg, 1.56 mmol) in 10 mL of DCM were stirred at 0 °C and PPA (50% in EtOAc; 580 mg, 0.91 mmol) was added. After stirring at 0 °C for 1 h, the cooling was removed and the mixture was stirred at ambient temperature for 16 h. The mixture was concentrated in vacuo, the residue was dissolved in NaHCO3 (half-concentrated, aq.) and extracted with DCM. The combined organic layers were concentrated in vacuo.

[0559] Yield: 150 mg (0.36 mmol; 41%) of Int-33d

[0560] MS(ESI + ):(M+H) + 422; HPLC: RT = 1.01 min, method: Z011_S03

[0561] Step 5:

[0562] Stir Int-33d (150 mg, 0.36 mmol) and ZnBr2 (160 mg, 0.71 mmol) in 5 mL of n-butyl acetate at 100 °C for 20 h. Add EtOAc and NaHCO3 (aq., 5%), filter, and concentrate the organic layer in vacuo. The residue is purified by preparative HPLC.

[0563] Yield: 8 mg (0.02 mmol; 6%) Example 33

[0564]

[0565]

[0566] Example 47:

[0567]

[0568] Step 1:

[0569] Under stirring at ambient temperature, add NaHCO3 (18.6 g, 221 mmol) to (2S)-2-Boc-amino-2-cyclopropyl-acetic acid in 160 mL of DMF, then add benzyl bromide (10.6 mL, 88.5 mmol). Stir the mixture for 22 h, then filter, and concentrate the filtrate in vacuo. Mix the residue with 500 mL of water and extract with tert-butyl methyl ether. The combined organic layers are washed with water, dried over MgSO4, and concentrated in vacuo.

[0570] Yield: 25.9 g (84.8 mmol, 96%) Int-47a

[0571] MS(ESI + ):(M+H) + 306

[0572] Step 2:

[0573] Under stirring at 10 °C, HCl in dioxane solution (4 M, 127 mL, 507 mmol) was added to Int-47a (25.8 g, 84.5 mmol) in 63 mL of dioxane and 63 mL of MeOH. The mixture was stirred at ambient temperature for 1.5 h, then concentrated in vacuo, dissolved in DCM, MeOH and diethyl ether respectively, and concentrated again in vacuo. Yield: 20.4 g (84.4 mmol; quantitative) of Int-47b

[0574] MS(ESI + ):(M+H) + 206; HPLC: RT = 0.87 min, method: Z011_S03

[0575] Step 3:

[0576] Under stirring at -15 °C, PPA (50% in EtOAc; 33 mL, 55.4 mmol) was added to a mixture of Int-47b (10.3 g, 42.6 mmol) and 2-methylpyrazine-5-carboxylic acid (6.69 g, 46.0 mmol) in 33 mL of pyridine. The mixture was stirred at 0 °C for 20 min and at ambient temperature for 1.5 h. Then, 5 mL of water was added and the mixture was concentrated in vacuo. The residue was dissolved in 150 mL each of water and tert-butyl methyl ether, and the aqueous layer was extracted with tert-butyl methyl ether. The combined organic layers were washed with NaCl (aq., semi-concentrated), dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent gradient: PE / EtOAc 80:20 -> 45:55). Yield: 10.4 g (30.4 mmol; 71%) of Int-47c

[0577] MS(ESI + ):(M+H) + 326; HPLC: RT = 0.99 min, method: Z011_S03

[0578] Step 4:

[0579] LiOH (aq., 1 N; 38.4 mL, 38.4 mmol) was added to Int-47c (10 g, 30.7 mmol) in 76 mL of dioxane, and the mixture was stirred at ambient temperature for 1 h. Then the mixture was adjusted to pH 3 by adding HCl (aq., 4 N, 9.6 mL, 38.4 mmol) and freeze-dried. The residue was dissolved in water, filtered, and the solid was washed with water and dried in vacuo.

[0580] Yield: 5.82 g (24.7 mmol; 80%) of Int-47d

[0581] MS (ESI + ): (M + H) + 236; HPLC: RT = 0.73 min, method: Z018_S04

[0582] Step 5:

[0583] Under stirring at -10 °C, NMM (752 μL, 6.84 mmol) and PPA (50% in EtOAc; 1.4 mL, 2.35 mmol) were added to a mixture of 4,5-diamino-2-trifluoromethyl-pyridine (416 mg, 2.35 mmol) and Int-47d (460 mg, 1.96 mmol) in 40 mL of DCM. The mixture was stirred at 0 °C for 3 h. Then, DCM was added, and the mixture was extracted with NaHCO3 (aq., 5%). The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo.

[0584] Yield: 579 mg (1.47 mmol; 75%) of Int-47e

[0585] MS (ESI + ): (M + H) + 395; HPLC: RT = 0.79 min, method: Z011_S03

[0586] Step 6:

[0587] At 85 °C, Int-47e (579 mg, 1.47 mmol) was stirred in 5 mL of AcOH for 4 d. The mixture was concentrated in vacuo, the residue was dissolved in MeOH, filtered, and the filtrate was purified by HPLC (XBridge C18, 10 μm, eluent: (H2O + 0.15% NH3):ACN 91:9). The fractions containing the product were combined and concentrated in vacuo.

[0588] Yield: 224 mg (0.60 mmol; 40%) of Int-47f

[0589] MS (ESI + ): (M + H) + 377; HPLC: RT = 0.69 min, method: Z011_S03

[0590] Step 7:

[0591] To Int-47f (223 mg, 0.59 mmol) in 5.0 mL of DMF was added Cs2CO3 (290 mg, 0.89 mmol) and iodoethane (57 μL, 0.71 mmol), and the mixture was stirred at 60 °C for 4.5 h. Then, more iodoethane (20 μL, 0.21 mmol) was added, and the mixture was stirred at 60 °C for 1.5 h. ACN was added, the mixture was filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (XBridge C-18 10 μm, 60 °C, eluent (H2O + 0.1% NH3):MeOH 61:39->41:59). The fractions containing the product were combined and concentrated in vacuo. The residue was further purified by chiral SFC.

[0592] Yield: 10 mg (0.025 mmol, 4.2%)

[0593]

[0594] Similar to Example 47, the following product was obtained:

[0595]

[0596]

[0597]

Claims

1. A compound of formula I: wherein A represents C1-C6 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl-C1-C2 alkyl-, C1-C3 alkyl-O-C1-C3 alkyl-, 4-6-membered heterocycloalkyl-, 4-6-membered heterocycloalkyl-C1-C3 alkyl-, and the following groups are optionally substituted with 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and fluorine; Xa represents N or C-R 2 ; Xb represents N or C-R 3 ; Xc represents N or C-R 4 ; Xd represents C-R 5 ; provided that one of Xa, Xb, and Xc represents N; R 1 represents C1-C7 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C7 cycloalkyl, 4-6 membered heteroalkyl, C3-C7 cycloalkyl-C1-C3 alkyl-, 4-6 membered heteroalkylmethyl-, C5-C6 heteroalkylethyl-, and the following groups are optionally substituted with 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C7 cycloalkoxy, hydroxy, and fluorine; R 2 、 R 3 、 R 4 and R 5 each independently represents hydrogen, halogen, cyano, C1-C4 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C6 cycloalkyl, 4-6 membered C4-C6 heterocycloalkyl, C1-C4 alkoxy-, C3-C6 cycloalkoxy-, and the latter six groups are optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and fluorine; R 6 represents a halogen, a C1-C3 alkyl group optionally substituted by 2-3 fluorine atoms; or a physiologically acceptable salt thereof.

2. The compound according to claim 1, namely a compound of formula Ia, formula Ia, Ib, or Ic wherein A represents C1-C6 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl-C1-C2 alkyl-, C1-C3 alkyl-O-C1-C3 alkyl-, 4-6-membered heterocycloalkyl-, 4-6-membered heterocycloalkyl-C1-C3 alkyl-, and the following groups are optionally substituted with 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and fluorine; R 1 represents C1-C7 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C7 cycloalkyl, 4-6 membered heterocycloalkyl-, C3-C7 cycloalkyl-C1-C3 alkyl-, 4-6 membered heterocycloalkylmethyl-, C5-C6 heterocycloalkylethyl-, the latter groups optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C7 cycloalkoxy, hydroxy, fluoro; R 2 、R 3 、R 4 and R 5 each independently represents hydrogen, halogen, cyano, C1-C4 alkyl, C1-C3 alkyl-O-C1-C3 alkyl-, C3-C6 cycloalkyl, 4-6 membered C4-C6 heteroalkyl-, C1-C4 alkoxy-, C3-C6 cycloalkoxy-, and the latter six groups are optionally substituted with 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, and fluoro; R 6 represents a halogen, a C1-C3 alkyl group optionally substituted with 2-3 fluorine atoms; or a physiologically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein A represents C1-C3 alkyl, C3-C6 cycloalkyl, C3-C5 cycloalkylmethyl-, tetrahydrofuranyl-, tetrahydropyranyl-, 1,4-dioxanyl, tetrahydrofuranylmethyl-, tetrahydropyranylmethyl-, 1,4-dioxanylmethyl-, C1-C2 alkyl-O-C1-C3 alkyl-, and the following groups are optionally substituted with 1-4 substituents selected from methyl, methoxy, hydroxy, and fluorine.

4. The compound according to any one of the preceding claims, wherein R 1 represents C1-C3 alkyl, C1-C2 alkyl-O-C1-C3 alkyl-, C3-C4 cycloalkyl, C4-C5 heterocycloalkyl-, C3-C4 cycloalkyl-O-C1-C3 alkyl-, and the latter group is optionally substituted by 1-4 substituents selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C4 cycloalkoxy, hydroxy, and fluorine.

5. 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, and the latter three groups are optionally substituted with 2 - 3 fluorine atoms.

6. The compound according to any one of the preceding claims, wherein R 6 represents a C1-C3 alkyl group optionally substituted with 2-3 fluorine atoms.

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

8. The compound according to any one of the preceding claims, wherein R 1 represents a substituent selected from ethyl, -CH2-CHF2, and isopropyl.

9. The compound according to any one of the preceding claims, wherein R 2 represents hydrogen; R 3 represents hydrogen, methyl and trifluoromethyl; R 4 represents hydrogen, fluorine, chlorine, bromine, cyano group, methyl group and trifluoromethyl group; R 5 represents hydrogen, methyl and methoxy.

10. The compound according to any one of the preceding claims, wherein R 6 represents methyl, trifluoromethyl and -CF2H.

11. The compound according to any one of the preceding claims, namely a compound selected from the following:

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

13. The compound according to any one of claims 1-11 or the pharmaceutically acceptable salt according to claim 12, which is used as a drug.

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

15. The compound according to any one of claims 1-11 or the pharmaceutically acceptable salt according to claim 12, which is used for treating or preventing a disease or disorder in which inhibiting the activity of metabotropic glutamate receptor subtype 4 (mGluR4) has a therapeutic benefit.

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

17. The compound according to any one of claims 1-11 or the pharmaceutically acceptable salt according to claim 12 for use according to claim 16, wherein the disease or disorder is selected from 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 disorders such as post-traumatic stress disorder; tic disorders such as Tourette syndrome; movement disorders such as restless legs syndrome; cognitive dysfunction in a psychiatric or neurological disorder, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancer and related conditions associated with maladaptive tumorigenesis such as osteosarcoma.

18. A method of treating an mGluR4-mediated disorder in an individual, the method comprising administering to the individual an effective amount of the compound according to any one of claims 1-11 or the pharmaceutically acceptable salt according to claim 12.

19. The method according to claim 18, wherein the mGluR4-mediated condition or disorder is a mental disorder, a neurological disorder, a neurodegenerative disorder, a non-neuronal disorder or a metabolic disorder, cancer or a related condition.

20. The method according to claim 19, wherein the mental disorder, neurological disorder, neurodegenerative disorder, non-neuronal disorder, cancer or related condition is selected from 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 disorders such as post-traumatic stress disorder; tic disorders such as Tourette syndrome; movement disorders such as restless legs syndrome; cognitive dysfunction in a psychiatric or neurological disorder, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancer and related conditions associated with maladaptive tumorigenesis such as osteosarcoma.

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